ABCMdb

ABCG8 p.Thr400Lys

ClinVar:	c.1199C>A , p.Thr400Lys N , Benign
Predicted by SNAP2:	A: D (75%), C: D (75%), D: D (91%), E: D (91%), F: D (85%), G: D (85%), H: D (85%), I: D (91%), K: D (85%), L: D (85%), M: D (85%), N: D (80%), P: D (95%), Q: D (91%), R: D (91%), S: N (53%), V: D (80%), W: D (91%), Y: D (80%),
Predicted by PROVEAN:	A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, V: N, W: N, Y: N,

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[hide] Mutations in ATP-cassette binding proteins G5 (ABC... Hum Mutat. 2001 Oct;18(4):359-60. Hubacek JA, Berge KE, Cohen JC, Hobbs HH
Mutations in ATP-cassette binding proteins G5 (ABCG5) and G8 (ABCG8) causing sitosterolemia.
Hum Mutat. 2001 Oct;18(4):359-60., [PMID:11668628]

Abstract [show]
Sitosterolemia is an autosomal recessive disorder caused by mutations in two adjacent genes encoding coordinately regulated ATP binding cassette (ABC) half transporters (ABCG5 and ABCG8). In this paper we describe three novel mutations causing sitosterolemia: 1) a frameshift mutation (c.336-337insA) in ABCG5 that results in premature termination of the protein at amino acid 197; 2) a missense mutation that changes a conserved residue c.1311C>G; N437K) in ABCG5 and 3) a splice site mutation in ABCG8 (IVS1-2A>G). This study expands the spectrum of the ABCG5 and ABCG8 mutations that cause sitosterolemia. Nine nonsynonymous polymorphisms are also reported: I523V, C600Y, Q604E, and M622V in ABCG5; and D19H, Y54C, T400K, A632V, and Y641F in ABCG8.

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6 Nine nonsynonymous polymorphisms are also reported: I523V, C600Y, Q604E, and M622V in ABCG5; and D19H, Y54C, T400K, A632V, and Y641F in ABCG8. Login to comment
36 Gene Exon NT change AA change Allele frequency RE ABCG5 ABCG8 ex. 11 ex. 13 ex. 13 ex. 13 ex. 1 ex. 2 ex. 8 ex. 13 ex. 13 c.1567 A>G c.1799 G>A c.1810 C>G c.1864 A>G c.52 G>C c.161 A>G c.1199 C>A c.1895 C>T c.1922 A>T I523V C600Y Q604E M622V D19H Y54C T400K A632V Y641F <1% <1% C=0.80/G=0.20 <1% G=0.94/C=0.06 A=0.61/G=0.39 C=0.80/A=0.20 C=0.83/T=0.17 A=0.99/T=0.01 XmnI TsrpI SexAI MseI NcoI MboII *The polymorphisms were found either in sitosterolemic probands or in genomic DNA from 24 individuals with high plasma cholesterol concentrations. Allele frequencies of the nonsynonymous sequence variants identified were determined in 50 unrelated Caucasians. Login to comment

[hide] Heritability of plasma noncholesterol sterols and ... J Lipid Res. 2002 Mar;43(3):486-94. Berge KE, von Bergmann K, Lutjohann D, Guerra R, Grundy SM, Hobbs HH, Cohen JC
Heritability of plasma noncholesterol sterols and relationship to DNA sequence polymorphism in ABCG5 and ABCG8.
J Lipid Res. 2002 Mar;43(3):486-94., [PMID:11893785]

Abstract [show]
The plasma concentrations of cholesterol precursor sterols and plant sterols vary over a 5- to 10-fold range among normolipidemic individuals, and provide indices of the relative rates of cholesterol synthesis and fractional absorption. In the present study, we examined the relative contributions of genetic and environmental factors to variation in the plasma concentrations and sterol-cholesterol ratios of five noncholesterol sterols, including the 5alpha-saturated derivative of cholesterol (cholestanol), two precursors in the cholesterol biosynthesis pathway (desmosterol and lathosterol), and two phytosterols (campesterol and sitosterol). Plasma sterol concentrations were highly stable in 30 individuals measured over a 48 week period. Regression of offspring sterol levels on the parental values indicated that plasma levels of all five noncholesterol sterols were highly heritable. Analysis of monozygotic and dizygotic twin pairs also indicated strong heritability of all five sterols. Two common sequence variations (D19H and T400K) in ABCG8, an ABC half-transporter defective in sitosterolemia, were associated with lower concentrations of plant sterols in parents, and in their offspring.Taken together, these findings indicate that variation in the plasma concentrations of noncholesterol sterols is highly heritable, and that polymorphism in ABCG8 contributes to genetic variation in the plasma concentrations of plant sterols.

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125 Linkage disequilibrium between polymorphisms in ABCG5 and ABCG8 Locus 1 Locus 2 DЈ P ABCG5 Q604E ABCG8 D19H 0.47 0.001 ABCG8 Y54C 0.29 0.095 ABCG8 T400K 0.31 0.299 ABCG8 A632V 0.06 0.451 ABCG8 D19H ABCG8 Y54C 0.62 0.122 ABCG8 T400K 0.63 0.408 ABCG8 A632V 0.04 0.979 ABCG8 Y54C ABCG8 T400K 0.85 0 ABCG8 A632V 0.04 0.959 ABCG8 T400K ABCG8 A632V 0.69 0.016 Haplotypes were determined in 74 nuclear families. Login to comment
5 Two common sequence variations (D19H and T400K) in ABCG8, an ABC half-transporter defective in sitosterolemia, were associated with lower concentrations of plant sterols in parents, and in their offspring. Login to comment
109 The D19H polymorphism in exon 1 of ABCG8 was associated with the plasma cholestanol-cholesterol and campesterol-cholesterol ratios, and the T400K polymorphism in ABCG8 was associated with the plasma sitosterol-cholesterol ratio. Login to comment
166 A common nonconservative substitution (T400K) was associated with the plasma concentrations of sitosterol, although the association of this polymorphism with plasma campesterol concentration was marginal. Login to comment
173 Effect of ABCG8 polymorphisms on plasma sterol-cholesterol ratios in siblings Cholesterol Cholestanol Desmosterol Lathosterol Sitosterol Campesterol ABCG8 D19H 0.097 0.08 0.005 0.001 0.13 0.045 ABCG8 T400K 0.29 0.02 0.34 0.24 0.05 0.03 ABCG8 A632V 0.018 0.29 0.18 0.39 0.26 0.22 The relationships between ABCG8 polymorphisms and plasma sterol-cholesterol ratios were assessed by comparing the plasma sterol levels of siblings with different genotypes. Login to comment
110 The D19H polymorphism in exon 1 of ABCG8 was associated with the plasma cholestanol-cholesterol and campesterol-cholesterol ratios, and the T400K polymorphism in ABCG8 was associated with the plasma sitosterol-cholesterol ratio. Login to comment
126 Linkage disequilibrium between polymorphisms in ABCG5 and ABCG8 Locus 1 Locus 2 D9 P ABCG5 Q604E ABCG8 D19H 0.47 0.001 ABCG8 Y54C 0.29 0.095 ABCG8 T400K 0.31 0.299 ABCG8 A632V 0.06 0.451 ABCG8 D19H ABCG8 Y54C 0.62 0.122 ABCG8 T400K 0.63 0.408 ABCG8 A632V 0.04 0.979 ABCG8 Y54C ABCG8 T400K 0.85 0 ABCG8 A632V 0.04 0.959 ABCG8 T400K ABCG8 A632V 0.69 0.016 Haplotypes were determined in 74 nuclear families. Login to comment
128 Mean plasma sterol concentrations and sterol-cholesterol ratios in unrelated men and women with different ABCG5 and ABCG8 genotypes ABCG8 D19H ABCG8 Y54C ABCG8 T400K ABCG8 A632V ABCG5 Q604E DD n 5 128 DH/HH n 5 14 YY n 5 54 YC/CC n 5 85 TT n 5 95 TK/KK n 5 48 AA n 5 94 VA/VV n 5 49 QQ n 5 91 QE/EE n 5 51 Plasma sterol concentrations Cholesterol 202 6 41 194 6 33 199 6 39 203 6 40 197 6 38 207 6 42 195 6 38 b 213 6 40 198 6 40 204 6 40 Cholestanol 420 6 110 b 340 6 72 400 6 104 419 6 114 410 6 115 418 6 103 400 6 97 437 6 131 411 6 114 416 6 105 Desmosterol 200 6 70 196 6 79 195 6 66 202 6 74 1916 67 221 6 79 197 6 75 210 6 68 197 6 74 208 6 70 Lathosterol 308 6 135 365 6 252 308 6 120 320 6 168 296 6 136 354 6 171 309 6 165 329 6 116 314 6 154 322 6 145 Sitosterol 257 6 105 b 177 6 53 231 6 93 261 6 109 256 6 114 238 6 83 239 6 87 274 6 130 250 6 107 250 6 104 Campesterol 338 6 147 b 233 6 72 310 6 133 339 6 152 332 6 149 324 6 144 308 6 124 a 375 6 177 328 6 154 332 6 136 Plasma sterol-cholesterol ratios (mg/mg) Cholestanol 2.09 6 0.40 c 1.76 6 0.31 2.02 6 0.37 2.07 6 0.39 2.09 6 0.44 2.01 6 0.31 2.06 6 0.41 2.05 6 0.39 2.08 6 0.40 2.04 6 0.42 Desmosterol 0.99 6 0.26 1.00 6 0.32 0.97 6 0.25 0.99 6 0.28 0.96 6 0.25 a 1.06 6 0.30 1.00 6 0.29 0.98 6 0.23 0.98 6 0.27 1.02 6 0.27 Lathosterol 1.53 6 0.60 1.84 6 1.06 1.57 6 0.60 1.57 6 0.70 1.48 6 0.57 a 1.73 6 0.78 1.57 6 0.70 1.56 6 0.57 1.57 6 0.67 1.58 6 0.63 Sitosterol 1.28 6 0.45 c 0.94 6 0.32 1.18 6 0.45 1.29 6 0.45 1.30 6 0.48 a 1.15 6 0.35 1.24 6 0.42 1.29 6 0.51 1.27 6 0.44 1.23 6 0.48 Campesterol 1.67 6 0.62 c 1.21 6 0.36 1.56 6 0.59 1.66 6 0.63 1.68 6 0.62 1.54 6 0.60 1.58 6 0.59 1.74 6 0.65 1.64 6 0.63 1.61 6 0.59 Values are means 6 SD. Plasma cholesterol concentrations are in mg/dl. Login to comment
171 A common nonconservative substitution (T400K) was associated with the plasma concentrations of sitosterol, although the association of this polymorphism with plasma campesterol concentration was marginal. Login to comment
178 Effect of ABCG8 polymorphisms on plasma sterol-cholesterol ratios in siblings Cholesterol Cholestanol Desmosterol Lathosterol Sitosterol Campesterol ABCG8 D19H 0.097 0.08 0.005 0.001 0.13 0.045 ABCG8 T400K 0.29 0.02 0.34 0.24 0.05 0.03 ABCG8 A632V 0.018 0.29 0.18 0.39 0.26 0.22 The relationships between ABCG8 polymorphisms and plasma sterol-cholesterol ratios were assessed by comparing the plasma sterol levels of siblings with different genotypes. Login to comment

[hide] ATP binding cassette transporter G5 and G8 genotyp... J Lipid Res. 2004 Apr;45(4):653-6. Epub 2004 Jan 1. Kajinami K, Brousseau ME, Nartsupha C, Ordovas JM, Schaefer EJ
ATP binding cassette transporter G5 and G8 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin.
J Lipid Res. 2004 Apr;45(4):653-6. Epub 2004 Jan 1., [PMID:14703505]

Abstract [show]
The mechanisms responsible for interindividual variation in response to statin therapy remain uncertain. It has been shown that hepatic cholesterol synthesis is associated with ATP binding cassette transporter G5 and G8 (ABCG5/8) activities. To test the hypothesis that genetic variation in ABCG5/8 might influence the plasma lipid response to statin therapy, we examined five nonsynonymous polymorphisms at the ABCG5/8 loci (Q604E, D19H, Y54C, T400K, and A632V) in 338 hypercholesterolemic patients treated with 10 mg atorvastatin. In carriers of the D19H variant, means of posttreatment values and adjusted percent reductions in LDL cholesterol (LDLC) were significantly lower (P = 0.028) and greater (P = 0.036) (112 mg/dl, 39.7%) than those of noncarriers (119 mg/dl, 36.2%), respectively, while no significant difference was observed in percent reductions in total cholesterol. Stepwise multiple regression analysis revealed significant and independent associations with absolute or percent reduction between D19H genotype and posttreatment LDL cholesterol levels. The other polymorphisms were not significantly associated with treatment effects. These results suggest that, in patients with hypercholesterolemia, the ABCG8 D19H variant is associated with greater LDLC-lowering response to atorvastatin therapy.

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37 In the present study, five prevalent DNA polymorphisms, one in ABCG5 (Q604E) and four in ABCG8 (D19H, Y54C, T400K, and A632V), were studied using a PCR-restriction length polymorphism method. Login to comment
58 RESULTS Genotype, allele, haplotype frequencies, linkage disequilibrium Genotype distributions (wild-type allele homozygote, variant heterozygote, variant homozygote) in each polymorphism were as follows; Q604E (212, 112, 14), D19H (294, 43, 1), Y54C (138, 146, 54), T400K (196, 130, 12), and A632V (225, 96, 17). Login to comment
60 Allele frequencies (wild-type, variant) were Q604E (0.79, 0.21), D19H (0.93, 0.07), Y54C (0.62, 0.38), T400K (0.77, 0.23), and A632V (0.81, 0.19). Login to comment
63 Significant linkage disequilibrium was found in 5 out of 10 pairs of five polymorphisms: Q604E/D19H (D` ϭ 0.6503, P Ͻ 0.0001), Q604E/Y54C (-0.3461, 0.0244), D19H/Y54C (-0.9986, 0.0003), Y54C/T400K (-0.4957, 0.0003), and T400K/A632V (-0.5484, 0.0456). Login to comment
38 For the D19H polymorphism, a 131 bp fragment, including a G to C substitution site at codon 19 of the ABCG8 gene, was amplified using an oligonucleotide primer set (5Ј-GCTGGGTCTAAGAGAGCTGC-3Ј and 5Ј-CTTCCCATTGCT- CACTCACC-3Ј) with 35 cycles of amplification (95ЊC for 30 s, 60ЊC for 30 s, and 72ЊC for 30 s). Login to comment

[hide] Polymorphisms in the ABCG5 and ABCG8 genes associa... J Lipid Res. 2004 Sep;45(9):1660-5. Epub 2004 Jun 1. Gylling H, Hallikainen M, Pihlajamaki J, Agren J, Laakso M, Rajaratnam RA, Rauramaa R, Miettinen TA
Polymorphisms in the ABCG5 and ABCG8 genes associate with cholesterol absorption and insulin sensitivity.
J Lipid Res. 2004 Sep;45(9):1660-5. Epub 2004 Jun 1., [PMID:15175352]

Abstract [show]
The roles of polymorphisms of the sitosterolemia genes ABCG5 and ABCG8 in the regulation of cholesterol metabolism and insulin sensitivity were studied in mildly hypercholesterolemic noncoronary subjects (n = 263, 144 men and 119 women) divided into tertiles by baseline serum cholestanol-to-cholesterol ratio (< or = 118.3 and > or = 147.7 10(2) x mmol/mol cholesterol), a surrogate marker of cholesterol absorption efficiency. The lowest cholestanol tertile was associated with high body mass index (BMI), plasma glucose, serum insulin and triglycerides, and cholesterol synthesis markers (cholestenol, desmosterol, lathosterol) and low HDL cholesterol and cholesterol absorption markers (campesterol, sitosterol) (P < 0.01 for all). The 19H allele of the ABCG8 gene accumulated in the lowest cholestanol tertile (P < 0.001) and was associated with low total and LDL cholesterol and absorption markers and with high synthesis markers (P < 0.05 for all). The 604E allele of the ABCG5 gene in men was associated with high BMI, plasma insulin, low serum sitosterol, and high serum cholestenol levels (P < 0.05 for all). In a subgroup of 71 men, the 604E allele was associated with insulin resistance measured with the hyperinsulinemic euglycemic clamp. In conclusion, low cholesterol absorption efficiency was associated with characteristics of the metabolic syndrome. Low serum cholesterol and cholesterol absorption were linked to the D19H polymorphism of the ABCG8 gene, and characteristics of the insulin resistance syndrome in men were linked with the Q604E polymorphism of the ABCG5 gene.

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18 Two sequence variations (D19H and T400K) in the G8 gene were shown to be associated with lower serum plant sterol levels in a normolipidemic family study (5). Login to comment
112 In a family study of a normal population by Berge et al. (5), the D19H substitution of the G8 gene resulted in a completely different situation: low serum cholestanol, sitosterol, and campesterol levels, suggesting limited sterol absorption. Login to comment
114 The authors also described the following two associations: the T400K polymorphism of the G8 gene was associated with high serum desmosterol and lathosterol ratios to cholesterol and low sitosterol ratios, and the A632V polymorphism of the G8 gene was associated with high serum total cholesterol value (5), none of which could be observed in the present study. Login to comment
17 Two sequence variations (D19H and T400K) in the G8 gene were shown to be associated with lower serum plant sterol levels in a normolipidemic family study (5). Login to comment
113 Concerning the D19H polymorphism of the G8 gene, the present results confirmed the findings by Berge et al. (5) that serum absorption marker sterols were lower in subjects with this polymorphism. Login to comment

[hide] ATP-binding cassette (ABC) transporters in human m... Physiol Res. 2004;53(3):235-43. Stefkova J, Poledne R, Hubacek JA
ATP-binding cassette (ABC) transporters in human metabolism and diseases.
Physiol Res. 2004;53(3):235-43., [PMID:15209530]

Abstract [show]
The ATP-binding cassette (ABC) superfamily of active transporters involves a large number of functionally diverse transmembrane proteins. They transport a variety of substrates including amino acids, lipids, inorganic ions, peptides, saccharides, metals, drugs, and proteins. The ABC transporters not only move a variety of substrates into and out of the cell, but also are also involved in intracellular compartmental transport. Energy derived from the hydrolysis of ATP is used to transport the substrate across the membrane against a concentration gradient. The typical ABC transporter consists of two transmembrane domains and two nucleotide-binding domains. Defects in 14 of these transporters cause 13 genetic diseases (cystic fibrosis, Stargardt disease, adrenoleukodystrophy, Tangier disease, etc.). Mutations in three genes affect lipid levels expressively. Mutations in ABCA1 cause severe HDL deficiency syndromes called Tangier disease and familial high-density lipoprotein deficiency, which are characterized by a severe deficiency or absence of high-density lipoprotein in the plasma. Two other ABCG transporters, ABCG5 and ABCG8, mutations of which cause sitosterolemia, have been identified. The affected individuals absorb and retain plant sterols, as well as shellfish sterols.

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105 A common nonconservative substitution (T400K) was associated with the plasma concentrations of sitosterol, although the association of this polymorphism with plasma campesterol concentration was marginal (Berge et al. 2002). Login to comment

[hide] Polymorphisms in ABCG5 and ABCG8 transporters and ... Physiol Res. 2004;53(4):395-401. Hubacek JA, Berge KE, Stefkova J, Pitha J, Skodova Z, Lanska V, Poledne R
Polymorphisms in ABCG5 and ABCG8 transporters and plasma cholesterol levels.
Physiol Res. 2004;53(4):395-401., [PMID:15311998]

Abstract [show]
ABCG5 and ABCG8 transporters play an important role in the absorption and excretion of sterols. Missence polymorphisms (Gln604Glu in the ABCG5 and Asp19His, Tyr54Cys, Thr400Lys, and Ala632Val in the ABCG8) in these genes have been described. In 131 males and 154 females whose dietary composition markedly changed and lipid parameters decreased over an 8-year follow-up study (total cholesterol decreased from 6.21+/-1.31 mmol/l in 1988 to 5.43+/-1.06 mmol/l in 1996), these polymorphisms were investigated using PCR. Plasma lipid levels and changes in plasma lipid levels were independent of the Gln604Glu polymorphism in ABCG5 and Asp19His and the Ala632Val polymorphisms in ABCG8. The Tyr54Cys polymorphism influenced the degree of reduction in total plasma cholesterol (delta -0.49 mmol/l in Tyr54 homozygotes vs. delta +0.12 mmol/l in Cys54 homozygotes, p<0.04) and LDL-cholesterol (delta -0.57 mmol/l in Tyr54 homozygotes vs. delta +0.04 mmol/l in Cys54 homozygotes, p<0.03) levels between 1988 and 1996 in females, but not in males. Male Thr400 homozygotes exhibited a greater decrease in total cholesterol (delta -0.90 mmol/l vs. delta -0.30 mmol/l, p<0.02) and LDL-cholesterol (delta -0.62 mmol/l vs. delta -0.19 mmol/l, p<0.04) than Lys400 carriers. No such association was observed in females. We conclude that Tyr54Cys and Thr400Lys variations in the ABCG8 gene may play a role in the genetic determination of plasma cholesterol levels and could possibly influence the gender-specific response of plasma cholesterol levels after dietary changes. These polymorphisms are of potential interest as genetic variants that may influence the lipid profile.

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5 Missence polymorphisms (Gln604Glu in the ABCG5 and Asp19His, Tyr54Cys, Thr400Lys, and Ala632Val in the ABCG8) in these genes have been described. Login to comment
23 To evaluate the role of the ABCG5 and ABCG8 variants in the genetic determination of plasma lipids, we analyzed non-synonymous polymorphisms in the ABCG5 (C1810G = Gln604Glu) and ABCG8 (G55C = Asp19His, A161G = Tyr54Cys, C1199A = Thr400Lys and C1895T = Ala632Val) genes, and searched for associations between the polymorphisms and plasma lipid levels, and between the polymorphisms and plasma lipid changes over a 8 years´ follow-up. Login to comment
33 Polymorphism Primer sequence PCR product Enzyme Size Allele ABCG8 5`atggccgggaaggcggcagaggagag 83 bp BamH I 83 C (His) Asp19His 5`acttcccattgctcactcaccgagggat 56 + 27 G (Asp) ABCG8 5`agggcctccaggatagattgttctcctc 128 bp Bgl I 128 A (Tyr) Tyr54Cys 5`ccttgaacccaggcgtgcgcctacctg 102 + 26 G (Cys) ABCG8 5`agatgcctggggcggtgcagcagctt 108 bp Afl II 108 C (Thr) Thr400Lys 5`ggcttaatgtgatatacaaagacttggg 81 + 27 A (Lys) ABCG8 5`atgtctgtgtctccagatcctcaggg 105 bp Hae III 105 T (Val) Ala632Val 5`tacaggaccatgaagccaccgctgacgcc 79 + 26 C (Ala) ABCG5 5`aaccacacctgacactgtcaatcttttcct 117 bp Xho I 117 G (Glu) Gln604Glu 5`gggcaggttttctcaatgaattgaattcctc 86 + 31 C (Gln) DNA analysis Three ml of blood collected into EDTA tubes for DNA isolation were diluted with sterile water at a 1:1 ratio and stored at -20 °C. DNA was isolated by a standard method (Miller et al. 1988). Login to comment
58 Polymorphism 11 12 22 N (%) ABCG8 2 34 249 1- His 38 (6.7 %) Asp19His (0.7) (11.9) (87.4) 2- Asp 532 (93.3 %) ABCG8 97 130 58 1- Tyr 324 (56.8 %) Tyr54Cys (34.0) (45.6) (20.4) 2-Cys 246 (43.2 %) ABCG8 178 85 9 1- Thr 441 (81.1 %) Thr400Lys (65.4) (31.3) (3.3) 2- Lys 103 (18.9 %) ABCG8 24 96 165 1- Val 144 (25.3 %) Ala632Val (8.4) (33.7) (57.9) 2- Ala 426 (74.7 %) ABCG5 200 77 8 1- Glu 477 (83.7 %) Gln604Glu (70.0) (27.0) (2.8) 2- Gln 93 (16.3 %) Results are given as numbers (%). Login to comment
11 We conclude that Tyr54Cys and Thr400Lys variations in the ABCG8 gene may play a role in the genetic determination of plasma cholesterol levels and could possibly influence the gender-specific response of plasma cholesterol levels after dietary changes. Login to comment
21 Recently, associations between the Asp19His and Thr400Lys polymorphisms and concentrations of plasma plant sterols (sitosterol and campesterol) have been described (Berge et al. 2002). Login to comment
39 In 13 individuals, the Thr400Lys polymorphism at the ABCG8 locus was unsuccessfully genotyped even when repeated 3 times. Login to comment
66 However, the Thr400Lys polymorphism in ABCG8 was associated with lipid level changes in males only. Login to comment
71 Thr400Lys polymorphism in ABCG8 and plasma levels of total cholesterol (T-C) and LDL-cholesterol (LDL-C) in 1988 and 1996 in males changes of T-C between 1988 and 1996. Login to comment
97 In males, a similar pattern was observed for the Thr400Lys polymorphism at the ABCG8 locus. Login to comment
103 In this sample, variations in the ABCG8 gene loci (Tyr54Cys and Thr400Lys polymorphisms) were found to play a role in gender-specific reduction in plasma lipid levels as a response to reduced dietary animal fat and cholesterol intake. Login to comment
104 Our results suggest that the Tyr54Cys and Thr400Lys polymorphisms in ABCG8 might play a role in the genetic determination of plasma lipids in a gender-specific gene-nutrition manner. Login to comment
57 Polymorphism 11 12 22 N (%) ABCG8 2 34 249 1- His 38 (6.7 %) Asp19His (0.7) (11.9) (87.4) 2- Asp 532 (93.3 %) ABCG8 97 130 58 1- Tyr 324 (56.8 %) Tyr54Cys (34.0) (45.6) (20.4) 2-Cys 246 (43.2 %) ABCG8 178 85 9 1- Thr 441 (81.1 %) Thr400Lys (65.4) (31.3) (3.3) 2- Lys 103 (18.9 %) ABCG8 24 96 165 1- Val 144 (25.3 %) Ala632Val (8.4) (33.7) (57.9) 2- Ala 426 (74.7 %) ABCG5 200 77 8 1- Glu 477 (83.7 %) Gln604Glu (70.0) (27.0) (2.8) 2- Gln 93 (16.3 %) Results are given as numbers (%). Login to comment
65 However, the Thr400Lys polymorphism in ABCG8 was associated with lipid level changes in males only. Login to comment
70 Thr400Lys polymorphism in ABCG8 and plasma levels of total cholesterol (T-C) and LDL-cholesterol (LDL-C) in 1988 and 1996 in males changes of T-C between 1988 and 1996. Login to comment
96 In males, a similar pattern was observed for the Thr400Lys polymorphism at the ABCG8 locus. Login to comment
102 In this sample, variations in the ABCG8 gene loci (Tyr54Cys and Thr400Lys polymorphisms) were found to play a role in gender-specific reduction in plasma lipid levels as a response to reduced dietary animal fat and cholesterol intake. Login to comment

[hide] Common sequence variations in ABCG8 are related to... J Lipid Res. 2005 Jan;46(1):68-75. Epub 2004 Nov 1. Plat J, Bragt MC, Mensink RP
Common sequence variations in ABCG8 are related to plant sterol metabolism in healthy volunteers.
J Lipid Res. 2005 Jan;46(1):68-75. Epub 2004 Nov 1., [PMID:15520451]

Abstract [show]
Polymorphisms in the ATP binding cassette (ABC) transporters ABCG5 and ABCG8 are related to plasma plant sterol concentrations. It is not known whether these polymorphisms are also associated with variations in serum plant sterol concentrations during interventions affecting plant sterol metabolism. We therefore decided to study changes in serum plant sterol concentrations with ABCG5/G8 polymorphisms after consumption of plant stanol esters, which decrease plasma plant sterol concentrations. Cholesterol-standardized serum campesterol and sitosterol concentrations were significantly associated with the ABCG8 T400K genotype, as were changes in serum plant sterol concentrations after consumption of plant stanols. The reduction of -57.1 +/- 38.3 10(2) x micromol/mmol cholesterol for sitosterol in TT subjects was significantly greater compared with the -36.0 +/- 18.7 reduction in subjects with the TK genotype (P = 0.021) and the -16.9 +/- 13.0 reduction in subjects with the KK genotype (P = 0.047). Changes in serum campesterol concentrations showed a comparable association. No association with serum LDL cholesterol was found. Genetic variation in ABCG8 not only explains cross-sectional differences in serum plant sterol concentrations but also determines a subject's responsiveness to changes in serum plant sterols during interventions known to affect plant sterol metabolism.

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44 These criteria resulted in the selection of three SNPs: ABCG8 T400K, ABCG8 A632V, and ABCG5 Q604E. Login to comment
54 Statistics Because of the limited number of subjects, and because plant sterol concentrations were not significantly different, heterozygous and homozygous carriers of the genetic variants [ABCG8 T400K (TKϩKK), ABCG8 A632V (VVϩVA), and ABCG5 Q604E (QEϩEE)] were combined before data analysis. Login to comment
61 Frequency distribution of the different genotypes in exons 8 (T400K) and 13 (A632V) of ABCG8 and in exon 13 (Q604E) of ABCG5 Subjects All Control Group Experimental Group All 112 42 70 ABCG8 T400K TT 77 (68.7) 30 (71.4) 47 (67.1) TK 31 (27.7) 11 (26.2) 20 (28.6) KK 4 (3.6) 1 (2.4) 3 (4.3) ABCG8 A632V AA 70 (62.5) 23 (54.8) 47 (67.1) VA 37 (33.0) 17 (40.5) 20 (28.6) VV 5 (4.5) 2 (4.8) 3 (4.3) ABCG5 Q604E QQ 81 (72.3) 33 (78.6) 48 (68.6) QE 29 (25.9) 9 (21.4) 20 (28.6) EE 2 (1.8) 0 (0) 2 (2.9) Values shown are absolute frequencies (with relative frequencies in parentheses). Login to comment
72 RESULTS Frequency distributions for the genotypes in exons 8 (T400K) and 13 (A632V) of ABCG8 and in exon 13 (Q604E) of ABCG5 are shown in Table 2. Login to comment
80 Linkage disequilibrium between genotypes in exons 8 (T400K) and 13 (A632V) of ABCG8 and in exon 13 (Q604E) of ABCG5 Locus 1 Locus 2 DЈ 95% Confidence Interval ABCG8 T400K ABCG8 A632V 0.29 0.03-0.76 ABCG5 Q604E 0.81 0.06-0.97 ABCG8 A632V ABCG5 Q604E 0.0 -0.01-0.22 DЈ and the corresponding 95% confidence intervals were calculated by using all 112 subjects included in the study. Login to comment
81 TABLE 4. Relationships between genetic polymorphisms in ABCG8 and ABCG5 with absolute and cholesterol-standardized serum noncholesterol sterol concentrations Subjects Campesterol Sitosterol Lathosterol Campestanol Sitostanol Absolute concentrations (␮mol/l) All 15.8 Ϯ 5.3 6.0 Ϯ 2.4 5.2 Ϯ 2.1 0.5 Ϯ 0.3 0.4 Ϯ 0.2 ABCG8 T400K TT 16.9 Ϯ 5.5 6.6 Ϯ 2.6 5.0 Ϯ 2.1 0.5 Ϯ 0.4 0.4 Ϯ 0.2 TK/KK 13.5 Ϯ 3.8 4.8 Ϯ 1.4 5.7 Ϯ 2.1 0.5 Ϯ 0.3 0.4 Ϯ 0.2 P value Ͻ0.001 Ͻ0.001 0.070 0.887 0.675 ABCG8 A632V AA 16.3 Ϯ 5.6 6.2 Ϯ 2.6 5.1 Ϯ 2.0 0.5 Ϯ 0.3 0.4 Ϯ 0.2 VV/VA 15.1 Ϯ 4.8 5.7 Ϯ 2.1 5.4 Ϯ 2.4 0.6 Ϯ 0.4 0.4 Ϯ 0.2 P value 0.280 0.266 0.516 0.349 0.759 ABCG5 Q604E QQ 16.3 Ϯ 5.4 6.3 Ϯ 2.5 5.1 Ϯ 2.1 0.5 Ϯ 0.3 0.4 Ϯ 0.2 QE/EE 14.6 Ϯ 5.0 5.4 Ϯ 2.2 5.4 Ϯ 2.3 0.6 Ϯ 0.4 0.4 Ϯ 0.2 P value 0.125 0.093 0.517 0.043 0.768 Cholesterol-standardized concentrations (102 ϫ ␮mol/mmol cholesterol) All 303.4 Ϯ 98.0 115.0 Ϯ 44.5 97.3 Ϯ 33.5 9.8 Ϯ 6.6 7.6 Ϯ 4.3 ABCG8 T400K TT 324.2 Ϯ 98.5 125.2 Ϯ 45.8 93.2 Ϯ 35.0 9.6 Ϯ 6.8 7.5 Ϯ 4.4 TK/KK 257.7 Ϯ 80.8 92.4 Ϯ 31.9 106.4 Ϯ 28.4 10.2 Ϯ 6.1 7.7 Ϯ 3.9 P value Ͻ0.001 Ͻ0.001 0.053 0.636 0.862 ABCG8 A632V AA 305.8 Ϯ 95.3 117.3 Ϯ 47.3 95.2 Ϯ 32.2 9.3 Ϯ 6.1 7.6 Ϯ 4.2 VV/VA 299.3 Ϯ 103.3 111.0 Ϯ 39.8 101.0 Ϯ 35.8 10.6 Ϯ 7.2 7.6 Ϯ 4.4 P value 0.736 0.467 0.377 0.332 0.938 ABCG5 Q604E QQ 310.5 Ϯ 98.8 118.3 Ϯ 43.7 95.3 Ϯ 34.8 8.9 Ϯ 5.7 7.6 Ϯ 4.3 QE/EE 284.8 Ϯ 94.9 106.2 Ϯ 46.2 102.7 Ϯ 29.9 11.9 Ϯ 8.1 7.6 Ϯ 4.2 P value 0.216 0.198 0.298 0.029 0.987 Values shown are means Ϯ SD and were analyzed after a 4-week period of consumption of rapeseed oil-based margarine and shortening. Login to comment
101 TABLE 5. Relationships between genetic polymorphisms in ABCG8 and ABCG5 with serum lipid and lipoprotein concentrations Subjects LDL Cholesterol HDL Cholesterol Triacylglycerol mmol/l All 2.95 Ϯ 0.78 1.59 Ϯ 0.38 0.92 Ϯ 0.52 ABCG8 T400K TT 2.97 Ϯ 0.74 1.59 Ϯ 0.37 0.85 Ϯ 0.47 TK/KK 2.89 Ϯ 0.86 1.60 Ϯ 0.40 1.08 Ϯ 0.58 P value 0.622 0.976 0.025 ABCG8 A632V AA 3.03 Ϯ 0.78 1.58 Ϯ 0.39 0.91 Ϯ 0.48 VV/VA 2.81 Ϯ 0.77 1.61 Ϯ 0.36 0.93 Ϯ 0.58 P value 0.137 0.666 0.883 ABCG5 Q604E QQ 3.04 Ϯ 0.75 1.56 Ϯ 0.35 0.89 Ϯ 0.45 QE/EE 2.70 Ϯ 0.81 1.68 Ϯ 0.43 0.99 Ϯ 0.65 P value 0.039 0.145 0.342 Values shown are means Ϯ SD and were analyzed after a 4-week period of consumption of rapeseed oil-based margarine and shortening. Login to comment
114 However, if ABCG8 transports the same proportion of plant sterols out of the enterocytes and hepatocytes into the lumen and bile, respectively, as before plant stanol ester TABLE 6. Relationships between genetic polymorphisms in ABCG8 and ABCG5 with changes in absolute and cholesterol-standardized serum noncholesterol sterol concentrations after consumption of plant stanol esters Subjects Campesterol Sitosterol Lathosterol Campestanol Sitostanol Absolute concentrations (␮mol/l) Experimental group Control -0.5 Ϯ 2.2 -0.5 Ϯ 1.2 0.0 Ϯ 1.1 -0.0 Ϯ 0.4 0.0 Ϯ 0.2 Stanol -6.3 Ϯ 3.9 -3.0 Ϯ 2.1 0.2 Ϯ 1.4 0.3 Ϯ 0.4 0.3 Ϯ 0.2 P value Ͻ0.001 Ͻ0.001 Ͻ0.001 Ͻ0.001 Ͻ0.001 Genotype group ABCG8 T400K TT -7.0 Ϯ 4.4 -3.4 Ϯ 2.3 0.2 Ϯ 1.2 0.2 Ϯ 0.4 0.3 Ϯ 0.2 TK/KK -4.9 Ϯ 2.4 -2.1 Ϯ 0.9 0.2 Ϯ 1.7 0.3 Ϯ 0.4 0.3 Ϯ 0.2 P value 0.042 0.017 0.989 0.526 0.967 ABCG8 A632V AA -6.5 Ϯ 4.5 -2.9 Ϯ 2.3 0.3 Ϯ 1.1 0.3 Ϯ 0.4 0.3 Ϯ 0.2 VV/VA -6.0 Ϯ 2.7 -3.0 Ϯ 1.6 0.2 Ϯ 1.3 0.2 Ϯ 0.4 0.3 Ϯ 0.2 P value 0.598 0.831 0.836 0.832 0.395 ABCG5 Q604E QQ -6.6 Ϯ 4.3 -3.1 Ϯ 2.3 0.1 Ϯ 1.5 0.2 Ϯ 0.4 0.3 Ϯ 0.2 QE/EE -5.8 Ϯ 3.1 -2.7 Ϯ 1.6 0.6 Ϯ 1.2 0.2 Ϯ 0.4 0.4 Ϯ 0.2 P value 0.448 0.413 0.185 0.956 0.097 Cholesterol-standardized concentrations (102 ϫ ␮mol/mmol cholesterol) Experimental group Control -5.9 Ϯ 39.2 -7.8 Ϯ 22.4 0.5 Ϯ 19.5 -0.6 Ϯ 7.2 0.4 Ϯ 4.0 Stanol -103.1 Ϯ 70.6 -49.3 Ϯ 34.9 17.4 Ϯ 22.2 6.3 Ϯ 8.1 8.2 Ϯ 4.5 P value Ͻ0.001 Ͻ0.001 Ͻ0.001 Ͻ0.001 Ͻ0.001 Genotype group ABCG8 T400K TT -116.7 Ϯ 76.5 -57.1 Ϯ 38.3 16.5 Ϯ 19.8 6.1 Ϯ 8.3 8.4 Ϯ 4.5 TK/KK -75.4 Ϯ 46.9 -33.5 Ϯ 19.0 19.2 Ϯ 26.7 6.8 Ϯ 7.6 7.7 Ϯ 4.6 P value 0.020 0.007 0.624 0.737 0.541 ABCG8 A632V AA -107.3 Ϯ 75.4 -49.3 Ϯ 38.8 16.0 Ϯ 23.9 6.1 Ϯ 8.3 8.3 Ϯ 4.4 VV/VA -94.6 Ϯ 60.3 -49.4 Ϯ 25.9 20.2 Ϯ 18.3 6.7 Ϯ 7.8 8.0 Ϯ 4.9 P value 0.483 0.998 0.465 0.756 0.780 ABCG5 Q604E QQ -106.3 Ϯ 75.6 -50.9 Ϯ 36.9 14.7 Ϯ 21.3 6.3 Ϯ 8.2 7.6 Ϯ 4.2 QE/EE -96.1 Ϯ 59.2 -46.0 Ϯ 30.6 23.2 Ϯ 23.5 6.3 Ϯ 7.9 9.5 Ϯ 4.9 P value 0.579 0.596 0.140 0.997 0.087 Values shown are means Ϯ SD. Changes in all parameters were calculated as the difference between values at the end of the run-in period (weeks 3 and 4) and the experimental period (weeks 11 and 12). Login to comment
142 TABLE 7. Relationships between genetic polymorphisms in ABCG8 and ABCG5 with changes in lipid and lipoprotein concentrations after consumption of plant stanol esters Subjects LDL Cholesterol HDL Cholesterol Triacylglycerol Control -0.06 Ϯ 0.36 0.01 Ϯ 0.16 0.02 Ϯ 0.23 Stanols -0.42 Ϯ 0.31 0.01 Ϯ 0.12 -0.04 Ϯ 0.30 P value Ͻ0.001 0.903 0.272 ABCG8 T400K TT -0.43 Ϯ 0.32 0.02 Ϯ 0.11 -0.01 Ϯ 0.22 TK/KK -0.38 Ϯ 0.30 -0.01 Ϯ 0.13 -0.09 Ϯ 0.42 P value 0.531 0.345 0.304 ABCG8 A632V AA -0.42 Ϯ 0.32 0.01 Ϯ 0.12 -0.00 Ϯ 0.25 VV/VA -0.41 Ϯ 0.29 -0.00 Ϯ 0.13 -0.10 Ϯ 0.38 P value 0.935 0.588 0.199 ABCG5 Q604E QQ -0.44 Ϯ 0.30 0.01 Ϯ 0.10 -0.01 Ϯ 0.34 QE/EE -0.36 Ϯ 0.34 -0.01 Ϯ 0.16 -0.09 Ϯ 0.18 P value 0.297 0.368 0.357 Values shown are means Ϯ SD. Changes in all parameters were calculated as the difference between values at the end of the run-in period (weeks 3 and 4) and the experimental period (weeks 11 and 12). Login to comment
3 Cholesterol-standardized serum campesterol and sitosterol concentrations were significantly associated with the ABCG8 T400K genotype, as were changes in serum plant sterol concentrations after consumption of plant stanols. Login to comment
82 T400K genotype (Table 4). Login to comment
92 Changes in cholesterol-standardized serum campesterol and sitosterol concentrations were significantly associated with the ABCG8 T400K polymorphism (Table 6, Fig. 1). Login to comment
95 Additional analysis to evaluate the association between the three different genotype groups of the ABCG8 T400K polymorphism (TT, TK, and KK) with changes in serum plant sterol and lipoprotein concentrations suggested an allele-dependent relation for both cholesterol-standardized serum campesterol and sitosterol concentrations (Fig. 1). Login to comment
97 Cholesterol-standardized campesterol (A), sitosterol (B), and LDL cholesterol (C) concentrations at the end of the run-in period (upper panels) and the change during the stanol ester feeding period (lower panels) in the different genotypes of the ABCG8 T400K polymorphism. Login to comment
103 Changes in serum campesterol concentrations showed a comparable association pattern with the ABCG8 T400K genotype. Login to comment
116 More detailed studies on the effects of the functional consequences of the T400K polymorphism on plant sterol metabolism are needed, which can be obtained through the development of specifically designed cell or transgenic animal models carrying this genetic variation. Login to comment
117 Concerning the potential functionality of the different genotypes, it should be remarked that the polymorphic site of the ABCG8 T400K polymorphisms is located in a coding region but is predicted not to contain a transmembrane domain, a signature, or a Walker motif (15). Login to comment
139 Furthermore, the observation that the T400K polymorphism in ABCG8 is associated with changes in plant sterol levels with stanol ester treatment, but not with changes in the cholesterol levels, suggests that individual variation in the cholesterol-lowering efficacy of plant stanols is not strongly determined by the magnitude of the reduction in intestinal cholesterol absorption achieved. Login to comment
43 These criteria resulted in the selection of three SNPs: ABCG8 T400K, ABCG8 A632V, and ABCG5 Q604E. Login to comment
53 Statistics Because of the limited number of subjects, and because plant sterol concentrations were not significantly different, heterozygous and homozygous carriers of the genetic variants [ABCG8 T400K (TKKK), ABCG8 A632V (VVVA), and ABCG5 Q604E (QEEE)] were combined before data analysis. Login to comment
60 Frequency distribution of the different genotypes in exons 8 (T400K) and 13 (A632V) of ABCG8 and in exon 13 (Q604E) of ABCG5 Subjects All Control Group Experimental Group All 112 42 70 ABCG8 T400K TT 77 (68.7) 30 (71.4) 47 (67.1) TK 31 (27.7) 11 (26.2) 20 (28.6) KK 4 (3.6) 1 (2.4) 3 (4.3) ABCG8 A632V AA 70 (62.5) 23 (54.8) 47 (67.1) VA 37 (33.0) 17 (40.5) 20 (28.6) VV 5 (4.5) 2 (4.8) 3 (4.3) ABCG5 Q604E QQ 81 (72.3) 33 (78.6) 48 (68.6) QE 29 (25.9) 9 (21.4) 20 (28.6) EE 2 (1.8) 0 (0) 2 (2.9) Values shown are absolute frequencies (with relative frequencies in parentheses). Login to comment
71 RESULTS Frequency distributions for the genotypes in exons 8 (T400K) and 13 (A632V) of ABCG8 and in exon 13 (Q604E) of ABCG5 are shown in Table 2. Login to comment
79 Linkage disequilibrium between genotypes in exons 8 (T400K) and 13 (A632V) of ABCG8 and in exon 13 (Q604E) of ABCG5 Locus 1 Locus 2 D 95% Confidence Interval ABCG8 T400K ABCG8 A632V 0.29 0.03-0.76 ABCG5 Q604E 0.81 0.06-0.97 ABCG8 A632V ABCG5 Q604E 0.0 0.01-0.22 D and the corresponding 95% confidence intervals were calculated by using all 112 subjects included in the study. Login to comment
91 Changes in cholesterol-standardized serum campesterol and sitosterol concentrations were significantly associated with the ABCG8 T400K polymorphism (Table 6, Fig. 1). Login to comment
94 Additional analysis to evaluate the association between the three different genotype groups of the ABCG8 T400K polymorphism (TT, TK, and KK) with changes in serum plant sterol and lipoprotein concentrations suggested an allele-dependent relation for both cholesterol-standardized serum campesterol and sitosterol concentrations (Fig. 1). Login to comment
96 Cholesterol-standardized campesterol (A), sitosterol (B), and LDL cholesterol (C) concentrations at the end of the run-in period (upper panels) and the change during the stanol ester feeding period (lower panels) in the different genotypes of the ABCG8 T400K polymorphism. Login to comment
100 TABLE 5. Relationships between genetic polymorphisms in ABCG8 and ABCG5 with serum lipid and lipoprotein concentrations Subjects LDL Cholesterol HDL Cholesterol Triacylglycerol mmol/l All 2.95 0.78 1.59 0.38 0.92 0.52 ABCG8 T400K TT 2.97 0.74 1.59 0.37 0.85 0.47 TK/KK 2.89 0.86 1.60 0.40 1.08 0.58 P value 0.622 0.976 0.025 ABCG8 A632V AA 3.03 0.78 1.58 0.39 0.91 0.48 VV/VA 2.81 0.77 1.61 0.36 0.93 0.58 P value 0.137 0.666 0.883 ABCG5 Q604E QQ 3.04 0.75 1.56 0.35 0.89 0.45 QE/EE 2.70 0.81 1.68 0.43 0.99 0.65 P value 0.039 0.145 0.342 Values shown are means SD and were analyzed after a 4-week period of consumption of rapeseed oil-based margarine and shortening. Login to comment
102 Changes in serum campesterol concentrations showed a comparable association pattern with the ABCG8 T400K genotype. Login to comment
113 However, if ABCG8 transports the same proportion of plant sterols out of the enterocytes and hepatocytes into the lumen and bile, respectively, as before plant stanol ester TABLE 6. Relationships between genetic polymorphisms in ABCG8 and ABCG5 with changes in absolute and cholesterol-standardized serum noncholesterol sterol concentrations after consumption of plant stanol esters Subjects Campesterol Sitosterol Lathosterol Campestanol Sitostanol Absolute concentrations (mol/l) Experimental group Control 0.5 2.2 0.5 1.2 0.0 1.1 0.0 0.4 0.0 0.2 Stanol 6.3 3.9 3.0 2.1 0.2 1.4 0.3 0.4 0.3 0.2 P value 0.001 0.001 0.001 0.001 0.001 Genotype group ABCG8 T400K TT 7.0 4.4 3.4 2.3 0.2 1.2 0.2 0.4 0.3 0.2 TK/KK 4.9 2.4 2.1 0.9 0.2 1.7 0.3 0.4 0.3 0.2 P value 0.042 0.017 0.989 0.526 0.967 ABCG8 A632V AA 6.5 4.5 2.9 2.3 0.3 1.1 0.3 0.4 0.3 0.2 VV/VA 6.0 2.7 3.0 1.6 0.2 1.3 0.2 0.4 0.3 0.2 P value 0.598 0.831 0.836 0.832 0.395 ABCG5 Q604E QQ 6.6 4.3 3.1 2.3 0.1 1.5 0.2 0.4 0.3 0.2 QE/EE 5.8 3.1 2.7 1.6 0.6 1.2 0.2 0.4 0.4 0.2 P value 0.448 0.413 0.185 0.956 0.097 Cholesterol-standardized concentrations (102 mol/mmol cholesterol) Experimental group Control 5.9 39.2 7.8 22.4 0.5 19.5 0.6 7.2 0.4 4.0 Stanol 103.1 70.6 49.3 34.9 17.4 22.2 6.3 8.1 8.2 4.5 P value 0.001 0.001 0.001 0.001 0.001 Genotype group ABCG8 T400K TT 116.7 76.5 57.1 38.3 16.5 19.8 6.1 8.3 8.4 4.5 TK/KK 75.4 46.9 33.5 19.0 19.2 26.7 6.8 7.6 7.7 4.6 P value 0.020 0.007 0.624 0.737 0.541 ABCG8 A632V AA 107.3 75.4 49.3 38.8 16.0 23.9 6.1 8.3 8.3 4.4 VV/VA 94.6 60.3 49.4 25.9 20.2 18.3 6.7 7.8 8.0 4.9 P value 0.483 0.998 0.465 0.756 0.780 ABCG5 Q604E QQ 106.3 75.6 50.9 36.9 14.7 21.3 6.3 8.2 7.6 4.2 QE/EE 96.1 59.2 46.0 30.6 23.2 23.5 6.3 7.9 9.5 4.9 P value 0.579 0.596 0.140 0.997 0.087 Values shown are means SD. Changes in all parameters were calculated as the difference between values at the end of the run-in period (weeks 3 and 4) and the experimental period (weeks 11 and 12). Login to comment
115 More detailed studies on the effects of the functional consequences of the T400K polymorphism on plant sterol metabolism are needed, which can be obtained through the development of specifically designed cell or transgenic animal models carrying this genetic variation. Login to comment
138 Furthermore, the observation that the T400K polymorphism in ABCG8 is associated with changes in plant sterol levels with stanol ester treatment, but not with changes in the cholesterol levels, suggests that individual variation in the cholesterol-lowering efficacy of plant stanols is not strongly determined by the magnitude of the reduction in intestinal cholesterol absorption achieved. Login to comment
141 TABLE 7. Relationships between genetic polymorphisms in ABCG8 and ABCG5 with changes in lipid and lipoprotein concentrations after consumption of plant stanol esters Subjects LDL Cholesterol HDL Cholesterol Triacylglycerol Control 0.06 0.36 0.01 0.16 0.02 0.23 Stanols 0.42 0.31 0.01 0.12 0.04 0.30 P value 0.001 0.903 0.272 ABCG8 T400K TT 0.43 0.32 0.02 0.11 0.01 0.22 TK/KK 0.38 0.30 0.01 0.13 0.09 0.42 P value 0.531 0.345 0.304 ABCG8 A632V AA 0.42 0.32 0.01 0.12 0.00 0.25 VV/VA 0.41 0.29 0.00 0.13 0.10 0.38 P value 0.935 0.588 0.199 ABCG5 Q604E QQ 0.44 0.30 0.01 0.10 0.01 0.34 QE/EE 0.36 0.34 0.01 0.16 0.09 0.18 P value 0.297 0.368 0.357 Values shown are means SD. Changes in all parameters were calculated as the difference between values at the end of the run-in period (weeks 3 and 4) and the experimental period (weeks 11 and 12). Login to comment

[hide] ATP-binding cassette transporter G8 M429V polymorp... Clin Sci (Lond). 2005 Aug;109(2):183-8. Miwa K, Inazu A, Kobayashi J, Higashikata T, Nohara A, Kawashiri M, Katsuda S, Takata M, Koizumi J, Mabuchi H
ATP-binding cassette transporter G8 M429V polymorphism as a novel genetic marker of higher cholesterol absorption in hypercholesterolaemic Japanese subjects.
Clin Sci (Lond). 2005 Aug;109(2):183-8., [PMID:15816807]

Abstract [show]
The ratio of serum plant sterols to cholesterol is positively correlated with the fractional cholesterol absorption, whereas serum precursors of cholesterol synthesis are positively correlated with cholesterol synthesis. Recently, two ABC (ATP-binding cassette) transporters, ABCG5 and ABCG8, have been described as playing an important role in the absorption and excretion of sterols. In the present study, we tested the hypothesis that genetic variation in ABCG5/ABCG8 influences the levels of serum plant sterol (sitosterol) and cholesterol precursor (lathosterol) in Japanese primary hypercholesterolaemic patients (n = 100). We identified a novel mutation [859T/C (C287R)] and a novel polymorphism [1285A/G (M429V)] at the ABCG5/ABCG8 loci, as well as four polymorphisms reported previously [1810C/G (Q604E), 161G/A (C54Y), 1199C/A (T400K) and 1895C/T (A632V)]. In carriers of the novel M429V variant, the serum level of sitosterol and the sitosterol/cholesterol ratio were significantly higher than those in non-carriers (3.64 compared with 2.56 microg/ml, and 1.45 microg/mg compared with 1.00 microg/mg respectively; P < 0.01 for both), and serum lathosterol tended to be lower (1.95 microg/ml compared with 3.03 microg/ml; P = 0.08), whereas no significant difference was observed in other lipid profiles. These four polymorphisms (1810C/G, 161G/A, 1199C/A and 1285A/G) generated six haplotypes, and the C/G/C/G haplotype was significantly associated with a higher sitosterol level and sitosterol/cholesterol ratio compared with the other five haplotypes (P < 0.05 for both). We conclude that, in 8% of patients with hypercholesterolaemia, the novel ABCG8 M429V variant was associated with higher cholesterol absorption efficiency. Future studies should investigate whether these findings have implications for the optimal cholesterol-lowering drug treatment in hypercholesterolaemic patients.

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3 We identified a novel mutation [859T/C (C287R)] and a novel polymorphism [1285A/G (M429V)] at the ABCG5/ABCG8 loci, as well as four polymorphisms reported previously [1810C/G (Q604E), 161G/A (C54Y), 1199C/A (T400K) and 1895C/T (A632V)]. Login to comment
14 Nucleotide Annealing Position Mutation change* Forward primer (5 → 3 ) Reverse primer (5 → 3 ) temperature (◦ C) Enzyme Size (bp) ABCG5 Exon 7 C287R 859T → C TCACACACTAACTACCTTCTGTTGTC ATGATGGGGAATGTGAAAGAAA 54 BstUI 191 Exon 13 Q604E 1810C → G ATCTAGATTCACAATGAACTTTCTA GTCCCTGCAAGTTGTAAGAG 53 XhoI 193 ABCG8 Exon 2 C54Y 161G → A GGAGGTCAGAGACCTCAAgT GCCCACCCTTTTATTTCCAC 56 RsaI 107 Exon 8 T400K 1199C → A ACACCTGTGTGGAAAGGTAAGGT GCGGGTTCAGTAATAAAATGACAG 57 MseI 216 Exon 9 M429V 1285A → G ATGCTGTTGCCTCAGCATCT AAGCTGTGTTCCTCTGAGCT 56 Tsp45I 306 Exon 13 A632V 1895C → T ATGTCTGTGTCTCCAGATCCTCAGgG TACAGGACCATGAAGCCACCGCTGAcGCC 63 HaeIII 105 sterols to cholesterol are known to be positively related to cholesterol absorption and negatively to cholesterol synthesis [1-4]. Login to comment
21 Indeed, it was previously proposed that common sequence variants in ABCG5 (Q604E) and ABCG8 (D19H and T400K) are associated with plasma plant sterol and lipid levels in normocholesterolaemic or mildly hypercholesterolaemic European-American populations [10-12]. Login to comment
48 Frequency distributions for the genotypes in exon 7 (C287R) and exon 13 (Q604E) of ABCG5, and in exon 2 (C54Y), exon 8 (T400K), exon 9 (M429V) and exon 13 (A632V) of ABCG8 are shown in Table 3. Login to comment
51 Parameters Value Age (years) 62.4 +- 12.1 Gender (men/women) 48/52 BMI (kg/m2 ) 23.0 +- 3.5 Total cholesterol (mg/dl) 261 +- 48 Triacylglycerol (mg/dl) 135 +- 69 HDL-C (mg/dl) 56 +- 16 LDL-C (mg/dl) 179 +- 48 Sitosterol (µg/ml) 2.63 +- 1.0 Lathosterol (µg/ml) 3.00 +- 1.3 Table 3 Genotype distribution and allele frequencies of the polymorphisms in the ABCG5/ABCG8 gene Gene Mutation Nucleotide change Polymorphism Allele frequency ABCG5 Exon 7 C287R 859T → C T 0.99 C 0.01 Exon 13 Q604E 1810C → G C 0.89 G 0.11 ABCG8 Exon 2 C54Y 161G → A G 0.82 A 0.18 Exon 8 T400K 1199C → A C 0.88 A 0.12 Exon 9 M429V 1285A → G A 0.96 G 0.04 Exon 13 A632V 1895C → T C 0.995 T 0.005 found and the A632V variant was rare in our Japanese subjects. Login to comment
57 Sitosterol Lathosterol Sitosterol/chol Polymorphism Genotype n (µg/ml) P value (µg/ml) P value (µg/mg) P value Lathosterol/chol (µg/mg) P value ABCG5 Exon 13 Q604E (1810C → G) QQ 78 2.63 +- 1.06 0.81 2.97 +- 1.36 0.73 1.03 +- 0.3 0.97 1.19 +- 0.55 0.84 QE 21 2.69 +- 0.72 3.09 +- 1.12 1.03 +- 0.40 1.16 +- 0.38 EE 1 1.2 3.2 0.6 1.57 ABCG8 Exon 2 C54Y (161G → A) CC 67 2.69 +- 0.98 0.19 2.82 +- 1.11 0.06 1.05 +- 0.36 0.06 1.12 +- 0.45 0.2 CY 30 2.57 +- 1.06 3.20 +- 1.33 1.02 +- 0.43 1.27 +- 0.57 YY 3 1.93 +- 0.31 4.23 +- 3.17 0.65 +- 0.12 1.38 +- 0.98 ABCG8 Exon 8 T400K (1199C → A) TT 76 2.64 +- 0.98 0.85 2.87 +- 1.10 0.14 1.03 +- 0.37 0.96 1.14 +- 0.45 0.17 TK 24 2.60 +- 1.07 3.34 +- 1.70 1.03 +- 0.44 1.31 +- 0.66 KK 0 ABCG8 Exon 9 M429V (1285A → G) MM 92 2.56 +- 0.94 0.003 3.03 +- 1.30 0.08 1.00 +- 0.36 0.002 1.19 +- 0.51 0.16 MV 8 3.64 +- 1.26 1.95 +- 0.53 1.45 +- 0.56 0.84 +- 0.36 VV 0 Table 5 Effect of the four polymorphism haplotypes in the ABCG5/ABCG8 gene on serum non-cholesterol levels Values are means +- S.D. The haplotype effects on serum non-cholesterol levels were assigned in all individuals using PHASE in 94 individuals. Login to comment
67 Of the 16 possible four-polymorphism haplotypes [1810C/G (Q604E), 161G/A (C54Y), 1199C/A (T400K) and 1285A/G (M429V)], six haplotypes were estimated to be present. Login to comment
75 This result does not appear to be consistent with previous reports that the sequence variants in ABCG5 (Q604E) and ABCG8 (D19H and T400K) are associated with lower serum plant sterol levels in Western countries [10-12]. Login to comment
76 The results of our present study suggest that the frequencies of D19H and A632V variants of ABCG8 are rarer in Japanese than in European-American populations, and that these Q604E and T400K variants may not be as important in the regulation of non-cholesterol sterol levels in Japanese populations. Login to comment

[hide] A detailed Hapmap of the Sitosterolemia locus span... BMC Med Genet. 2006 Feb 28;7:13. Pandit B, Ahn GS, Hazard SE, Gordon D, Patel SB
A detailed Hapmap of the Sitosterolemia locus spanning 69 kb; differences between Caucasians and African-Americans.
BMC Med Genet. 2006 Feb 28;7:13., [PMID:16507104]

Abstract [show]
BACKGROUND: Sitosterolemia is an autosomal recessive disorder that maps to the sitosterolemia locus, STSL, on human chromosome 2p21. Two genes, ABCG5 and ABCG8, comprise the STSL and mutations in either cause sitosterolemia. ABCG5 and ABCG8 are thought to have evolved by gene duplication event and are arranged in a head-to-head configuration. We report here a detailed characterization of the STSL in Caucasian and African-American cohorts. METHODS: Caucasian and African-American DNA samples were genotypes for polymorphisms at the STSL locus and haplotype structures determined for this locus RESULTS: In the Caucasian population, 13 variant single nucleotide polymorphisms (SNPs) were identified and resulting in 24 different haplotypes, compared to 11 SNPs in African-Americans resulting in 40 haplotypes. Three polymorphisms in ABCG8 were unique to the Caucasian population (E238L, INT10-50 and G575R), whereas one variant (A259V) was unique to the African-American population. Allele frequencies of SNPs varied also between these populations. CONCLUSION: We confirmed that despite their close proximity to each other, significantly more variations are present in ABCG8 compared to ABCG5. Pairwise D' values showed wide ranges of variation, indicating some of the SNPs were in strong linkage disequilibrium (LD) and some were not. LD was more prevalent in Caucasians than in African-Americans, as would be expected. These data will be useful in analyzing the proposed role of STSL in processes ranging from responsiveness to cholesterol-lowering drugs to selective sterol absorption.

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144 A number of studies have been implicated this locus in disease (or physiologi- Table 4: Results of pair-wise LD analyses Population M1 M2 ChiSq Pval ∆2 D' Caucasian INT1-21 INT1-7 20.01 1E-05 0.545 0.866 5'UTR-19 INT1-7 9.61 0.002 0.256 0.594 Q604E INT1-7 7.14 0.008 0.239 0.489 T400K A632V 6.13 0.013 0.125 1.000 5'UTR-19 T400K 5.84 0.016 0.153 1.000 Q604E D19H 5.02 0.025 0.174 1.000 INT1-7 T400K 4.94 0.026 0.111 1.000 R50C D19H 4.79 0.029 0.234 0.484 INT1-21 T400K 4.45 0.035 0.153 1.000 E238L INT10-50 4.42 0.036 0.238 1.000 INT1-7 C54Y 4.41 0.036 0.138 0.739 5'UTR-19 C54Y 4.24 0.040 0.134 0.619 T400K INT10-50 3.92 0.048 0.040 1.000 5'UTR-19 A565A 3.86 0.049 0.127 1.000 Q604E INT1-21 3.66 0.056 0.128 0.420 INT10-50 A632V 3.29 0.070 0.132 0.641 5'UTR-19 INT1-21 2.86 0.091 0.071 0.267 C54Y T400K 2.74 0.098 0.082 0.433 African-American 5'UTR-19 T400K 11.01 9E-04 0.080 1.000 INT1-7 A565A 8.09 0.004 0.085 0.587 R50C D19H 6.96 0.008 0.205 1.000 T400K A565A 6.56 0.010 0.088 0.557 Q604E INT1-21 5.82 0.016 0.119 0.505 5'UTR-19 A565A 5.10 0.024 0.059 0.460 C54Y A565A 3.93 0.047 0.053 0.270 5'UTR-19 C54Y 3.49 0.062 0.047 0.481 R50C INT1-7 3.05 0.081 0.044 1.000 INT1-7 A632V 3.05 0.081 0.044 1.000 Q604E D19H 3.01 0.083 0.038 1.000 M1 = 1st marker in pair of SNPs, M2 = 2nd marker in pair of SNPs, ChiSq = Value of chi-square test of association, Pval = Two-sided P-value corresponding to chi-square value in ChiSq column assuming 1 degree of freedom. Login to comment
177 SNP Allele Number of Disease Chromosomes* Number of Healthy Chromosomes* Frequency (disease chromosome) Frequency (healthy chromosome) Recombination Fraction Age Estimate (generations) R50C C 12 12 1 1 NA Q604E G 2 1 0.167 0.083 0.058833 17.7 5'UTR-19 T 11 10 0.917 0.833 0.033059 9.1 D19H G 12 12 1 1 NA NA INT1-21 C 12 7 1 0.583 0.005 0 INT1-7 C 11 11 0.917 0.917 NA C54Y A 9 5 0.75 0.417 0.02749 8.8 E238L G 12 12 1 1 NA T400K A 10 3 0.833 0.25 0.0002 2387 INT10-50 T 12 12 1 1 NA A565A C 12 12 1 1 NA G575R G 12 12 1 1 NA A632V C 11 10 0.917 0.833 0.005692 52.9 *Out of a total of 12 disease and 12 normal chromosomes, see Methods and ABCG8 are proposed to function as obligate heterodimers [54], and complete mutations in either gene seems to result in an identical phenotype [8], these genetic findings posit an enigma. Login to comment
124 Of the non-synonymous cSNPs, T400K of ABCG8 was found to be oldest polymorphism that arose GOLD plot of pair-wise ∆2 values for SNPs in CEPH and Yoruba Africans genotyped by the HapMap ConsortiumFigure 3 GOLD plot of pair-wise ∆2 values for SNPs in CEPH and Yoruba Africans genotyped by the HapMap Consortium. Login to comment

[hide] Plasma concentrations of plant sterols: physiology... Nutr Rev. 2006 Sep;64(9):385-402. Chan YM, Varady KA, Lin Y, Trautwein E, Mensink RP, Plat J, Jones PJ
Plasma concentrations of plant sterols: physiology and relationship with coronary heart disease.
Nutr Rev. 2006 Sep;64(9):385-402., [PMID:17002235]

Abstract [show]
Recently, it has been questioned whether elevated levels of circulating plant sterols increase the risk of coronary heart disease (CHD). To date, no definitive conclusions regarding such a relationship have been reached, nor have there been any studies summarizing the factors that contribute to the observed elevations in plant sterol concentrations in plasma. Thus, the purpose of this review is to systematically compare the plant sterol levels of subjects from the general population and to describe factors that contribute to the variations observed. The question of whether elevated plasma concentrations of plant sterols are associated with an increased risk of CHD was also assessed. Results indicate that the key factors accounting for variations in circulating plant sterol concentrations include: apolipoprotein E phenotypes, ATP-binding cassette transporter polymorphisms, use of statin drugs, presence of metabolic syndrome, dietary intake of plant sterols, gender, and analytical techniques used in the measurement of plant sterols in the plasma. An analysis of the studies examining the relationship between circulating levels of plant sterols and CHD risk in non-sitosterolemic populations revealed no clear associations. Furthermore, it was shown that the above-mentioned factors play an important role in determining the levels of plant sterols in plasma. Since these factors may act as potential confounders, they must be controlled for before more solid conclusions can be reached.

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71 Aside from the rare mutation of a homozygous form resulting in sitosterolemia, several common sequence variations have been described.71 Different studies have shown independently that the cross-sectional plant sterol-to-cholesterol ratio is associated with different ABCG5 and ABCG8 polymorphisms.10,27,72 Out of the five polymorphisms analyzed in relation to concentrations of plant sterols, D19H, Y54C, T400K, A632V, and Q604E, the polymorphisms D19H in exon 1 and T400K in exon 8 of ABCG8 show the most pronounced association. Login to comment
72 Carriers of the H allele of the D19H polymorphism in ABCG8 were found to have a lower plasma campesterol-to-cholesterol ratio10,27 and sitosterol-to-cholesterol ratio,10 suggesting a higher activity of this variant. Login to comment
73 A similar finding was observed for the K allele of the T400K polymorphism in exon 8 of ABCG8.27,72 Interestingly, no consistent cross-sectional associations between plasma cholesterol concentrations and any of these ABCG5 or ABCG8 polymorphisms have been described so far.10,27,72,73 In addition to these cross-sectional associations, genetic variations in these ABC transporters may also predict which subjects are prone to develop elevated plant sterol concentrations. Login to comment
74 In this respect, carriers of the T allele of the T400K polymorphism showed a larger reduction in both the campesterol-to-cholesterol and the sitosterol-to-cholesterol ratios during interventions known to lower plasma plant sterols.72 Although not evaluated, it can be speculated that these subjects would also show larger elevations in circulating plant sterol levels as a result of consuming plant sterol-enriched functional foods18,70 or undergoing treatment with statins74 Table1. Login to comment
75 In this respect, carriers of the T allele of the T400K polymorphism showed a larger reduction in both the campesterol-to-cholesterol and the sitosterol-to-cholesterol ratios during interventions known to lower plasma plant sterols.72 Although not evaluated, it can be speculated that these subjects would also show larger elevations in circulating plant sterol levels as a result of consuming plant sterol-enriched functional foods18,70 or undergoing treatment with statins74 Table 1. Login to comment

[hide] Single nucleotide polymorphisms in ABCG5 and ABCG8... J Lipid Res. 2007 Dec;48(12):2607-13. Epub 2007 Sep 7. Santosa S, Demonty I, Lichtenstein AH, Ordovas JM, Jones PJ
Single nucleotide polymorphisms in ABCG5 and ABCG8 are associated with changes in cholesterol metabolism during weight loss.
J Lipid Res. 2007 Dec;48(12):2607-13. Epub 2007 Sep 7., [PMID:17827468]

Abstract [show]
The purpose of this study was to examine whether changes in cholesterol metabolism after weight loss were affected by single nucleotide polymorphisms (SNPs) in ABCG5 and ABCG8 genes. Thirty-five hypercholesterolemic women lost 11.7 +/- 2.5 kg (P < 0.001). Cholesterol kinetics were assessed using stable isotope techniques. TaqMan PCR was used to detect SNPs in ABCG5/G8. Homozygous Q604E variants in ABCG5 had larger (P < 0.05) reductions in cholesterol absorption and greater increases (P < 0.05) in synthesis in contrast to heterozygous and homozygous wild-type carriers. Heterozygous C54Y carriers had smaller declines (P = 0.047) in synthesis compared with homozygous variant individuals. The presence of at least one Y54 variant was associated with higher (P = 0.042) post-weight-loss synthesis compared with carriers of the C54 genotype. The direction of the results is consistent with cross-sectional studies on the effects of Q604E and C54Y polymorphisms on plasma cholesterol. SNPs in ABCG5/G8 were found to be associated with the response of cholesterol metabolism to weight loss. The evidence for associations between SNPs in ABCG5/G8 and various parameters of cholesterol metabolism indicates the potential effectiveness of establishing genetic screening tools to determine optimal lipid-lowering treatment routes for individuals during weight reduction.

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32 More specifically, these SNPs include Q604E (RS6720173), I18427 (RS4148189), I7892 (RS4131229), and M216 (RS3806471) in ABCG5 and C54Y (RS4148211), D19H (RS11887534), T400K (RS4148217), and I14222 (RS6709904) in ABCG8 (11, 13, 16, 17). Login to comment
82 SNPs Q604E, I18429, I7892, and M216 in ABCG5 and C54Y, D19H, I14222, and T400K in ABCG8 were determined using PCR-based TaqMan allele discrimination assays (Applied Biosystems, Foster City, CA) (29). Login to comment
132 Individual subject genotypes for each SNP in ABCG5 and ABCG8 ABCG5 ABCG8 Q604E I18429 I7892 M216 C54Y D19H I14222 T400K 11 11 12 12 12 11 11 11 11 11 11 11 11 11 11 12 12 12 11 11 11 12 12 12 11 11 12 12 12 11 11 12 11 11 22 22 22 11 11 11 11 11 22 12 12 11 12 11 12 12 11 11 11 11 11 12 11 11 11 11 11 11 11 22 22 12 11 11 11 12 12 11 11 11 12 12 12 12 12 12 11 11 22 22 22 11 11 11 12 12 12 12 22 11 11 11 12 12 11 11 11 12 12 12 11 11 11 11 12 11 11 11 12 12 11 11 11 12 12 11 22 12 11 11 11 12 12 11 11 11 12 12 12 11 11 11 11 11 12 11 11 12 12 11 11 11 12 12 22 11 11 11 12 12 11 11 11 11 11 12 12 11 11 11 11 11 11 12 12 12 22 22 12 11 11 12 11 12 11 11 11 11 11 22 11 11 22 22 22 11 11 11 11 11 12 12 12 11 11 11 12 12 12 11 11 12 12 11 22 12 12 11 11 11 12 11 12 11 12 12 12 11 11 12 11 11 22 22 22 11 11 11 12 11 22 22 22 11 11 11 11 11 11 11 12 11 11 11 11 11 12 22 12 11 11 11 12 11 11 11 11 12 11 11 11 11 11 11 11 11 11 11 12 12 12 12 12 11 11 12 SNP, single nucleotide polymorphism. Login to comment
138 The Q604E SNP is located on exon 13 of the ABCG5 gene and is encoded on a loop that faces the luminal or cell surface (16). Login to comment
150 Cholesterol metabolism and change according to exon SNPs in ABCG5 and ABCG8 Cholesterol Biosynthesis Cholesterol Absorption Cholesterol Turnover SNP Initial Final Change Initial Final Change Initial Final Change %/day %/day %/day % % % % % % Q604E QQ 8.48 6 6.76 6.16 6 5.66 22.32 6 8.86 59.7 6 18.5a 65.7 6 13.7 5.94 6 18.3c 39.1 6 5.99 36.5 6 8.14 22.45 6 9.76 QE 13.9 6 9.05 6.48 6 3.95 27.39 6 9.36a 57.2 6 11.8b 64.5 6 18.0 7.33 6 15.6d 37.5 6 9.27 39.5 6 6.31 1.93 6 8.59 EE 7.91 6 4.91 9.60 6 5.09 1.69 6 10.0a 86.5 6 13.3a,b 55.7 6 13.5 230.8 6 1.90c,d 40.8 6 3.72 45.3 6 8.63 4.47 6 12.1 QE 1 EE 12.8 6 8.63 7.07 6 4.18 25.69 6 9.84 62.6 6 16.6 62.8 6 17.2 0.18 6 20.7 38.2 6 8.44 40.6 6 6.86 2.43 6 8.94 C54Y CC 9.96 6 8.83 5.18 6 4.88a 24.78 6 9.62 64.9 6 15.4 67.5 6 16.4 2.67 6 22.0 37.0 6 8.43 38.1 6 7.68 1.13 6 10.6 CY 8.95 6 5.34 8.79 6 5.35 20.17 6 7.60a 54.2 6 13.5 65.4 6 12.2 11.2 6 12.9 38.3 6 5.00 40.1 6 8.42 1.77 6 8.67 YY 14.1 6 9.07 5.99 6 3.74 28.09 6 10.3a 64.1 6 25.6 55.3 6 15.6 28.80 6 17.9 43.3 6 6.57 36.2 6 7.00 27.03 6 6.42 CY 1 YY 10.8 6 7.16 7.76 6 4.90a 23.08 6 9.28 57.9 6 18.8 61.7 6 14.0 3.85 6 17.5 40.0 6 5.87 38.8 6 8.00 21.17 6 8.89 D19H DD 10.1 6 6.68 6.54 6 5.28 23.55 6 8.28 58.8 6 15.9 61.8 6 13.3 3.00 6 17.2 39.1 6 6.00 38.2 6 7.59 20.70 6 8.41 DH 11.4 6 11.0 6.68 6 4.35 24.76 6 12.4 67.5 6 21.2 71.7 6 18.8 4.19 6 25.9 37.5 6 10.2 39.1 6 8.57 1.45 6 12.3 T400K TT 10.4 6 8.91 6.91 6 5.51 23.53 6 10.9 64.4 6 19.4 63.6 6 17.2 20.76 6 20.2 40.4 6 5.15 38.9 6 7.39 21.61 6 9.46 TK 1 KK 10.4 6 5.99 6.01 6 4.12 24.42 6 6.29 55.4 6 12.2 65.6 6 11.6 10.2 6 16.5 35.8 6 9.10 37.7 6 8.52 2.24 6 9.64 a,b Significant difference between groups (P , 0.05). Login to comment
153 Genotype distribution and frequency of SNPs in introns and exons of ABCG5 and ABCG8 in the studied population Homozygous Wild Type Heterozygous Homozygous Variant SNP n Age BMI n Age BMI n Age BMI % years kg/m2 % years kg/m2 % years kg/m2 ABCG5 Q604E 19 (54.3) 48.6 6 6.56 31.0 6 2.92 13 (37.1) 50.2 6 7.24 32.0 6 2.79 3 (8.6) 51.0 6 6.56 30.6 6 2.45 I18429 22 (62.9) 49.1 6 6.91 31.2 6 2.81 13 (37.1) 49.9 6 6.51 31.7 6 2.91 0 (0) I7892 15 (42.9) 50.1 6 7.09 30.6 6 2.55 13 (37.1) 46.9 6 6.59 32.1 6 3.02 7 (20.0) 52.3 6 4.96 31.5 6 2.98 M216 18 (51.4) 50.3 6 6.89 30.6 6 2.33a 10 (28.6) 45.0 6 5.19b 33.2 6 2.99a 7 (20.0) 53.1 6 5.21b 30.6 6 2.85 ABCG8 C54Y 16 (45.7) 50.4 6 7.10 30.8 6 2.42 12 (34.3) 46.9 6 6.33 31.5 6 2.28 7 (20.0) 51.3 6 5.88 32.5 6 4.26 D19H 26 (74.3) 48.9 6 7.06 31.7 6 3.00 9 (25.7) 50.8 6 5.89 30.3 6 2.01 0 (0) I14222 25 (71.4) 48.6 6 7.16 31.5 6 3.06 10 (28.6) 51.2 6 5.18 31.0 6 2.17 0 (0) T400K 22 (62.9) 50.6 6 5.67 31.2 6 3.03 11 (31.4) 46.6 6 8.43 31.9 6 2.40 2 (5.7) 50.5 6 3.54 31.0 6 3.82 BMI, body mass index. Login to comment
96 A Mann-Whitney U test was used to determine whether differences existed among the I18429 genotypes in final synthesis, initial turnover, and change in turnover, among the I1422 genotypes in final synthesis, final turnover, and change in turnover, and among the T400K genotypes in final synthesis. Login to comment
139 Nonsynonymous SNPs on ABCG8, specifically, D19H, C54Y, and T400K, are located on exons 1, 2, and 8, respectively (33). Login to comment
97 A Mann-Whitney U test was used to determine whether differences existed among the I18429 genotypes in final synthesis, initial turnover, and change in turnover, among the I1422 genotypes in final synthesis, final turnover, and change in turnover, and among the T400K genotypes in final synthesis. Login to comment
131 Individual subject genotypes for each SNP in ABCG5 and ABCG8 ABCG5 ABCG8 Q604E I18429 I7892 M216 C54Y D19H I14222 T400K 11 11 12 12 12 11 11 11 11 11 11 11 11 11 11 12 12 12 11 11 11 12 12 12 11 11 12 12 12 11 11 12 11 11 22 22 22 11 11 11 11 11 22 12 12 11 12 11 12 12 11 11 11 11 11 12 11 11 11 11 11 11 11 22 22 12 11 11 11 12 12 11 11 11 12 12 12 12 12 12 11 11 22 22 22 11 11 11 12 12 12 12 22 11 11 11 12 12 11 11 11 12 12 12 11 11 11 11 12 11 11 11 12 12 11 11 11 12 12 11 22 12 11 11 11 12 12 11 11 11 12 12 12 11 11 11 11 11 12 11 11 12 12 11 11 11 12 12 22 11 11 11 12 12 11 11 11 11 11 12 12 11 11 11 11 11 11 12 12 12 22 22 12 11 11 12 11 12 11 11 11 11 11 22 11 11 22 22 22 11 11 11 11 11 12 12 12 11 11 11 12 12 12 11 11 12 12 11 22 12 12 11 11 11 12 11 12 11 12 12 12 11 11 12 11 11 22 22 22 11 11 11 12 11 22 22 22 11 11 11 11 11 11 11 12 11 11 11 11 11 12 22 12 11 11 11 12 11 11 11 11 12 11 11 11 11 11 11 11 11 11 11 12 12 12 12 12 11 11 12 SNP, single nucleotide polymorphism. Login to comment
149 Cholesterol metabolism and change according to exon SNPs in ABCG5 and ABCG8 Cholesterol Biosynthesis Cholesterol Absorption Cholesterol Turnover SNP Initial Final Change Initial Final Change Initial Final Change %/day %/day %/day % % % % % % Q604E QQ 8.48 6 6.76 6.16 6 5.66 22.32 6 8.86 59.7 6 18.5a 65.7 6 13.7 5.94 6 18.3c 39.1 6 5.99 36.5 6 8.14 22.45 6 9.76 QE 13.9 6 9.05 6.48 6 3.95 27.39 6 9.36a 57.2 6 11.8b 64.5 6 18.0 7.33 6 15.6d 37.5 6 9.27 39.5 6 6.31 1.93 6 8.59 EE 7.91 6 4.91 9.60 6 5.09 1.69 6 10.0a 86.5 6 13.3a,b 55.7 6 13.5 230.8 6 1.90c,d 40.8 6 3.72 45.3 6 8.63 4.47 6 12.1 QE 1 EE 12.8 6 8.63 7.07 6 4.18 25.69 6 9.84 62.6 6 16.6 62.8 6 17.2 0.18 6 20.7 38.2 6 8.44 40.6 6 6.86 2.43 6 8.94 C54Y CC 9.96 6 8.83 5.18 6 4.88a 24.78 6 9.62 64.9 6 15.4 67.5 6 16.4 2.67 6 22.0 37.0 6 8.43 38.1 6 7.68 1.13 6 10.6 CY 8.95 6 5.34 8.79 6 5.35 20.17 6 7.60a 54.2 6 13.5 65.4 6 12.2 11.2 6 12.9 38.3 6 5.00 40.1 6 8.42 1.77 6 8.67 YY 14.1 6 9.07 5.99 6 3.74 28.09 6 10.3a 64.1 6 25.6 55.3 6 15.6 28.80 6 17.9 43.3 6 6.57 36.2 6 7.00 27.03 6 6.42 CY 1 YY 10.8 6 7.16 7.76 6 4.90a 23.08 6 9.28 57.9 6 18.8 61.7 6 14.0 3.85 6 17.5 40.0 6 5.87 38.8 6 8.00 21.17 6 8.89 D19H DD 10.1 6 6.68 6.54 6 5.28 23.55 6 8.28 58.8 6 15.9 61.8 6 13.3 3.00 6 17.2 39.1 6 6.00 38.2 6 7.59 20.70 6 8.41 DH 11.4 6 11.0 6.68 6 4.35 24.76 6 12.4 67.5 6 21.2 71.7 6 18.8 4.19 6 25.9 37.5 6 10.2 39.1 6 8.57 1.45 6 12.3 T400K TT 10.4 6 8.91 6.91 6 5.51 23.53 6 10.9 64.4 6 19.4 63.6 6 17.2 20.76 6 20.2 40.4 6 5.15 38.9 6 7.39 21.61 6 9.46 TK 1 KK 10.4 6 5.99 6.01 6 4.12 24.42 6 6.29 55.4 6 12.2 65.6 6 11.6 10.2 6 16.5 35.8 6 9.10 37.7 6 8.52 2.24 6 9.64 a,b Significant difference between groups (P , 0.05). Login to comment
152 Genotype distribution and frequency of SNPs in introns and exons of ABCG5 and ABCG8 in the studied population Homozygous Wild Type Heterozygous Homozygous Variant SNP n Age BMI n Age BMI n Age BMI % years kg/m2 % years kg/m2 % years kg/m2 ABCG5 Q604E 19 (54.3) 48.6 6 6.56 31.0 6 2.92 13 (37.1) 50.2 6 7.24 32.0 6 2.79 3 (8.6) 51.0 6 6.56 30.6 6 2.45 I18429 22 (62.9) 49.1 6 6.91 31.2 6 2.81 13 (37.1) 49.9 6 6.51 31.7 6 2.91 0 (0) I7892 15 (42.9) 50.1 6 7.09 30.6 6 2.55 13 (37.1) 46.9 6 6.59 32.1 6 3.02 7 (20.0) 52.3 6 4.96 31.5 6 2.98 M216 18 (51.4) 50.3 6 6.89 30.6 6 2.33a 10 (28.6) 45.0 6 5.19b 33.2 6 2.99a 7 (20.0) 53.1 6 5.21b 30.6 6 2.85 ABCG8 C54Y 16 (45.7) 50.4 6 7.10 30.8 6 2.42 12 (34.3) 46.9 6 6.33 31.5 6 2.28 7 (20.0) 51.3 6 5.88 32.5 6 4.26 D19H 26 (74.3) 48.9 6 7.06 31.7 6 3.00 9 (25.7) 50.8 6 5.89 30.3 6 2.01 0 (0) I14222 25 (71.4) 48.6 6 7.16 31.5 6 3.06 10 (28.6) 51.2 6 5.18 31.0 6 2.17 0 (0) T400K 22 (62.9) 50.6 6 5.67 31.2 6 3.03 11 (31.4) 46.6 6 8.43 31.9 6 2.40 2 (5.7) 50.5 6 3.54 31.0 6 3.82 BMI, body mass index. Login to comment

[hide] Significant association of ABCG5 604Q and ABCG8 D1... Br J Surg. 2008 Aug;95(8):1005-11. Kuo KK, Shin SJ, Chen ZC, Yang YH, Yang JF, Hsiao PJ
Significant association of ABCG5 604Q and ABCG8 D19H polymorphisms with gallstone disease.
Br J Surg. 2008 Aug;95(8):1005-11., [PMID:18457353]

Abstract [show]
BACKGROUND: Adenosine triphosphate-binding cassette (ABC) transporters ABCG5 and ABCG8 are sterol export pumps regulating biliary cholesterol excretion. The formation of gallstones, supersaturated with cholesterol in bile, is determined by genetic and environmental factors. The interaction of susceptible gene polymorphisms with age, sex and body mass index in gallstone disease is unclear. METHODS: In a cross-sectional study, 979 subjects (880 men and 99 women, mean(s.d.) age 47.7(10.4) years) were recruited from a hospital-based population. Of these, 74 were diagnosed with gallstone disease by abdominal ultrasonography. Five non-synonymous polymorphisms, E604Q (ABCG5), D19H, C54Y, T400K and A632V (ABCG8), were analysed using the TaqMan genotyping assay. RESULTS: The serum total cholesterol and both low- and high-density lipoprotein cholesterol levels were significantly lower in subjects with gallstones than in those without. 604Q (CC) and D19H (GC) genotypes were significantly associated with gallstone disease, even when adjusted for age, sex and body mass index. The genetic risk of developing gallstone disease was further stratified by age. The risk was greatly increased in subjects younger than 50 years with the D19H genotype and those of 50 years or more with the 604Q genotype. CONCLUSION: Carriers of ABCG5 604Q or ABCG8 D19H polymorphisms have an increased risk of gallstone disease independent of age, sex and body mass index.

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5 Five non-synonymous polymorphisms, E604Q (ABCG5), D19H, C54Y, T400K and A632V (ABCG8), were analysed using the TaqMan genotyping assay. Login to comment
26 In previous studies, five non-synonymous polymorphisms in ABCG5 (E604Q) and ABCG8 (C54Y, D19H, T400K, A632V) have been linked to cholesterol homeostasis, especially in cholesterol absorption efficiency and cholesterol saturation of bile. Login to comment
44 Relevant non-synonymous polymorphisms of ABCG5 (E604Q) and ABCG8 (C54Y, D19H, T400K, A632V) associated with biliary cholesterol secretion were chosen for this study. Login to comment
46 The specific primers were designed using Primer 3 software according to SNP reference of GenBank mapping in the National Center for Biotechnology Information database (rs6720173 for E604Q, rs11887534 for D19H, rs4148211 for C54Y, rs4148217 for T400K, rs6544718 for A632V). Login to comment
67 Table 2 shows allele frequencies of the five nonsynonymous polymorphisms (ABCG5: E604Q; ABCG8: D19H, C54Y, T400K, A632V). Login to comment
83 *Two-sample Student`s t test, except †Pearson χ2 test. Table 2 Allele frequencies of the polymorphisms in ABCG5 and ABCG8 genes in 979 subjects Gene Allele NCBI SNP reference Ratio Frequency (%) ABCG5: E604Q G1810C rs 6720173 G : C 89·5 : 10·5 ABCG8: D19H G55C rs 11887534 G : C 98·6 : 1·4 ABCG8: C54Y G161A rs 4148211 G : A 90·3 : 9·7 ABCG8: T400K C1199A rs 4148217 C : A 92·0 : 8·0 ABCG8: A632V T1895C rs 6544718 T : C 0 : 100 NCBI, National Center for Biotechnology Information; SNP, single nucleotide polymorphism. Login to comment
84 Table 3 Association of genotype frequency of ABCG5 and ABCG8 with gallstone development No stones (n = 905) Gallstones (n = 74) P* Power (%) ABCG5: E604Q (G1810C) Genotype GG 691 (79·2) 52 (74) 0·011 18 GC 175 (20·1) 15 (21) CC 6 (0·7) 3 (4) ABCG8: D19H (G55C) Genotype GG 851 (97·9) 66 (92) 0·001 79 GC 18 (2·1) 6 (8) ABCG8: C54Y (G161A) Genotype GG 747 (82·5) 54 (73) 0·041 53 GA 152 (16·8) 18 (24) AA 6 (0·7) 2 (3) ABCG8: T400K (C1199A) Genotype CC 739 (84·5) 58 (79) 0·463 22 CA 134 (15·3) 15 (21) AA 2 (0·2) 0 (0) Values in parentheses are percentages. Login to comment

[hide] Polymorphisms in ABCG5/G8 transporters linked to h... Nutr Rev. 2008 Jun;66(6):343-8. Rudkowska I, Jones PJ
Polymorphisms in ABCG5/G8 transporters linked to hypercholesterolemia and gallstone disease.
Nutr Rev. 2008 Jun;66(6):343-8., [PMID:18522623]

Abstract [show]
ATP-binding cassette (ABC) transporters function in the homeostasis of lipids. Dysfunction of ABC transporters is frequently associated with disease. This review examines links between polymorphisms of ABC G5 (ABCG5) and G8 (ABCG8) transporter genes to hypercholesterolemia and to gallstone disease risk. Various polymorphisms (A632V, T400K, D19H, M429V, and C54Y) in the ABCG8 and ABCG5 (Q604E) gene have been found to be associated with several facets of cholesterol metabolism, including baseline cholesterol level, cholesterol kinetics, individual responsiveness of plasma cholesterol to dietary and pharmaceutical interventions for hypercholesterolemia, and increased risk of gallstones. Clearly, the ABCG5 and ABCG8 genes play an important role in cholesterol homeostasis. However, more research is needed to establish how specific polymorphisms of these genes confer to higher risk of these diseases.

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3 Various polymorphisms (A632V, T400K, D19H, M429V, and C54Y) in the ABCG8 and ABCG5 (Q604E) gene have been found to be associated with several facets of cholesterol metabolism, including baseline cholesterol level, cholesterol kinetics, individual responsiveness of plasma cholesterol to dietary and pharmaceutical interventions for hypercholesterolemia, and increased risk of gallstones. Login to comment
27 In addition, these investigators also observed that carriers of the T400K and A632V polymorphisms in the ABCG8 gene exhibited higher cholesterol synthesis and higher plasma TC, respectively.8 Gylling et al.9 failed to show an association between cholesterol kinetics and T400K and A632V polymorphisms in the ABCG8 gene, but found that carriers of the mutant Q604E allele of the ABCG5 gene had high cholesterol absorption and thus had higher characteristics of the insulin resistance syndrome. Login to comment
29 ROLE OF RACE-RELATED DIFFERENCES IN ABC GENOTYPES Miwa et al.,15 studying a Japanese population, concluded that carriers of a novel ABCG8 M429V allele or a specific haplotype (wild-type allele of Q604E ABCG5, and wild-type allele of C54Y, wild-type allele of T400K, mutant allele of M429V in the ABCG8 gene), were associated with higher cholesterol absorption efficiency, as well as lower cholesterol synthesis rates. Login to comment
30 These findings in the Japanese group are not without exception; no difference was observed in lipid profiles in relation to common polymorphisms studied previously [ABCG8 (A632V, T400K, D19H, and C54Y) and ABCG5 (Q604E)],6,7,11,12 which might be explained by the fact that carriers of ABCG8 D19H and A632A polymorphisms are rare in the Japanese population compared to Western populations. Login to comment
31 Also, polymorphisms of Q604E and T400K alleles may not be as important in the regulation of non-cholesterol-sterol levels in the Japanese population.15 In a more recent trial, no detection of this SNP (ABCG8 M429V allele) was recorded in either the Caucasian or the African-American population studied, thereby potentially demonstrating a race-specific polymorphism.16 In general, these studies demonstrate the benefits of using an intermediate phenotype, such as cholesterol absorption and synthesis, to determine the link between SNPs and blood lipids in relation to a dietary treatment. Login to comment
38 Other ABCG5 and G8 polymorphisms (Q604E, C54Y, T400K, and A632V) and CYP7A1 in hypercholesterolemic patients had no apparent association with responsiveness to statin treatment. Login to comment
51 On the other hand, Wang et al.24 investigated a possible association between three polymorphisms, including C54Y, T400K alleles of ABCG8, and Q604E of ABCG5 gene, and gallstone formation in a Chinese population. Login to comment
61 Overall, these studies identify a variety of polymorphisms in ABCG8 (A632V, T400K, D19H, and C54Y) and in ABCG5 (Q604E) that have been linked with baseline cholesterol levels, cholesterol absorption, or responsiveness to dietary intervention.3-12,15-17 In addition, genetic variations in the ABCG8 gene (D19H and T400K) may increase the risk of gallstone disease in certain populations.22-24 Table 1 summarizes potential SNPs and the effects of the mutant allele on baseline blood lipid concentrations, cholesterol kinetics, responsiveness to interventions, and gallstone disease risk. Login to comment
22 Yet, when a subanalysis of male participants was performed, the ABCG8 T400K wild-type allele carriers exhibited a greater decrease in plasma TC and LDL-C than mutant allele carriers.12 This same study also demonstrated that subjects with the ABCG8 C54Y Tyr54 genotype had greater plasma TC and LDL-C reduction than theABCG8 C54Y Cys54 genotype, but only in female subjects.12 Therefore, the investigators concluded that ABCG8 T400K and ABCG5 C54Y genotypes influence plasma TC in a gender-specific manner following dietary intervention.12 Overall, the various studies reviewed above suggest that different ABC transporter gene polymorphisms influence plasma lipids in relation to dietary treatment; however, no single, common,ABC transporter gene polymorphism has been identified across existing studies. Login to comment
39 ABC GENE POLYMORPHISMS AND PLANT STEROL ABSORPTION Plat et al.17 found that cholesterol-standardized serum campesterol and sitosterol concentrations, as well as changes in serum campesterol and sitosterol concentrations after plant stanol consumption, were associated with the ABCG8 T400K genotype. Login to comment
40 Reductions in serum campesterol and sitosterol levels in subjects with a mutated allele of ABCG8 T400K were greater compared with reductions in subjects with the wild-type allele.17 These investigators hypothesized that their findings indicate the functionality of the ABCG5 and G8 heterodimer is reduced in the wild-type allele, resulting in decreased transport of plant sterols from enterocytes back into the gut lumen, or from hepatocytes into bile, thereby increasing serum concentrations of plant sterols.17 Given that the wild-type ABCG8 T400K allele is present in about 70% of the population,17 it should be relatively straightforward to verify these findings in future plant sterol/stanol studies. Login to comment
53 Wang et al.24 found that only male carriers of the mutant allele of ABCG8 T400K had an elevated risk for gallstone disease compared to males with the common genotype. Login to comment
55 Overall, these studies on ABC gene polymorphisms and gallstone disease associations demonstrate that the mutant allele of D19H and T400K of ABCG8 might help to predict gallstone disease risk within a given individual. Login to comment

[hide] Significant association of ABCG8:D19H gene polymor... J Hum Genet. 2008;53(8):757-63. Epub 2008 Jun 26. Chen ZC, Shin SJ, Kuo KK, Lin KD, Yu ML, Hsiao PJ
Significant association of ABCG8:D19H gene polymorphism with hypercholesterolemia and insulin resistance.
J Hum Genet. 2008;53(8):757-63. Epub 2008 Jun 26., [PMID:18581044]

Abstract [show]
The absorption efficiency of cholesterol is closely correlated to dietary phytosterol content and determined by genetic factors. The ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 act as a sterol efflux pump to regulate the absorption of cholesterol and phytosterol. The levels of cholesterol and phytosterol associated with a Chinese diet are very different from those associated with a Western diet. This study aims to explore the association between serum total cholesterol/LDL-C levels and ABCG5/ABCG8 polymorphisms in a Taiwanese population consuming an ordinary Chinese diet. A total of 1,046 subjects (894 men and 152 women) were recruited in a hospital-based health check-up center in Kaohsiung Medical University Hospital. Five nonsynonymous polymorphisms of Q604E (ABCG5), D19H, C54Y, T400 K and A632 V (ABCG8) were analyzed by TaqMan genotyping assay. Analysis showed that the D19H polymorphism of the ABCG8 gene was significantly associated with serum total cholesterol, LDL-C levels and HOMA-IR index. Adjusting for sex and age, subjects with the D19H (GC) genotype were significantly associated with a threefold higher risk of high cholesterol and LDL-C levels than subjects with D19 (GG). These results suggest that the D19H polymorphism of ABCG8 could be considered a susceptible gene marker indicating an increased likelihood of developing high cholesterol and LDL-C levels in Taiwanese consuming an ordinary Chinese diet. It is supposed that the coexistence of higher insulin resistance and hypercholesterolemia for carriers of the D19H polymorphism may result in a greater risk of cardiovascular disease.

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42 Five nonsynonymous polymorphisms, including Q604E (rs6720173) of the ABCG5 gene and D19H (rs11887534), C54Y (rs4148211), T400K (rs4148217) and A632V (rs6544718) of the ABCG8 gene, were chosen for genotyping (http://www.ncbi.nlm.nih.gov/). Login to comment
62 Five nonsynonymous polymorphisms (ABCG5: Q604E; ABCG8:D19H, C54Y, T400K, A632V) were genotyped in our population. Login to comment
64 The minor allele frequencies (MAFs) of Q604E (C:G); D19H (G:C), C54Y (G:A) and T400K (C:A) were 10.5, 1.4, 9.7 and 8.0%, respectively. Login to comment
43 Five nonsynonymous polymorphisms, including Q604E (rs6720173) of the ABCG5 gene and D19H (rs11887534), C54Y (rs4148211), T400K (rs4148217) and A632V (rs6544718) of the ABCG8 gene, were chosen for genotyping (http://www.ncbi.nlm.nih.gov/). Login to comment
63 Five nonsynonymous polymorphisms (ABCG5: Q604E; ABCG8:D19H, C54Y, T400K, A632V) were genotyped in our population. Login to comment
65 The minor allele frequencies (MAFs) of Q604E (C:G); D19H (G:C), C54Y (G:A) and T400K (C:A) were 10.5, 1.4, 9.7 and 8.0%, respectively. Login to comment

[hide] The effects of ABCG5/G8 polymorphisms on plasma HD... J Lipid Res. 2009 Mar;50(3):565-73. Epub 2008 Nov 12. Junyent M, Tucker KL, Smith CE, Garcia-Rios A, Mattei J, Lai CQ, Parnell LD, Ordovas JM
The effects of ABCG5/G8 polymorphisms on plasma HDL cholesterol concentrations depend on smoking habit in the Boston Puerto Rican Health Study.
J Lipid Res. 2009 Mar;50(3):565-73. Epub 2008 Nov 12., [PMID:19005228]

Abstract [show]
Low HDL-cholesterol (HDL-C) is associated with an increased risk for atherosclerosis, and concentrations are modulated by genetic factors and environmental factors such as smoking. Our objective was to assess whether the association of common single-nucleotide polymorphisms (SNPs) at ABCG5/G8 (i18429G>A, i7892T>C, Gln604GluC>G, 5U145A>C, Tyr54CysA>G, Asp19HisG>C, i14222A>G, and Thr400LysC>A) genes with HDL-C differs according to smoking habit. ABCG5/G8 SNPs were genotyped in 845 participants (243 men and 602 women). ABCG5/G8 (i7892T>C, 5U145A>C, Tyr54CysA>G, Thr400LysC>A) SNPs were significantly associated with HDL-C concentrations (P < 0.001-0.013) by which carriers of the minor alleles at the aforementioned polymorphisms and homozygotes for the Thr400 allele displayed lower HDL-C. A significant gene-smoking interaction was found, in which carriers of the minor alleles at ABCG5/G8 (Gln604GluC>G, Asp19HisG>C, i14222A>G) SNPs displayed lower concentrations of HDL-C only if they were smokers (P = 0.001-0.025). Also, for ABCG8_Thr400LysC>A SNP, smokers, but not nonsmokers, homozygous for the Thr400 allele displayed lower HDL-C (P = 0.004). Further analyses supported a significant haplotype global effect on lowering HDL-C (P = 0.002) among smokers. In conclusion, ABCG5/G8 genetic variants modulate HDL-C concentrations, leading to an HDL-C-lowering effect and thereby a potential increased risk for atherosclerosis only in smokers.

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30 Only two studies in patients with gallstone disease reported significant associations with HDL-C (16) and triglyceride (TG) concentrations (16, 18), but not with total cholesterol and LDL-C, for ABCG5 Gln604Glu and ABCG8 Thr400Lys SNPs, respectively. Login to comment
29 Only two studies in patients with gallstone disease reported significant associations with HDL-C (16) and triglyceride (TG) concentrations (16, 18), but not with total cholesterol and LDL-C, for ABCG5 Gln604Glu and ABCG8 Thr400Lys SNPs, respectively. Login to comment

[hide] ABCG5/G8 polymorphisms and markers of cholesterol ... J Lipid Res. 2010 Oct;51(10):3016-23. Epub 2010 Jun 25. Jakulj L, Vissers MN, Tanck MW, Hutten BA, Stellaard F, Kastelein JJ, Dallinga-Thie GM
ABCG5/G8 polymorphisms and markers of cholesterol metabolism: systematic review and meta-analysis.
J Lipid Res. 2010 Oct;51(10):3016-23. Epub 2010 Jun 25., [PMID:20581104]

Abstract [show]
Genetic variation at the ABCG5/G8 locus has been associated with markers of cholesterol homeostasis. As data originate from small-scale studies, we performed a meta-analysis to study these associations in a large dataset. We first investigated associations between five common ABCG5/G8 polymorphisms (p.Q604E, p.D19H, p.Y54C, p.T400K, and p.A632V) and plasma sterol levels in 245 hypercholesterolaemic individuals. No significant associations were found. Subsequently, our data were pooled into a meta-analysis that comprised 3,364 subjects from 16 studies (weighted mean age, 46.7 +/- 10.5 years; BMI, 23.9 +/- 3.5 kg/m(2)). Presence of the minor 632V allele correlated with reduced LDL-C concentrations (n = 367) compared with homozygosity for the 632A variant [n = 614; -0.11 mmol/l (95% CI, range: -0.20 to -0.02 mmol/l); P = 0.01]. The remaining polymorphisms were not associated with plasma lipid levels. Carriers of the 19H allele exhibited lower campesterol/TC (n = 83; P < 0.001), sitosterol/TC (P < 0.00001), and cholestanol/TC (P < 0.00001), and increased lathosterol/TC ratios (P = 0.001) compared with homozygous 19D allele carriers (n = 591). The ABCG8 632V variant was associated with a clinically irrelevant LDL-C reduction, whereas the 19H allele correlated with decreased cholesterol absorption and increased synthesis without affecting the lipid profile. Hence, associations between frequently studied missense ABCG5/G8 polymorphisms and markers of cholesterol homeostasis are modest at best.

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141 Associations between ABCG5/G8 polymorphisms and plasma lipids and non-cholesterol sterol ratios Lipids and Lipoproteins (mmol/l) Non-Cholesterol Sterol Ratios (␮g/mg) SNP N TC LDL-C HDL-C Triglycerides Campesterol/TC Sitosterol/TC Cholestanol/TC Lathosterol/TC Q604E QQ 171 6.16 ± 0.76 4.05 ± 0.61 1.54 ± 0.40 1.09 [0.29-3.56] 1.45 ± 0.64 1.12 ± 0.53 1.49 ± 0.33 1.24 ± 0.49 QE/EE 72 6.23 ± 0.73 4.11 ± 0.63 1.49 ± 0.36 1.19 [0.47-3.93] 1.47 ± 0.88 1.16 ± 0.63 1.46 ± 0.38 1.28 ± 0.57 D19H DD 219 6.19 ± 0.75 4.08 ± 0.61 1.52 ± 0.40 1.10 [0.29-3.93] 1.49 ± 0.69 1.16 ± 0.55 1.49 ± 0.34 1.24 ± 0.49 DH/HH 24 6.04 ± 0.81 3.90 ± 0.63 1.60 ± 0.38 1.15 [0.47-1.97] 1.24 ± 0.82 0.92 ± 0.53 1.38 ± 0.34 1.35 ± 0.64 Y54C YY 73 6.32 ± 0.73 4.14 ± 0.64 1.58 ± 0.37 1.09 [0.45-3.93] 1.59 ± 0.76 1.22 ± 0.60 1.53 ± 0.33 1.24 ± 0.53 YC/CC 171 6.12 ± 0.76 4.03 ± 0.61 1.51 ± 0.41 1.11 [0.29-3.56] 1.41 ± 0.68 1.09 ± 0.53 1.46 ± 0.34 1.26 ± 0.50 T400K TT 183 6.16 ± 0.75 4.03 ± 0.60 1.55 ± 0.40 1.10 [0.29-3.93] 1.48 ± 0.69 1.14 ± 0.55 1.49 ± 0.35 1.25 ± 0.48 TK/KK 61 6.24 ± 0.76 4.19 ± 0.66 1.47 ± 0.37 1.14 [0.47-2.61] 1.38 ± 0.76 1.09 ± 0.59 1.45 ± 0.31 1.27 ± 0.59 A632V AA 139 6.22 ± 0.72 4.12 ± 0.60 1.51 ± 0.37 1.12 [0.33-2.90] 1.49 ± 0.72 1.16 ± 0.58 1.51 ± 0.37 1.21 ± 0.49 AV/VV 105 6.14 ± 0.79 3.99 ± 0.63 1.57 ± 0.43 1.07 [0.29-3.93] 1.42 ± 0.70 1.09 ± 0.52 1.44 ± 0.30 1.31 ± 0.52 Values shown are means ± SD. Triglycerides are shown as median [range]. Login to comment
145 TABLE3.Characteristicsofstudiesincludedinthemeta-analysis Reference Number of SubjectsAge Male/ Female BodyMass IndexEthnicitySingleNucleotidePolymorphismsLipidsNon-CholesterolSterols nyearsnkg/m 2 Berge,2002(5)14855±1174/74NotreportedCaucasianD19H,T400K,Y54C,Q604E,A632VTCCAMP,SITO,CHOLST,LATHO Weggemans,2002(7)48626.3±11.6257/22921.7±3.0CaucasianQ604ETC- Gylling,2004(13)26253.1±8.1143/11926.4±6.5CaucasianD19H,T400K,Y54C,Q604E,A632VTC,LDL-C,HDL-C,TGCAMP,SITO,CHOLST,LATHO Plat,2005(11)a 11233±1641/7122.9±3.6CaucasianT400K,Q604E,A632VLDL-C,HDL-C,TGCAMP,SITO,LATHO Acalovschi,2006(27)72 e 56.3(36-80)30/4230.1±4.9CaucasianD19H,T400K,Y54C,Q604E,A632VTC,HDL-C,TG- Jakulj,etal. b 24558.4±7.5189/4825.8±3.0CaucasianD19H,T400K,Y54C,Q604E,A632VTC,LDL-C,HDL-C,TGCAMP,SITO,CHOLST,LATHO Miwa,2005(28)10062.4±12.148/5223.0±3.5AsianT400K,Y54C,Q604E-SITO,LATHO Wang,2007(29) a,c 13454.1±8.1134/023.2±2.3AsianT400K,Y54C,Q604ETC,LDL-C,HDL-C,TG- Chen,2008(8) a 104647.0±9.3894/15224.9±2.4AsianD19H,T400K,Y54C,Q604E i TC,LDL-C,HDL-C,TG- Caamano,2008(30) d 10440±1058/4625.5±3.3HispanicY54C,Q604ETC,LDL-C,HDL-C,TG- 11844±771/4727.6±4.9HispanicY54C,Q604ETC,LDL-C,HDL-C,TG- Santosa,2007(31) a 3549.4±6.70/3531.4±2.8Mixed f D19H,T400K,Y54C,Q604ETC,LDL-C,HDL-C,TG- Rudkowska,2008(32)2659.6±9.615/1126.4±2.7Mixed f D19H,T400K,Y54C,Q604ETC,LDL-C,HDL-C,TG- Chan,2004(33) a 4754.5±8.447/032±3.6Notreported g D19H,T400KTC,LDL-C,HDL-C,TGCAMP,SITO,LATHO Kajinami,2004(12) a 33858±11203/13527.0±3.0Notreported h D19H,T400K,Y54C,Q604E,A632VTC,LDL-C,HDL-C,TG- Herron,2006(9) a 9131.1±9.240/5124.8±4.7Notreported h Q604ETC,LDL-C,HDL-C- Total(WM)336446.7±10.52251/111323.9±3.5 Numberandcharacteristicsofstudiesincludedinthemeta-analysis.CAMP,campesterol/TCratio;CHOLST,cholestanol/TCratio;HDL-C,HDL-cholesterol;LATHO,lathosterol/TCratio;LDL-C, LDL-cholesterol;SITO,sitosterol/TCratio;TC,totalcholesterol;TG,triglyceride;WM,weightedmean. Login to comment
12 We first investigated associations between five common ABCG5/G8 polymorphisms (p.Q604E, p.D19H, p.Y54C, p. T400K, and p.A632V) and plasma sterol levels in 245 hypercholesterolaemic individuals. Login to comment
68 We genotyped five nonsynonymous polymorphisms in ABCG5/G8 [ABCG5: p.Q604E (rs6720173); ABCG8: p.D19H (rs11887534), p.Y54C (rs4148211), p.T400K (rs4148217), and p.A632V (rs6544718)] using allelic discrimination. Login to comment
131 The p.T400K polymorphism showed similar trends with borderline significance, whereas the remaining three polymorphisms were not associated with baseline non-cholesterol sterol levels (supplementary Table II). Login to comment
159 One study evaluated associations between p.T400K and p.D19H polymorphisms and CVD risk in a cohort of 2,012 heterozygous FH patients (22). Login to comment
160 Neither of the two variants was independently associated with total CVD risk; however, when combined p.T400K and p.D19H gene scores were calculated, a positive correlation was found. Login to comment
281 Twelve studies reported significant associations with baseline triglyceride levels, which mostly involved the p.T400K polymorphism (13, 29, 33); however, this was not consistent throughout all included studies (8, 11, 12, 27, 30-32). Login to comment
66 We genotyped five nonsynonymous polymorphisms in ABCG5/G8 [ABCG5: p.Q604E (rs6720173); ABCG8: p.D19H (rs11887534), p.Y54C (rs4148211), p.T400K (rs4148217), and p.A632V (rs6544718)] using allelic discrimination. Login to comment
129 The p.T400K polymorphism showed similar trends with borderline significance, whereas the remaining three polymorphisms were not associated with baseline non-cholesterol sterol levels (supplementary Table II). Login to comment
139 Associations between ABCG5/G8 polymorphisms and plasma lipids and non-cholesterol sterol ratios Lipids and Lipoproteins (mmol/l) Non-Cholesterol Sterol Ratios (òe;g/mg) SNP N TC LDL-C HDL-C Triglycerides Campesterol/TC Sitosterol/TC Cholestanol/TC Lathosterol/TC Q604E QQ 171 6.16 &#b1; 0.76 4.05 &#b1; 0.61 1.54 &#b1; 0.40 1.09 [0.29-3.56] 1.45 &#b1; 0.64 1.12 &#b1; 0.53 1.49 &#b1; 0.33 1.24 &#b1; 0.49 QE/EE 72 6.23 &#b1; 0.73 4.11 &#b1; 0.63 1.49 &#b1; 0.36 1.19 [0.47-3.93] 1.47 &#b1; 0.88 1.16 &#b1; 0.63 1.46 &#b1; 0.38 1.28 &#b1; 0.57 D19H DD 219 6.19 &#b1; 0.75 4.08 &#b1; 0.61 1.52 &#b1; 0.40 1.10 [0.29-3.93] 1.49 &#b1; 0.69 1.16 &#b1; 0.55 1.49 &#b1; 0.34 1.24 &#b1; 0.49 DH/HH 24 6.04 &#b1; 0.81 3.90 &#b1; 0.63 1.60 &#b1; 0.38 1.15 [0.47-1.97] 1.24 &#b1; 0.82 0.92 &#b1; 0.53 1.38 &#b1; 0.34 1.35 &#b1; 0.64 Y54C YY 73 6.32 &#b1; 0.73 4.14 &#b1; 0.64 1.58 &#b1; 0.37 1.09 [0.45-3.93] 1.59 &#b1; 0.76 1.22 &#b1; 0.60 1.53 &#b1; 0.33 1.24 &#b1; 0.53 YC/CC 171 6.12 &#b1; 0.76 4.03 &#b1; 0.61 1.51 &#b1; 0.41 1.11 [0.29-3.56] 1.41 &#b1; 0.68 1.09 &#b1; 0.53 1.46 &#b1; 0.34 1.26 &#b1; 0.50 T400K TT 183 6.16 &#b1; 0.75 4.03 &#b1; 0.60 1.55 &#b1; 0.40 1.10 [0.29-3.93] 1.48 &#b1; 0.69 1.14 &#b1; 0.55 1.49 &#b1; 0.35 1.25 &#b1; 0.48 TK/KK 61 6.24 &#b1; 0.76 4.19 &#b1; 0.66 1.47 &#b1; 0.37 1.14 [0.47-2.61] 1.38 &#b1; 0.76 1.09 &#b1; 0.59 1.45 &#b1; 0.31 1.27 &#b1; 0.59 A632V AA 139 6.22 &#b1; 0.72 4.12 &#b1; 0.60 1.51 &#b1; 0.37 1.12 [0.33-2.90] 1.49 &#b1; 0.72 1.16 &#b1; 0.58 1.51 &#b1; 0.37 1.21 &#b1; 0.49 AV/VV 105 6.14 &#b1; 0.79 3.99 &#b1; 0.63 1.57 &#b1; 0.43 1.07 [0.29-3.93] 1.42 &#b1; 0.70 1.09 &#b1; 0.52 1.44 &#b1; 0.30 1.31 &#b1; 0.52 Values shown are means &#b1; SD. Triglycerides are shown as median [range]. Login to comment
144 Characteristics of studies included in the meta-analysis Reference Number of Subjects Age Male/ Female Body Mass Index Ethnicity Single Nucleotide Polymorphisms Lipids Non-Cholesterol Sterols n years n kg/m 2 Berge, 2002 (5) 148 55 &#b1; 11 74/74 Not reported Caucasian D19H, T400K, Y54C, Q604E, A632V TC CAMP, SITO, CHOLST, LATHO Weggemans, 2002 (7) 486 26.3 &#b1; 11.6 257/229 21.7 &#b1; 3.0 Caucasian Q604E TC - Gylling, 2004 (13) 262 53.1 &#b1; 8.1 143/119 26.4 &#b1; 6.5 Caucasian D19H, T400K, Y54C, Q604E, A632V TC, LDL-C, HDL-C, TG CAMP, SITO, CHOLST, LATHO Plat, 2005 (11) a 112 33 &#b1; 16 41/71 22.9 &#b1; 3.6 Caucasian T400K, Q604E, A632V LDL-C, HDL-C, TG CAMP, SITO, LATHO Acalovschi, 2006 (27) 72 e 56.3 (36-80) 30/42 30.1 &#b1; 4.9 Caucasian D19H, T400K, Y54C, Q604E, A632V TC, HDL-C, TG - Jakulj, et al. b 245 58.4 &#b1; 7.5 189/48 25.8 &#b1; 3.0 Caucasian D19H, T400K, Y54C, Q604E, A632V TC, LDL-C, HDL-C, TG CAMP, SITO, CHOLST, LATHO Miwa, 2005 (28) 100 62.4 &#b1; 12.1 48/52 23.0 &#b1; 3.5 Asian T400K, Y54C, Q604E - SITO, LATHO Wang, 2007 (29) a , c 134 54.1 &#b1; 8.1 134/0 23.2 &#b1; 2.3 Asian T400K, Y54C, Q604E TC, LDL-C, HDL-C, TG - Chen, 2008 (8) a 1046 47.0 &#b1; 9.3 894/152 24.9 &#b1; 2.4 Asian D19H, T400K, Y54C, Q604E i TC, LDL-C, HDL-C, TG - Caamano, 2008 (30) d 104 40 &#b1; 10 58/46 25.5 &#b1; 3.3 Hispanic Y54C, Q604E TC, LDL-C, HDL-C, TG - 118 44 &#b1; 7 71/47 27.6 &#b1; 4.9 Hispanic Y54C, Q604E TC, LDL-C, HDL-C, TG - Santosa, 2007 (31) a 35 49.4 &#b1; 6.7 0/35 31.4 &#b1; 2.8 Mixed f D19H, T400K, Y54C, Q604E TC, LDL-C, HDL-C, TG - Rudkowska, 2008 (32) 26 59.6 &#b1; 9.6 15/11 26.4 &#b1; 2.7 Mixed f D19H, T400K, Y54C, Q604E TC, LDL-C, HDL-C, TG - Chan, 2004 (33) a 47 54.5 &#b1; 8.4 47/0 32 &#b1; 3.6 Not reported g D19H, T400K TC, LDL-C, HDL-C, TG CAMP, SITO, LATHO Kajinami, 2004 (12) a 338 58 &#b1; 11 203/135 27.0 &#b1; 3.0 Not reported h D19H, T400K, Y54C, Q604E, A632V TC, LDL-C, HDL-C, TG - Herron, 2006 (9) a 91 31.1 &#b1; 9.2 40/51 24.8 &#b1; 4.7 Not reported h Q604E TC, LDL-C, HDL-C - Total (WM) 3364 46.7 &#b1; 10.5 2251/ 1113 23.9 &#b1; 3.5 Number and characteristics of studies included in the meta-analysis. Login to comment
161 One study evaluated associations between p.T400K and p.D19H polymorphisms and CVD risk in a cohort of 2,012 heterozygous FH patients (22). Login to comment
162 Neither of the two variants was independently associated with total CVD risk; however, when combined p.T400K and p.D19H gene scores were calculated, a positive correlation was found. Login to comment
282 Twelve studies reported significant associations with baseline triglyceride levels, which mostly involved the p.T400K polymorphism (13, 29, 33); however, this was not consistent throughout all included studies (8, 11, 12, 27, 30-32). Login to comment
67 We genotyped five nonsynonymous polymorphisms in ABCG5/G8 [ABCG5: p.Q604E (rs6720173); ABCG8: p.D19H (rs11887534), p.Y54C (rs4148211), p.T400K (rs4148217), and p.A632V (rs6544718)] using allelic discrimination. Login to comment
130 The p.T400K polymorphism showed similar trends with borderline significance, whereas the remaining three polymorphisms were not associated with baseline non-cholesterol sterol levels (supplementary Table II). Login to comment
140 Associations between ABCG5/G8 polymorphisms and plasma lipids and non-cholesterol sterol ratios Lipids and Lipoproteins (mmol/l) Non-Cholesterol Sterol Ratios (òe;g/mg) SNP N TC LDL-C HDL-C Triglycerides Campesterol/TC Sitosterol/TC Cholestanol/TC Lathosterol/TC Q604E QQ 171 6.16 &#b1; 0.76 4.05 &#b1; 0.61 1.54 &#b1; 0.40 1.09 [0.29-3.56] 1.45 &#b1; 0.64 1.12 &#b1; 0.53 1.49 &#b1; 0.33 1.24 &#b1; 0.49 QE/EE 72 6.23 &#b1; 0.73 4.11 &#b1; 0.63 1.49 &#b1; 0.36 1.19 [0.47-3.93] 1.47 &#b1; 0.88 1.16 &#b1; 0.63 1.46 &#b1; 0.38 1.28 &#b1; 0.57 D19H DD 219 6.19 &#b1; 0.75 4.08 &#b1; 0.61 1.52 &#b1; 0.40 1.10 [0.29-3.93] 1.49 &#b1; 0.69 1.16 &#b1; 0.55 1.49 &#b1; 0.34 1.24 &#b1; 0.49 DH/HH 24 6.04 &#b1; 0.81 3.90 &#b1; 0.63 1.60 &#b1; 0.38 1.15 [0.47-1.97] 1.24 &#b1; 0.82 0.92 &#b1; 0.53 1.38 &#b1; 0.34 1.35 &#b1; 0.64 Y54C YY 73 6.32 &#b1; 0.73 4.14 &#b1; 0.64 1.58 &#b1; 0.37 1.09 [0.45-3.93] 1.59 &#b1; 0.76 1.22 &#b1; 0.60 1.53 &#b1; 0.33 1.24 &#b1; 0.53 YC/CC 171 6.12 &#b1; 0.76 4.03 &#b1; 0.61 1.51 &#b1; 0.41 1.11 [0.29-3.56] 1.41 &#b1; 0.68 1.09 &#b1; 0.53 1.46 &#b1; 0.34 1.26 &#b1; 0.50 T400K TT 183 6.16 &#b1; 0.75 4.03 &#b1; 0.60 1.55 &#b1; 0.40 1.10 [0.29-3.93] 1.48 &#b1; 0.69 1.14 &#b1; 0.55 1.49 &#b1; 0.35 1.25 &#b1; 0.48 TK/KK 61 6.24 &#b1; 0.76 4.19 &#b1; 0.66 1.47 &#b1; 0.37 1.14 [0.47-2.61] 1.38 &#b1; 0.76 1.09 &#b1; 0.59 1.45 &#b1; 0.31 1.27 &#b1; 0.59 A632V AA 139 6.22 &#b1; 0.72 4.12 &#b1; 0.60 1.51 &#b1; 0.37 1.12 [0.33-2.90] 1.49 &#b1; 0.72 1.16 &#b1; 0.58 1.51 &#b1; 0.37 1.21 &#b1; 0.49 AV/VV 105 6.14 &#b1; 0.79 3.99 &#b1; 0.63 1.57 &#b1; 0.43 1.07 [0.29-3.93] 1.42 &#b1; 0.70 1.09 &#b1; 0.52 1.44 &#b1; 0.30 1.31 &#b1; 0.52 Values shown are means &#b1; SD. Triglycerides are shown as median [range]. Login to comment
163 Neither of the two variants was independently associated with total CVD risk; however, when combined p.T400K and p.D19H gene scores were calculated, a positive correlation was found. Login to comment
284 Twelve studies reported significant associations with baseline triglyceride levels, which mostly involved the p.T400K polymorphism (13, 29, 33); however, this was not consistent throughout all included studies (8, 11, 12, 27, 30-32). Login to comment

[hide] ABCG8 D19H polymorphism: a basis for the genetic p... J Gastroenterol Hepatol. 2010 Nov;25(11):1713-4. doi: 10.1111/j.1440-1746.2010.06484.x. Yoon JH, Kuver R, Choi HS
ABCG8 D19H polymorphism: a basis for the genetic prediction of cholesterol gallstone disease.
J Gastroenterol Hepatol. 2010 Nov;25(11):1713-4. doi: 10.1111/j.1440-1746.2010.06484.x., [PMID:21039829]

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11 Other studies have identified a variety of polymorphisms in ABCG8 (A632V, T400K, D19H, and C54Y) and in ABCG5 (Q604E) that have been linked to baseline plasma cholesterol levels, cholesterol absorption, or responsiveness to dietary intervention. Login to comment
15 Wang et al.11 examined five common polymorphisms in the ABCG5 (Q604E) and ABCG8 (D19H,Y54C, T400K, A632V) genes in 287 patients with gallstone disease. Login to comment
12 In addition, genetic variations in the ABCG8 gene (D19H and T400K) might increase the risk of gallstone disease in certain populations.9 These sex- and population-specific gene polymorphisms, and the interactions between sex, genes, and diet also need to be considered in studies of polymorphisms of Lith genes. Login to comment
14 Yet when a subanalysis of male participants was performed, the ABCG8 T400K wild-type allele carriers exhibited a greater decrease in plasma total cholesterol and low-density lipoprotein cholesterol (LDL-C) than mutant allele carriers.10 Wang et al.11 suggested that the T400K polymorphism in ABCG8 might be associated with gallstone disease in Chinese males by revealing a possible association between this transporter gene polymorphism and gallstone formation. Login to comment
16 The relative risk of gallstone formation was 2.31 (95% CI: 1.12-4.76) for males carrying the K400 allele of ABCG8 T400K. Login to comment

[hide] Interactions between CYP7A1 A-204C and ABCG8 C1199... J Clin Pharm Ther. 2010 Dec 3. doi: 10.1111/j.1365-2710.2010.01227.x. Wei KK, Zhang LR, Zhang Y, Hu XJ
Interactions between CYP7A1 A-204C and ABCG8 C1199A polymorphisms on lipid lowering with atorvastatin.
J Clin Pharm Ther. 2010 Dec 3. doi: 10.1111/j.1365-2710.2010.01227.x., 2010-12-03 [PMID:21128988]

Abstract [show]
What is known and Objective: Cholesterol excretion by ATP binding cassette transporters G5 and G8 (ABCG5/G8) and bile acid biosynthesis by 7a-hydroxylase (CYP7A1) are major pathways for the removal of cholesterol into bile. This suggests that variations in the CYP7A1 and ABCG8 genes may influence the statin response. We aimed to investigate the effect of CYP7A1 A-204C and ABCG8 C1199A polymorphisms and their interactions on the lipid-lowering response to atorvastatin in a Chinese population. Methods: Genotypes were determined by using polymerase chain reaction-restrict fragment length polymorphism (PCR-RFLP) in 185 hyperlipidaemic patients treated with atorvastatin, 20 mg once daily for 4 weeks. Serum levels of triglycerides (TGs), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were determined before and after treatment. Results and Discussion: For 181 patients (89 males), variant allele frequencies of CYP7A1 -204C and ABCG8 1199A were 0.347 and 0.128, respectively. Among all patients, homozygotes for the -204A allele showed a slightly significant mean percentage reduction from baseline in TG level after treatment than heterozygotes and homozygotes for the -204C allele (-25.49 +/- 8.12%vs. -22.80 +/- 8.72%, P = 0.054, and -25.49 +/- 8.12%vs.-22.51 +/- 8.82%, P = 0.048, respectively). For patients with the ABCG8 C1199A variant allele, the difference in percentage reduction from baseline in TG level was increased between the CYP7A1 A-204C wild-type allele homozygotes and variant allele homozygotes after atorvastatin treatment (-28.35%vs.-19.28%, P = 0.001), and increased differences were found between the CYP7A1 A-204C wild-allele homozygotes and variant allele homozygotes (-18.95%vs.-15.61%, P = 0.009) and between the CYP7A1 A-204C variant allele heterozygotes and homozygotes (-18.69%vs.-15.61%, P = 0.012, respectively). What is new and Conclusion: The CYP7A1 -204A and ABCG8 1199A alleles appear to interact to affect lipid-lowering response to atorvastatin. However, given the relatively small number of subjects with the influential variant allele combinations, and the heterogeneity in response, even in the selected sub-populations, testing would be of little clinical utility in the Chinese population sampled.

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27 Several previous studies have found that 5 nonsynonymous single-nucleotide polymorphisms in the ABCG5 (Q604E) and ABCG8 (D19H, Y54C, T400K, A632V) coding sequences may affect plasma plant sterol or cholesterol levels (16-19). Login to comment
29 Allele frequencies of 19H and 632V were found to be rare in a Chinese population (20), and the Y54C and T400K alleles showed strong linkage disequilibrium. Login to comment
30 Therefore, we investigated the effect of the interactions between the CYP7A1 A-204C and ABCG8 C1199A (T400K) polymorphisms on lipid-lowering with atorvastatin treatment in a Chinese population. Login to comment
88 However, these findings are inconsistent with those of Kajinami et al., who found homozygotes for both CYP7A1 A-204 and ABCG8 19H alleles with increased reduction in LDL-C level and ABCG8 T400K polymorphism without an important interaction with CYP7A1 polymorphism (15). Login to comment

[hide] Phytosterols and phytosterolemia: gene-diet intera... Genes Nutr. 2011 Feb;6(1):17-26. Epub 2010 Aug 28. Izar MC, Tegani DM, Kasmas SH, Fonseca FA
Phytosterols and phytosterolemia: gene-diet interactions.
Genes Nutr. 2011 Feb;6(1):17-26. Epub 2010 Aug 28., [PMID:21437027]

Abstract [show]
Phytosterol intake is recommended as an adjunctive therapy for hypercholesterolemia, and plant sterols/stanols can reduce cholesterol absorption at the intestinal lumen through the Niemann-Pick C1 Like 1 (NPC1L1) transporter pathway by competitive solubilization in mixed micelles. Phytosterol absorption is of less magnitude than cholesterol and is preferably secreted in the intestinal lumen by ABCG5/G8 transporters. Therefore, plasma levels of plant sterols/stanols are negligible compared with cholesterol, under an ordinary diet. The mechanisms of cholesterol and plant sterols absorption and the whole-body pool of sterols are discussed in this chapter. There is controversy about treatment with statins inducing further increase in plasma non-cholesterol sterols raising concerns about the safety of supplementation of plant sterols to such drugs. In addition, increase in plant sterols has also been reported upon consumption of plant sterol-enriched foods, regardless of other treatments. Rare mutations on ABCG5/G8 transporters affecting cholesterol/non-cholesterol extrusion, causing sitosterolemia with xanthomas and premature atheroslerotic disease are now known, and cholesterol/plant sterols absorption inhibitor, ezetimibe, emerges as the drug that reduces phytosterolemia and promotes xanthoma regression. On the other hand, common polymorphisms affecting the NPC1L1 transporter can interfere with the action of ezetimibe. Gene-diet interactions participate in this intricate network modulating the expression of genetic variants on specific phenotypes and can also affect the individual response to the hypolipidemic treatment. These very interesting aspects promoted a great deal of research in the field.

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127 Missense polymorphisms (Gln604Glu in the ABCG5, and Asp19His, Tyr54Cys, Thr400Lys, and Ala632Val in the ABCG8) were examined, and the Thr400Lys in the ABCG8 gene was associated with changes in lipid levels in response to reduced dietary animal fat and cholesterol intake. Login to comment
129 Missense polymorphisms (Gln604Glu in the ABCG5, and Asp19His, Tyr54Cys, Thr400Lys, and Ala632Val in the ABCG8) were examined, and the Thr400Lys in the ABCG8 gene was associated with changes in lipid levels in response to reduced dietary animal fat and cholesterol intake. Login to comment

[hide] Loci on chromosomes 14 and 2, distinct from ABCG5/... Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16215-9. Epub 2002 Nov 22. Sehayek E, Duncan EM, Lutjohann D, Von Bergmann K, Ono JG, Batta AK, Salen G, Breslow JL
Loci on chromosomes 14 and 2, distinct from ABCG5/ABCG8, regulate plasma plant sterol levels in a C57BL/6J x CASA/Rk intercross.
Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16215-9. Epub 2002 Nov 22., 2002-12-10 [PMID:12446833]

Abstract [show]
Plasma plant sterol levels differ among humans due to genetic and dietary factors. A disease characterized by high plasma plant sterol levels, beta-sitosterolemia, was recently found to be due to mutations at the ABCG5ABCG8 locus. To detect variants at this and other loci, a genetic cross was carried out between two laboratory mouse strains. Parental C57BL6J had almost twice the campesterol and sitosterol levels compared with parental CASARk mice, and F(1) mice had levels halfway between the parentals. An intercross between F(1)s was performed and plasma plant sterol levels measured in 102 male and 99 female F(2) mice. Plasma plant sterols in F(2)s displayed a unimodal distribution, suggesting the effects of several rather a single major gene. In the F(2) mice, a full genome scan revealed significant linkages on chromosomes 14 and 2. With regard to chromosome 14, analysis showed a single peak for linkage at 17 cM with a logarithm of odds (LOD) score of 9.9, designated plasma plant sterol 14 (Plast14). With regard to chromosome 2, analysis showed two significant peaks for linkage at 18 and 65 cMs with LOD scores of 4.1 and 3.65, respectively, designated Plast2a and Plast2b, respectively. Four interactions between loci, predominantly of an additive nature, were also demonstrated, the most significant between Plast14 and Plast2b (LOD 16.44). No significant linkage or gene interaction was detected for the ABCG5ABCG8 locus on chromosome 17. Therefore, other genes besides ABCG5ABCG8 influence plasma plant sterol levels and now become candidates to explain differences in plasma plant sterol levels between humans.

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159 ABCG8 D19H in 10% of the population had a 31% lower genotypic mean campesterol level, and ABCG8 T400K in 36% of the population had a 2% lower genotypic mean. Login to comment

[hide] Response of obligate heterozygotes for phytosterol... J Lipid Res. 2003 Jun;44(6):1143-55. Epub 2003 Apr 1. Kwiterovich PO Jr, Chen SC, Virgil DG, Schweitzer A, Arnold DR, Kratz LE
Response of obligate heterozygotes for phytosterolemia to a low-fat diet and to a plant sterol ester dietary challenge.
J Lipid Res. 2003 Jun;44(6):1143-55. Epub 2003 Apr 1., [PMID:12671028]

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Twelve obligate heterozygotes from two kindreds were ascertained through phytosterolemic probands homozygous for molecular defects in the ATP binding cassette (ABC) half transporter, ABCG8. The response of these heterozygotes to a Step 1 diet low in fat, saturated fat, and cholesterol, and to 2.2 g daily of plant sterols (as esters) was determined in Protocol I (16 weeks) and Protocol II (28 weeks) during three consecutive feeding periods: Step 1/placebo spread; Step 1/plant sterol spread; and Step 1/placebo spread (washout). At baseline, half the heterozygotes had moderate dyslipidemia and one-third had mildly elevated campesterol and sitosterol levels. On the Step 1/placebo spread, mean LDL cholesterol decreased significantly, 11.2% in Protocol I (n = 12), and 16.0% in Protocol II (n = 7). Substitution with plant sterol spread produced a significant treatment effect on LDL levels in Protocols I and II. Conversely, the mean levels of campesterol and sitosterol increased 119% and 54%, respectively, during the use of plant sterol spread for 6 weeks in Protocol I, an effect mirrored for 12 weeks in Protocol II. During the placebo spread washouts, LDL levels increased, while those of plant sterols decreased to baseline levels in both protocols. In conclusion, phytosterolemic heterozygotes respond well to a Step 1 diet, and their response to a plant sterol ester challenge appears similar to that observed in normals.

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258 Berge et al. (50) have recently found that the plasma levels of campesterol and sitosterol are heritable, and that two common DNA sequence variations (D19H and T400K) in the ABCG8 gene are associated with lower concentrations of these plant sterols. Login to comment

[hide] Genetic regulation of cholesterol absorption and p... J Lipid Res. 2003 Nov;44(11):2030-8. Epub 2003 Aug 1. Sehayek E
Genetic regulation of cholesterol absorption and plasma plant sterol levels: commonalities and differences.
J Lipid Res. 2003 Nov;44(11):2030-8. Epub 2003 Aug 1., [PMID:12897193]

Abstract [show]
The molecular basis of the processes that control two closely related traits, the absorption of cholesterol from the intestines and plasma plant sterol levels, are only partially understood. The discovery that mutations in two novel hemitransporters, ATP binding cassette transporter G5 (ABCG5) and ABCG8, underlie a rare inborn error in plant sterol metabolism, beta-sitosterolemia, represents a major breakthrough in this field. More recently, genetic studies in the mouse that mapped loci in linkage with cholesterol absorption and plasma plant sterol levels and studies in humans that examined the relationship of plasma plant sterol levels to sequence variation in the ABCG5/ABCG8 locus suggested the involvement of other genes. Moreover, studies in beta-sitosterolemic patients, in ABCG5/ABCG8-targeted animals, and on a newly developed cholesterol absorption inhibitor, ezetimibe, suggest commonalities and differences in the regulation of the two traits. This review summarizes the evidence for genetic control of cholesterol absorption and plasma plant sterol levels, presents the evidence for commonalities and differences between the two traits, and discusses recent developments and future perspectives in this field.

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109 Carriers of ABCG8 D19H in 10% of the population had a 31% lower genotypic mean in absolute campesterol level, and carriers of ABCG8 T400K in 36% of the population had a 2% lower genotypic mean. Login to comment
108 Carriers of ABCG8 D19H in 10% of the population had a 31% lower genotypic mean in absolute campesterol level, and carriers of ABCG8 T400K in 36% of the population had a 2% lower genotypic mean. Login to comment
107 Carriers of ABCG8 D19H in 10% of the population had a 31% lower genotypic mean in absolute campesterol level, and carriers of ABCG8 T400K in 36% of the population had a 2% lower genotypic mean. Login to comment

[hide] ATP-binding cassette transporter G8 gene as a dete... Arterioscler Thromb Vasc Biol. 2004 Nov;24(11):2188-91. Epub 2004 Aug 26. Chan DC, Watts GF, Barrett PH, Whitfield AJ, van Bockxmeer FM
ATP-binding cassette transporter G8 gene as a determinant of apolipoprotein B-100 kinetics in overweight men.
Arterioscler Thromb Vasc Biol. 2004 Nov;24(11):2188-91. Epub 2004 Aug 26., [PMID:15331430]

Abstract [show]
OBJECTIVE: We examined the influence of genetic variation of the ATP-binding cassette (ABC) transporter G8 on apolipoprotein B (apoB) kinetics in overweight/obese men. METHODS AND RESULTS: Very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) apoB kinetics were determined in 47 men (body mass index 32+/-3 kg/m2) using stable isotope and multicompartmental modeling to estimate production rate (PR), fractional catabolic rate (FCR), and VLDL to LDL-apoB conversion. Relative to the wild-type (400TT), subjects carrying the ABCG8 400K allele had significantly decreased plasma concentrations of triglycerides, sitosterol, and campesterol, lower PR of VLDL-apoB, and higher VLDL to LDL-apoB conversion (P<0.05). The PR and FCR of LDL-apoB were also significantly higher with 400K allele (P<0.05). No association was found with ABCG8 D19H. Compared with APOE2 or APOE3, APOE4 carriers had significantly higher plasma LDL-cholesterol concentrations and lower LDL-apoB FCR. During multiple regression analysis including age, homeostasis model assessment score, plasma concentrations of sitosterol, and lathosterol, ABCG8 and apoE genotypes were independent determinants of VLDL-apoB PR and LDL-apoB FCR, respectively (P<0.05). CONCLUSIONS: Variation in the ABC transporter G8 appears to independently influence the metabolism of apoB-containing lipoproteins in overweight/obese subjects. This may have therapeutic implications for the management of dyslipidemia in these subjects.

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38 Plasma lathosterol, sitosterol, and campesterol concentrations were measured by gas-liquid chromatography and expressed in mmol/Lϫ102 per mol/L cholesterol.13,14 ABCG8 (T400K, D19H) and ApoE Genotyping ABCG8 (exon 1 D19H, exon 8 T400K) genotypes were determined by polymerase chain reaction amplification using as forward primer 5Ј AGG AAA CAG AGT GAA GAC ACT GG 3Ј and as reverse primer 5Ј AGA AAG GTT TGA TTT CTC CTA CCC 3Ј (T400K); and for D19H forward primer 5Ј ACA CCT GTG TGG AAA GGT AAG GT 3Ј and reverse primer 5Ј GCG GGT trichloroacetic acid GTA ATA AAA TGA CAG 3Ј as described by Hubacek et al.10 ApoE genotype was determined as described by Hixson and Vernier.15 Statistical Analysis All analyses were performed using SPSS 10.1 (SPSS). Login to comment
48 Allele frequencies of T400K were 0.86 (wild-type) and 0.14 (variant) and D19H were 0.92 (wild-type) and 0.08 (variant). Login to comment
49 Significant linkage disequilibrium was not found between T400K and D19H (DЈϭ0.44; Pϭ0.32). Login to comment
67 Discussion This is the first study to demonstrate that ABCG8 (T400K) genotype may determine the metabolism of apoB in overweight/obese subjects. Our major finding was that compared with TT, ABCG8 TK individuals had lower VLDL-apoB PR and higher LDL production and FCRs. Login to comment
35 Plasma lathosterol, sitosterol, and campesterol concentrations were measured by gas-liquid chromatography and expressed in mmol/Lϫ102 per mol/L cholesterol.13,14 ABCG8 (T400K, D19H) and ApoE Genotyping ABCG8 (exon 1 D19H, exon 8 T400K) genotypes were determined by polymerase chain reaction amplification using as forward primer 5Ј AGG AAA CAG AGT GAA GAC ACT GG 3Ј and as reverse primer 5Ј AGA AAG GTT TGA TTT CTC CTA CCC 3Ј (T400K); and for D19H forward primer 5Ј ACA CCT GTG TGG AAA GGT AAG GT 3Ј and reverse primer 5Ј GCG GGT trichloroacetic acid GTA ATA AAA TGA CAG 3Ј as described by Hubacek et al.10 ApoE genotype was determined as described by Hixson and Vernier.15 Statistical Analysis All analyses were performed using SPSS 10.1 (SPSS). Login to comment
45 Allele frequencies of T400K were 0.86 (wild-type) and 0.14 (variant) and D19H were 0.92 (wild-type) and 0.08 (variant). Login to comment
46 Significant linkage disequilibrium was not found between T400K and D19H (DЈϭ0.44; Pϭ0.32). Login to comment
64 Discussion This is the first study to demonstrate that ABCG8 (T400K) genotype may determine the metabolism of apoB in overweight/obese subjects. Our major finding was that compared with TT, ABCG8 TK individuals had lower VLDL-apoB PR and higher LDL production and FCRs. Login to comment

[hide] Intestinal cholesterol transport proteins: an upda... Curr Opin Lipidol. 2007 Jun;18(3):310-8. Levy E, Spahis S, Sinnett D, Peretti N, Maupas-Schwalm F, Delvin E, Lambert M, Lavoie MA
Intestinal cholesterol transport proteins: an update and beyond.
Curr Opin Lipidol. 2007 Jun;18(3):310-8., [PMID:17495606]

Abstract [show]
PURPOSE OF REVIEW: Various studies have delineated the causal role of dietary cholesterol in atherogenesis. Strategies have thus been developed to minimize cholesterol absorption, and cholesterol transport proteins found at the apical membrane of enterocytes have been extensively investigated. This review focuses on recent progress related to various brush-border proteins that are potentially involved in alimentary cholesterol transport. RECENT FINDINGS: Molecular mechanisms responsible for dietary cholesterol and plant sterol uptake have not been completely defined. Growing evidence, however, supports the concept that several proteins are involved in mediating intestinal cholesterol transport, including SR-BI, NPC1L1, CD36, aminopeptidase N, P-glycoprotein, and the caveolin-1/annexin-2 heterocomplex. Other ABC family members (ABCA1 and ABCG5/ABCG8) act as efflux pumps favoring cholesterol export out of absorptive cells into the lumen or basolateral compartment. Several of these cholesterol carriers influence intracellular cholesterol homeostasis and are controlled by transcription factors, including RXR, LXR, SREBP-2 and PPARalpha. The lack of responsiveness of NPC1L1-deficient mice to ezetimibe suggests that NPC1L1 is likely to be the principal target of this cholesterol-lowering drug. SUMMARY: The understanding of the role, genetic regulation and coordinated function of proteins mediating intestinal cholesterol transport may lead to novel ways of treating cardiovascular disease.

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100 On the other hand, patients with primary hypercholesterolemia, according to NCEP,were associated with a specific ABCB1 haplotype, suggesting this polymorphism may contribute to increased plasma cholesterol and LDL levels [42].ABCG8(A632V,T400K,Y54C)andABCG5(Q604E) variants, however, are likely to be important forthe genetic determination of plasma cholesterol levels, probably via their influence on intestinal absorption and biliary secretion [43-45]. Login to comment

[hide] Increased gallstone risk in humans conferred by co... Hepatology. 2007 Sep;46(3):793-801. Grunhage F, Acalovschi M, Tirziu S, Walier M, Wienker TF, Ciocan A, Mosteanu O, Sauerbruch T, Lammert F
Increased gallstone risk in humans conferred by common variant of hepatic ATP-binding cassette transporter for cholesterol.
Hepatology. 2007 Sep;46(3):793-801., [PMID:17626266]

Abstract [show]
Genomewide scans of inbred strains of mice have linked the genes encoding the hepatocanalicular cholesterol transporter ABCG5/G8 to gallstone formation. Five nonsynonymous coding single-nucleotide polymorphisms (SNPs) in the orthologous human genes are associated with differences in serum cholesterol and plant sterol levels. We now tested these ABCG5/G8 SNPs for linkage and association with gallstone susceptibility in humans. Prospectively, we collected data from 178 white individuals with gallbladder stones or history of cholecystectomy in 84 families and from 70 stone-free controls, as confirmed by abdominal ultrasound. We performed nonparametric linkage (NPL) analysis of affected sib pairs (ASPs) and association tests of cases and controls. In ASPs, gallstones were strongly linked to the D19H variant of the ABCG8 gene (NPL score = 7.1; P = 4.6 x 10(-13)). The risk of gallstones in carriers of the 19H allele was significantly increased in randomly selected cases from the ASP cohort compared to the stone-free controls (OR = 3.018; P = 0.017). Consistent with the mouse model, heterozygosity for the lithogenic ABCG8 allele was associated with gallstones in humans; 21.4% of gallstone patients carried the heterozygous D19H genotype, compared with 8.6% of controls (OR = 2.954; P = 0.026). CONCLUSION: The linkage and association studies identified the cholesterol transporter ABCG5/G8 as a genetic determinant of gallstone formation, or LITH gene, in humans. The function of this transporter and the results of the genetic study taken together indicate that in gallstone-susceptible carriers of the ABCG8 19H allele, cholesterol cholelithiasis is secondary to increased hepatobiliary cholesterol secretion.

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94 In contrast to ABCG8 D19H, no significant single-point linkage was detected for the other ABCG5/G8 SNPs (p.E604Q, p.Y54C, p.T400K, p.A632V). Login to comment
52 Forgenotyping,weselectedfunctionallyrelevantnonsyn- onymous coding single-nucleotide polymorphisms (SNPs) of the ABCG5/G8 genes (Fig. 1): ABCG5 rs6720173 ϭ c.1810GϾC(p.E604Q);ABCG8rs11887534ϭc.55GϾC (p.D19H), rs4148211 ϭ c.161AϾG (p.Y54C), rs4148217 ϭ c.1199CϾA (p.T400K), and rs6544718 ϭ c.1895CϾT (p.A632V).22,23,25,28,29 All SNPs were genotyped using solution-phase hybridization reactions with 5Ј-nuclease and fluorescence detection (TaqMan assays) in a 7300 Real-Time polymerase chain reaction (PCR) system (Applera, Norwalk, CT). Login to comment

[hide] Genetics of biliary tract diseases: new insights i... Curr Opin Gastroenterol. 2008 May;24(3):363-71. Hoblinger A, Lammert F
Genetics of biliary tract diseases: new insights into gallstone disease and biliary tract cancers.
Curr Opin Gastroenterol. 2008 May;24(3):363-71., [PMID:18408466]

Abstract [show]
PURPOSE OF REVIEW: Chronic biliary diseases are due to complex interactions between environmental and genetic factors. Here we summarize the current knowledge of genetic factors that contribute to common biliary diseases, focusing on gallstones and carcinogenesis, and review the recent association studies. RECENT FINDINGS: Since most studies were based on small sample sizes, replication of the findings is mandatory. Recently a large twin study confirmed a genetic predisposition to gallstones and a genome-wide association scan identified the hepatocanalicular cholesterol transporter ABCG8 as the common susceptibility factor for gallstone disease. Genetic studies in patients with cholangiocarcinoma indicate that genes controlling the metabolism and transport of xenobiotics or modulating chronic inflammation may determine individual susceptibility. SUMMARY: Genetic studies have identified the first susceptibility factors for gallstones and biliary tract cancers, but most results have yet to be replicated. In the future, genome-wide studies in different populations are likely to identify the entire set of genes contributing to chronic biliary diseases. Since the disease phenotypes result from the manifestation of susceptibility factors under the influence of environmental triggers, the discovery of these genes will open avenues to control environmental challenges and lead to novel strategies for risk assessment ('gene signatures') and prevention.

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21 Of note, this variant was also a susceptibility factor for gallstones in Chilean Hispanics [18 ] and yet another ABCG8 variant (T400K) may affect the risk of gallstone disease among Chinese males [20]. Login to comment

[hide] The ABCG5 ABCG8 sterol transporter and phytosterol... Curr Opin Endocrinol Diabetes Obes. 2009 Apr;16(2):172-7. Sabeva NS, Liu J, Graf GA
The ABCG5 ABCG8 sterol transporter and phytosterols: implications for cardiometabolic disease.
Curr Opin Endocrinol Diabetes Obes. 2009 Apr;16(2):172-7., [PMID:19306529]

Abstract [show]
PURPOSE OF REVIEW: This review summarizes recent developments in the activity, regulation, and physiology of the ABCG5 ABCG8 (G5G8) transporter and the use of its xenobiotic substrates, phytosterols, as cholesterol lowering agents in the treatment of cardiovascular disease. Recent progress has significant implications for the role of G5G8 and its substrates in complications associated with features of the metabolic syndrome. RECENT FINDINGS: Recent reports expand the clinical presentation of sitosterolemia to include platelet and adrenal dysfunction. The G5G8 sterol transporter is critical to hepatobiliary excretion of cholesterol under nonpathological conditions and has been linked to the cholesterol gallstone susceptibility. Finally, the cardiovascular benefits of cholesterol lowering through the use of phytosterol supplements were offset by vascular dysfunction, suggesting that alternative strategies to reduced cholesterol absorption offer greater benefit. SUMMARY: Insulin resistance elevates G5G8 and increases susceptibility to cholesterol gallstones. However, this transporter is critical for the exclusion of phytosterols from the absorptive pathways in the intestine. Challenging the limits of this protective mechanism through phytosterol supplementation diminishes the cardioprotective benefits of cholesterol lowering in mouse models of cardiovascular disease.

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123 In this same cohort, the presence of both D19H and T400K increased risk of coronary heart disease and cardiovascular disease . Login to comment
126 Although the T400K polymorphism in ABCG8 influences the cholesterol-lowering effect of phytosterol supplementation, efficacy is independent of baseline plant sterol levels as well as cholesterol intake [31,34,35]. Login to comment

[hide] Genetic regulation of serum phytosterol levels and... Circ Cardiovasc Genet. 2010 Aug;3(4):331-9. Epub 2010 Jun 7. Teupser D, Baber R, Ceglarek U, Scholz M, Illig T, Gieger C, Holdt LM, Leichtle A, Greiser KH, Huster D, Linsel-Nitschke P, Schafer A, Braund PS, Tiret L, Stark K, Raaz-Schrauder D, Fiedler GM, Wilfert W, Beutner F, Gielen S, Grosshennig A, Konig IR, Lichtner P, Heid IM, Kluttig A, El Mokhtari NE, Rubin D, Ekici AB, Reis A, Garlichs CD, Hall AS, Matthes G, Wittekind C, Hengstenberg C, Cambien F, Schreiber S, Werdan K, Meitinger T, Loeffler M, Samani NJ, Erdmann J, Wichmann HE, Schunkert H, Thiery J
Genetic regulation of serum phytosterol levels and risk of coronary artery disease.
Circ Cardiovasc Genet. 2010 Aug;3(4):331-9. Epub 2010 Jun 7., [PMID:20529992]

Abstract [show]
BACKGROUND: Phytosterols are plant-derived sterols that are taken up from food and can serve as biomarkers of cholesterol uptake. Serum levels are under tight genetic control. We used a genomic approach to study the molecular regulation of serum phytosterol levels and potential links to coronary artery disease (CAD). METHODS AND RESULTS: A genome-wide association study for serum phytosterols (campesterol, sitosterol, brassicasterol) was conducted in a population-based sample from KORA (Cooperative Research in the Region of Augsburg) (n=1495) with subsequent replication in 2 additional samples (n=1157 and n=1760). Replicated single-nucleotide polymorphisms (SNPs) were tested for association with premature CAD in a metaanalysis of 11 different samples comprising 13 764 CAD cases and 13 630 healthy controls. Genetic variants in the ATP-binding hemitransporter ABCG8 and at the blood group ABO locus were significantly associated with serum phytosterols. Effects in ABCG8 were independently related to SNPs rs4245791 and rs41360247 (combined P=1.6 x 10(-50) and 6.2 x 10(-25), respectively; n=4412). Serum campesterol was elevated 12% for each rs4245791 T-allele. The same allele was associated with 40% decreased hepatic ABCG8 mRNA expression (P=0.009). Effects at the ABO locus were related to SNP rs657152 (combined P=9.4x10(-13)). Alleles of ABCG8 and ABO associated with elevated phytosterol levels displayed significant associations with increased CAD risk (rs4245791 odds ratio, 1.10; 95% CI, 1.06 to 1.14; P=2.2 x 10(-6); rs657152 odds ratio, 1.13; 95% CI, 1.07 to 1.19; P=9.4 x 10(-6)), whereas alleles at ABCG8 associated with reduced phytosterol levels were associated with reduced CAD risk (rs41360247 odds ratio, 0.84; 95% CI, 0.78 to 0.91; P=1.3 x 10(-5)). CONCLUSION: Common variants in ABCG8 and ABO are strongly associated with serum phytosterol levels and show concordant and previously unknown associations with CAD.

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55 These included SNP rs4245791, which had initially violated quality criteria (call rate and Hardy-Weinberg equilibrium) on the 500K Array Set due to misgenotyping, and the 2 coding SNPs rs11887534 (D19H) and rs4148217 (T400K) not present on the 500K Array Set with known associations with serum phytosterol levels.9 SNPs were genotyped using the Sequenom assay. Login to comment
49 These included SNP rs4245791, which had initially violated quality criteria (call rate and Hardy-Weinberg equilibrium) on the 500K Array Set due to misgenotyping, and the 2 coding SNPs rs11887534 (D19H) and rs4148217 (T400K) not present on the 500K Array Set with known associations with serum phytosterol levels.9 SNPs were genotyped using the Sequenom assay. Login to comment
48 These included SNP rs4245791, which had initially violated quality criteria (call rate and Hardy-Weinberg equilibrium) on the 500K Array Set due to misgenotyping, and the 2 coding SNPs rs11887534 (D19H) and rs4148217 (T400K) not present on the 500K Array Set with known associations with serum phytosterol levels.9 SNPs were genotyped using the Sequenom assay. Login to comment

[hide] Hepatic cholesterol transporter ABCG8 polymorphism... J Gastroenterol Hepatol. 2010 Jun;25(6):1093-8. Siddapuram SP, Mahurkar S, Duvvuru NR, Mitnala S, Guduru VR, Rebala P, Mansard MJ
Hepatic cholesterol transporter ABCG8 polymorphisms in gallstone disease in an Indian population.
J Gastroenterol Hepatol. 2010 Jun;25(6):1093-8., [PMID:20594224]

Abstract [show]
BACKGROUND AND AIM: Gallstone formation is characterized by the abnormal regulation of cholesterol trafficking and solubilization. The prevalence of gallstone disease (GSD) differs between ethnic groups sharing the common environment. These differences can be explained by a genetic predisposition to gallstone formation. Studies have identified single nucleotide polymorphisms (SNP) D19H and T400K in the cholesterol transporter gene ATP-binding cassette, subfamily G, member 8 (ABCG8) in patients with cholesterol gallstones. The aim of this study was to analyze the relationship between D19H and T400K polymorphisms in the ABCG8 gene and GSD in an Indian population, and the effects of these polymorphisms on cholesterol levels in sera and bile. METHODS: A total of 226 patients with GSD were analyzed for their lipid profile in plasma and bile. A total of 289 controls were recruited, and their plasma lipid profile was analyzed by standard protocols. The genotype of SNP D19H and T400K of ABCG8 was analyzed in 226 patients and 222 control samples. SNP D19H was analyzed by direct sequencing, and SNP T400K genotyping was assayed by the amplification refractory mutation system-polymerase chain reaction. RESULTS: There was no significant difference in the allelic distribution of SNP T400K between the GSD and gallstone-free groups (P > 0.05), but the distribution of the SNP variant, D19H, was significantly higher (P = 0.017, odds ratio = 2.274) in patients compared to controls. The analysis of serum and bile cholesterol followed a strong association with genotypes. CONCLUSION: SNP D19H, but not SNP T400K, in the ABCG8 gene is significantly associated with GSD in an Indian population.

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3 Studies have identified single nucleotide polymorphisms (SNP) D19H and T400K in the cholesterol transporter gene ATP-binding cassette, subfamily G, member 8 (ABCG8) in patients with cholesterol gallstones. Login to comment
4 The aim of this study was to analyze the relationship between D19H and T400K polymorphisms in the ABCG8 gene and GSD in an Indian population, and the effects of these polymorphisms on cholesterol levels in sera and bile. Login to comment
7 The genotype of SNP D19H and T400K of ABCG8 was analyzed in 226 patients and 222 control samples. Login to comment
8 SNP D19H was analyzed by direct sequencing, and SNP T400K genotyping was assayed by the amplification refractory mutation system-polymerase chain reaction. Login to comment
9 Results: There was no significant difference in the allelic distribution of SNP T400K between the GSD and gallstone-free groups (P > 0.05), but the distribution of the SNP variant, D19H, was significantly higher (P = 0.017, odds ratio = 2.274) in patients compared to controls. Login to comment
11 Conclusion: SNP D19H, but not SNP T400K, in the ABCG8 gene is significantly associated with GSD in an Indian population. Login to comment
18 Principally, gallstones are composed of cholesterol monohydrate crystals.14 Previous studies have found that the single nucleotide polymorphism (SNP) D19H of ABCG8 was stronger in patients with cholesterol gallstones (odds ratio =3.3), suggesting that H19 might be associated with more efficient transport of cholesterol into the bile; SNP T400K is found in Chinese males.15,16 The present study was undertaken to investigate, for the first time, the relationship between these two polymorphisms and GSD within an Indian population and to analyze their association with cholesterol in sera and bile. Login to comment
26 ABCG8 T400K analysis SNP T400K genotyping was assayed by tetra-primer ARMS-PCR that adopts principles of both the tetra-primer PCR method and the ARMS. Login to comment
42 The PCR reaction mixture and PCR conditions described for T400K were similar to SNP D19H, with the exception of the annealing temperature, which was 68°C. Login to comment
45 Low-density lipoprotein (LDL) cholesterol was Table 1 Polymerase chain reaction primer details of single nucleotide polymorphisms D19H and T400K of the ABCG8 gene Polymorphisms Primer sequence Annealing temperature Amplicon size D19H Forward primer: 68°C 306 bp 5'-ACTCGCAGCCCTGTTTCTAG 3' Reverse primer: 5'-GATGGGCTTTCACCTTGTTG 3' T400K Forward inner primer (A allele): 5'-ATGCCTGGGGCGGTGCAGCAGTTCAA3' Reverse inner primer (C allele): 5'-AAATGACAGATAATTACCGGATCAGCGCCG3' Forward outer primer (5'-3'): 5'-ACATCCCCTGCTTGCAGTGGACCTGACC3' Reverse outer primer (5'-3'): 5'-AGATGGGCTTTCACCTTGTTGCCCAGGC3' 65°C 287 bp (A allele) 365 bp (C allele) 596 bp (from two outer primers) Genetic basis of gallstone disease in India SP Siddapuram et al. 1094 Journal of Gastroenterology and Hepatology 25 (2010) 1093-1098 calculated using the Friedewald formula: T/5 = very low density lipoprotein (VLDL) TC-(HDL + VLDL). Login to comment
54 2 3 4 5 6 7 8 9 10 11 12 13 14 M 596 bp 365 bp 287 bp Figure 1 Electrophoresis of single nucleotide polymorphism T400K amplification refractory mutation system-polymerase chain reaction products. Login to comment
55 Tetra-primer-based genotyping of the ABCG8 T400K polymorphism: 596-bp product is common to both mutant and wild-type alleles; 365-bp product is specific for wild-type alleles; and 287-bp product is specific for mutant alleles. Login to comment
69 Distribution of SNP T400K and D19H between the GSD and GSF groups In the present study, 226 patients and 222 controls were analyzed for two SNP: T400K and D19H of the ABCG8 gene. Login to comment
71 No significant difference was observed in the distribution of genotypic frequency of SNP T400K when compared to the GSD and GSF groups (P = 0.520), whereas the distribution of SNP D19H showed a significant difference between the patient and control groups (P = 0.046). Login to comment
74 No significant difference was noted in any allele distribution of SNP T400K between the GSD and GSF groups, but the distribution of the heterozygous variant allele of SNP D19H was significantly higher (P = 0.048, OR = 2.219, CI: 1.054-4.672) in the GSD patients compared to the GSF individuals (Table 4). Login to comment
76 Thus, in the present study, allelic distribution infers that the T400K genotype might not be associated with gallstone formation in our cohort, whereas SNP D19H was shown to be associated with the disease. Login to comment
78 A strong association between elevated bile cholesterol and SNP D19H (P < 0.001) was observed in the analysis, where the mean bile cholesterol for SNP T400K (heterozygous + homozygous variants) was 155.13 mg/dL, and that of SNP D19H (heterozygous + homozygous variants) was 385.37 mg/dL Table 2 Demography and plasma lipid profile of gallstone disease and gallstone-free individuals Parameter Patient group Control group P-value Mean SD Mean SD Age (years) 45.88 14.840 39.92 11.864 0.063 BMI (kg/m2 ) 26.430 10.830 24.727 5.003 0.018 Plasma CH CH (mg/dL) 182.623 55.996 224.979 0.352 0.0001 HDL-C (mg/dL) 32.168 9.130 39.081 9.771 0.0001 LDL-C (mg/dL) 120.305 43.311 138.896 39.712 0.0001 TG (mg/dL) 149.672 83.945 147.207 89.148 0.324 BMI, body mass index; CH, cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SD, standard deviation; TG, triglycerides. Login to comment
79 Table 3 Frequency of genotype distribution of single nucleotide polymorphisms T400K and D19H between gallstone disease and gallstone-free individuals Single nucleotide polymorphisms of ABCG8 Wild type Heterozygous Homozygous P-value T400K (patients/controls) 69.47%/67.56% 29.20%/31.98% 1.32%/0.45% 0.520 D19H (patients/controls) 86.72%/93.69% 10.17%/4.95% 3.09%/1.35% 0.046 Table 4 Statistical analysis of single nucleotide polymorphisms T400K and D19H of ABCG8 between the gallstone disease and gallstone-free groups for possible alleles Allele P-value c2 -test Odds ratio 95% confidence interval T400K TT vs TK 0.608 0.33 0.888 0.594-1.329 TT vs. Login to comment
84 Discussion Genotyping The aim of present study was to determine whether SNP T400K and D19H of the ABCG8 gene were associated with GSD. Login to comment
87 A previous study mapped a susceptibility locus for gallstone formation to the murine ortholog of the ABCG5/ABCG8 genes, using a quantitative trait locus analysis in experimental crosses of inbred mouse strains.20 A recent linkage study of 715 individuals from 39 Mexican-American families with gallstone disease provided suggestive evidence of linkage to gallbladder disease on chromosome 2p21, the site of the ABCG5/ABCG8 genes.21 A genetic association study demonstrated that the ABCG8 D19H variant was significantly associated with the presence of gallstones in cases; the 19H (c.55C) allele was significantly more common in cases than in controls (OR = 3.018, P = 0.017).15 Carriers of the 19H allele, whether homozygous or heterozygous, were significantly overrepresented in the cases compared with the controls (OR = 3.118, P = 0.019), and in a case-control study, heterozygous 19H carriers (OR = 2.2) indicated a robust association of ABCG8 with gallstones in different populations.22 Previous studies have indicated the role of T400K polymorphisms in lipid parameters and the formation of gallstones.12 The frequencies of the K400 allele (12.4% vs 6.2%, P = 0.018) of ABCG8, and the TK/KK genotype (24.8% vs 12.4%, P = 0.025) were significantly higher in GSD groups than in GSF groups.23 In contrast, the present study frequencies of SNP genotypes T400K were not significantly different (Table 4) between patients and controls. Login to comment
88 Demography and lipid profile Several studies have reported that gallstones are more common in women than men and at all age groups, as the present study has indicated.24 In the present study, of the 226 patients, 56.7% (128) were females and 43.3% (98) were males. The demographic analysis in the present study showed a significantly higher BMI in GSD patients, which supports an earlier study.16 Hypersecretion of cholesterol from the liver and supersaturation of bile with cholesterol represents the common defects in patients with cholesterol gallstones.25,26 Another study suggested that the ABCG8 T400K polymorphism affects the reduction in total plasma cholesterol and LDL cholesterol levels.23 In earlier studies, researchers found a lower concentration of serum campesterol in 19H carriers, and hypothesized that the H allele leads to increased ABCG8transporter activity.10 Further, this hypothesis was supported by the observation that 19H carriership is associated with lower total serum cholesterol levels.27 Perhaps the basic function of both the T400K and D19H polymorphisms is the same to regulate cholesterol transport. Login to comment
92 In conclusion, our study shows for the first time in India that the D19H SNP of ABCG8 was shown to have a strong association with GSD, whereas the T400K SNP of ABCG8 was not found to be significant with the disease in the study cohort. Login to comment
96 Our sincere thanks to Dr Jamuna Cherri (Asian Healthcare Foundation) for her constant help in the plasma lipid profile analysis. We are extremely thankful to Ms Mary Thomas and Ms Vasantha Rani (Asian Healthcare Foundation) for 3040N = Group D19hT400k Bilecholesterol 700 600 500 400 300 200 100 0 Figure 3 Distribution of bile cholesterol in gallstone patients between mutant alleles of single nucleotide polymorphisms T400K and D19H of ABCG8. Login to comment
25 DNA was isolated from lymphocytes using standard methods.17 Two SNP, rs 4148217 = c.1199C>A (p.T400K) and rs 11887534 = c.55G>C (p.D19H) in the ABCG8 gene were analyzed by the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR; tetra-primer based) and direct sequencing methods, respectively. Login to comment

[hide] Role of ABCG8 D19H (rs11887534) variant in gallsto... J Gastroenterol Hepatol. 2010 Nov;25(11):1758-62. doi: 10.1111/j.1440-1746.2010.06349.x. Srivastava A, Srivastava A, Srivastava K, Choudhuri G, Mittal B
Role of ABCG8 D19H (rs11887534) variant in gallstone susceptibility in northern India.
J Gastroenterol Hepatol. 2010 Nov;25(11):1758-62. doi: 10.1111/j.1440-1746.2010.06349.x., [PMID:21039838]

Abstract [show]
BACKGROUND AND AIM: The excretion of cholesterol from the liver is regulated by the ATP-binding cassette transporter ABCG8. A common genetic polymorphism D19H of ABCG8 might be related to the genetic predisposition of gallstone disease, which is causatively related to supersaturation of cholesterol in bile. We aimed to examine the role of the ABCG8 D19H (rs11887534) polymorphism in susceptibility to gallstone disease in the northern Indian population. METHODS: The study included 220 confirmed gallstone patients and 230 controls. Genotyping for the ABCG8 D19H polymorphism was carried out using the PCR-RFLP method. RESULTS: We observed that the ABCG8 DH genotype frequency was significantly higher in gallstone patients (P = 0.038; odds ratio [OR] = 2.20; 95% confidence interval [CI] = 1.1-4.6). At allele level also, the ABCG8 variant allele conferred an increased risk for gallstone susceptibility (P = 0.043; OR = 2.12; 95% CI = 1.2-4.3). The risk as a result of ABCG8 D19H variation was more pronounced in female gallstone patients at genotype (P = 0.026; OR = 3.01, 95% CI = 1.1-7.9) as well as allele level (P = 0.030; OR = 2.85; 95% CI = 1.1-7.3). However, the molecular modeling results of the rs11887534 polymorphism showed that the overall configuration of both wild-type and polymorphic ABCG8 protein were similar, with negligible deviation at the site of polymorphism. Conclusion: Carriers of the DH genotype and H allele of the ABCG8 D19H polymorphism harbor a higher risk for gallstone susceptibility in the northern Indian population.

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70 Various recent studies have identified the ABCG8 D19H variant as the first common susceptibility factor for cholesterol gallstones in humans.16,34,35 However, Wang et al.17 showed that the ABCG8 T400K polymorphism, not D19H, might play a role in the lipid metabolism and formation of gallstones in the Chinese population. Login to comment

[hide] Association of selected ABC gene family single nuc... Atherosclerosis. 2010 Jul;211(1):203-9. Epub 2010 Jan 29. Abellan R, Mansego ML, Martinez-Hervas S, Martin-Escudero JC, Carmena R, Real JT, Redon J, Castrodeza-Sanz JJ, Chaves FJ
Association of selected ABC gene family single nucleotide polymorphisms with postprandial lipoproteins: results from the population-based Hortega study.
Atherosclerosis. 2010 Jul;211(1):203-9. Epub 2010 Jan 29., [PMID:20170916]

Abstract [show]
The aim of the study was to determine the influence of twenty single nucleotide polymorphisms (SNPs) of the ABCA1, ABCG1, ABCG5 and ABCG8 genes on the plasmatic concentrations of total cholesterol (TC), HDL and LDL cholesterol (HDLc, LDLc) in the postprandial state with a representative Spanish Caucasian population (1473 individuals, 50.0% women, ages ranging 21-85 years). In men, subjects with the AA genotype of the ABCA1 rs2230806 (R219K) polymorphism were associated with increased plasma LDLc levels, while the ABCA1 haplotype, which included the rs2230806 A allele, was associated with higher TC and LDLc plasma concentrations. In women, significant relationships were found between rs1893590 polymorphisms (ABCG1 gene) and HDLc plasma concentrations (subjects with the AA genotype had lower HDLc levels). For the ABCG8 gene, the rs4148211 polymorphism was associated with higher plasma TC and LDLc concentrations in the total population. Moreover, an ABCG5-G8 haplotype, which included the rs6544718 T allele, was associated with higher HDLc plasma concentrations in women. In conclusion, different SNPs of the ABCA1, ABCG1 and ABCG5-ABCG8 genes were associated, some under gender-specific analysis, with variations in the plasma lipid levels under postprandial conditions in a representative Spanish population.

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149 Regarding the Y54H polymorphism, diverging results have been observed in previous studies for associations with lipid levels [13,14,16,18,19]; these divergences in the results could be related with the degree of the reduction of total plasma cholesterol and LDLc with dietary changes [13]. Login to comment
151 However, Wang et al. [17] found higher but not significant plasma LDLc levels for carriers of the less frequent K allele of ABCG8 T400K, which was in strong linkage disequilibrium with the SNP Y54C of ABCG8. Login to comment

[hide] Intestinal absorption, hepatic synthesis, and bili... Hepatology. 2012 May;55(5):1313-6. doi: 10.1002/hep.25604. Epub 2012 Apr 4. Portincasa P, Wang DQ
Intestinal absorption, hepatic synthesis, and biliary secretion of cholesterol: where are we for cholesterol gallstone formation?
Hepatology. 2012 May;55(5):1313-6. doi: 10.1002/hep.25604. Epub 2012 Apr 4., [PMID:22271308]

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32 The ABCG8 p.D19H and p.T400K coding variants might play a role as putative susceptibility variants for gallstone formation in humans.14-16 Despite much evidence in this respect, the authors could not confirm such an interesting hypothesis, possibly due to the small cohort size. Login to comment

[hide] Phytosterol and cholesterol precursor levels indic... Hepatology. 2012 May;55(5):1507-17. doi: 10.1002/hep.25563. Epub 2012 Apr 4. Krawczyk M, Lutjohann D, Schirin-Sokhan R, Villarroel L, Nervi F, Pimentel F, Lammert F, Miquel JF
Phytosterol and cholesterol precursor levels indicate increased cholesterol excretion and biosynthesis in gallstone disease.
Hepatology. 2012 May;55(5):1507-17. doi: 10.1002/hep.25563. Epub 2012 Apr 4., [PMID:22213168]

Abstract [show]
In hepatocytes and enterocytes sterol uptake and secretion is mediated by Niemann-Pick C1-like 1 (NPC1L1) and ATP-binding cassette (ABC)G5/8 proteins, respectively. Whereas serum levels of phytosterols represent surrogate markers for intestinal cholesterol absorption, cholesterol precursors reflect cholesterol biosynthesis. Here we compare serum and biliary sterol levels in ethnically different populations of patients with gallstone disease (GSD) and stone-free controls to identify differences in cholesterol transport and synthesis between these groups. In this case-control study four cohorts were analyzed: 112 German patients with GSD and 152 controls; two distinct Chilean ethnic groups: Hispanics (100 GSD, 100 controls), and Amerindians (20 GSD, 20 controls); additionally an 8-year follow-up of 70 Hispanics was performed. Serum sterols were measured by gas chromatography / mass spectrometry. Gallbladder bile sterol levels were analyzed in cholesterol GSD and controls. Common ABCG5/8 variants were genotyped. Comparison of serum sterols showed lower levels of phytosterols and higher levels of cholesterol precursors in GSD patients than in controls. The ratios of phytosterols to cholesterol precursors were lower in GSD patients, whereas biliary phytosterol and cholesterol concentrations were elevated as compared with controls. In the follow-up study, serum phytosterol levels were significantly lower even before GSD was detectable by ultrasound. An ethnic gradient in the ratios of phytosterols to cholesterol precursors was apparent (Germans > Hispanics > Amerindians). ABCG5/8 variants did not fully explain the sterol metabolic trait of GSD in any of the cohorts. CONCLUSION: Individuals predisposed to GSD display increased biliary output of cholesterol in the setting of relatively low intestinal cholesterol absorption, indicating enhanced whole-body sterol clearance. This metabolic trait precedes gallstone formation and is a feature of ethnic groups at higher risk of cholesterol GSD.

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47 p.Y54C (rs4148211, c__29535502_10), p.T400K (rs4148217, c__375061_10), and p.A632V (rs6544718, c__25642779_10) variants, as described in Supporting Methods. Login to comment
48 The ABCG8 p.D19H and p.T400K coding variants have been described previously as putative susceptibility variants for gallstone formation in humans.13-15 Measurement of Sterols and Clinical Chemical Parameters. Login to comment

[hide] Macrothrombocytopenia/Stomatocytosis specially ass... Clin Appl Thromb Hemost. 2012 Nov;18(6):582-7. doi: 10.1177/1076029611435090. Epub 2012 Jan 31. Wang G, Cao L, Wang Z, Jiang M, Sun X, Bai X, Ruan C
Macrothrombocytopenia/Stomatocytosis specially associated with phytosterolemia.
Clin Appl Thromb Hemost. 2012 Nov;18(6):582-7. doi: 10.1177/1076029611435090. Epub 2012 Jan 31., [PMID:22297561]

Abstract [show]
Phytosterolemia is a rare autosomal recessive disease of plant sterol metabolism, the pathophysiological features of which are high plasma levels of plant sterols and xanthomatosis caused by mutations of ABCG5 and ABCG8 genes, and the combination of hemolysis and macrothrombocytopenia is an unusual clinical manifestation. All the patients of the 3 unrelated phytosterolemia first presented with prominent macrothrombocytopenia and stomatocytosis. They were either homozygous or compound heterozygous for ABCG5/ABCG8 gene mutations and had significantly elevated serum plant sterols levels quantified using high-performance liquid chromatography. The in vitro study demonstrated that sitosterol can cause changes in shape and osmotic fragility of red blood cells. These findings suggest that macrothrombocytopenia and stomatocytosis could be initial and main features in some patients with phytosterolemia and that serum phytosterols and relevant genes should be analyzed in patients whose macrothrombocytopenia and/or stomatocytosis are unexplained, especially whose parents are of consanguineous marriage.

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72 In addition, several neutral polymorphisms, such as Q604E of ABCG5, C54Y, T400K, and A632V of ABCG8 which had been previously described were also found in this study (not shown). Login to comment
71 In addition, several neutral polymorphisms, such as Q604E of ABCG5, C54Y, T400K, and A632V of ABCG8 which had been previously described were also found in this study (not shown). Login to comment

[hide] ATP-binding cassette transporter G5 and G8 polymor... PLoS One. 2012;7(5):e37972. Epub 2012 May 24. Li Q, Yin RX, Wei XL, Yan TT, Aung LH, Wu DF, Wu JZ, Lin WX, Liu CW, Pan SL
ATP-binding cassette transporter G5 and G8 polymorphisms and several environmental factors with serum lipid levels.
PLoS One. 2012;7(5):e37972. Epub 2012 May 24., [PMID:22655090]

Abstract [show]
BACKGROUND: The association of ATP-binding cassette (ABC) transporter single nucleotide polymorphisms (SNPs) and serum lipid profiles is inconsistent. The present study was undertaken to detect the association of ABCG5/G8 SNPs and several environmental factors with serum lipid levels. METHODOLOGY/PRINCIPAL FINDINGS: Genotyping of the ABCG5 (rs4131229 and rs6720173) and ABCG8 (rs3806471 and rs4148211) SNPs was performed in 719 unrelated subjects of Mulao nationality and 782 participants of Han nationality. There were no differences in the genotypic and allelic frequencies of four SNPs between the two ethnic groups besides the genotypic frequencies of rs4131229 SNP in Han. The levels of triglyceride (TG), apolipoprotein (Apo) A1, and ApoA1/ApoB ratio (rs4131229); low-density lipoprotein cholesterol (LDL-C) and ApoB (rs6720173); high-density lipoprotein cholesterol (HDL-C), ApoA1, ApoB, and ApoA1/ApoB ratio (rs3806471); and HDL-C, ApoA1, and ApoA1/ApoB ratio (rs4148211) in Han were different among their genotypes (P<0.05-0.001). The levels of LDL-C (rs6720173) and ApoA1 (rs3806471) in Mulao were also different among their genotypes (P<0.05 for each). The levels of TC, TG, HDL-C, ApoA1, and ApoA1/ApoB ratio (rs4131229); LDL-C and ApoB (rs6720173); HDL-C, ApoA1, and ApoA1/ApoB ratio (rs3806471); and TG, HDL-C, ApoA1, and ApoA1/ApoB ratio (rs4148211) in Han males; and ApoA1/ApoB ratio (rs4131229); LDL-C, ApoB, and ApoA1/ApoB ratio (rs3806471); HDL-C, ApoA1, and ApoA1/ApoB ratio (rs4148211) in Han females were different between the genotypes (P<0.05-0.001). The levels of LDL-C in Mulao females were also different between GG and GC/CC genotypes of rs6720173 (P<0.05). The correlation between serum lipid parameters and genotypes of four SNPs was observed in Han, especially in Han males. Serum lipid parameters were also correlated with several environmental factors. CONCLUSIONS: The associations of four ABCG5/G8 SNPs and serum lipid levels are different between the Mulao and Han populations, or between males and females, suggesting that there may be a racial/ethnic- and/or sex-specific association between ABCG5/G8 SNPs and some serum lipid parameters.

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182 Allele frequencies of the ABCG8 D19H, Y54C, T400K, and A632V SNPs in patients with ischemic vascular diseases showed no significant differences compared with controls. Login to comment
217 The other ABCG5/G8 SNPs (Q604E, Y54C, T400K and A632V) did not show any significant interactions with the CYP7A1 polymorphism. Login to comment
218 No association was observed between ABCG8 T400K and total and LDL-C levels [32-34,36,38-41]. Login to comment
226 The remaining SNPs (Q604E, D19H, Y54C, and T400K) were not associated with plasma lipid levels [60]. Login to comment
241 020 0.062 2.509 0.012 Systolic blood pressure 0.001 0.001 0.066 2.590 0.010 ApoA1/ApoB Waist circumference 20.019 0.002 20.198 27.862 0.000 Age 20.005 0.001 20.089 23.544 0.000 Han TC Waist circumference 0.019 0.005 0.131 3.767 0.000 Age 0.009 0.003 0.126 3.443 0.001 Alcohol consumption 0.302 0.057 0.179 5.286 0.000 Diastolic blood pressure 0.017 0.004 0.168 4.661 0.000 Blood glucose 0.066 0.024 0.095 2.723 0.007 TG Waist circumference 0.075 0.013 0.254 5.661 0.000 Cigarette smoking 0.805 0.165 0.185 4.889 0.000 Blood glucose 0.265 0.049 0.186 5.407 0.000 Diastolic blood pressure 0.030 0.007 0.147 4.120 0.000 Age 20.017 0.005 20.113 23.114 0.002 Alcohol consumption 0.269 0.132 0.078 2.040 0.042 Body mass index 20.065 0.030 20.096 22.157 0.031 HDL-C Waist circumference 20.011 0.002 20.155 24.279 0.000 Gender 0.130 0.046 0.120 2.825 0.005 Alcohol consumption 0.111 0.034 0.138 3.317 0.001 LDL-C Age 0.012 0.002 0.212 6.219 0.000 Body mass index 0.026 0.012 0.101 2.222 0.027 Waist circumference 0.013 0.005 0.115 2.471 0.014 Cigarette smoking 20.310 0.072 20.187 24.227 0.000 hypercholesterolaemic Japanese subjects, Miwa et al. [42] reported that carriers of the ABCG8 M429V or a specific haplotype (wild-type allele of ABCG5 Q604E, and wild-type alleles of ABCG8 C54Y, T400K, and M429V) had higher cholesterol absorption efficiency than non-carriers. Login to comment
242 However, no difference was observed in serum lipid profiles in relation to common SNPs studied previously in Caucasian populations (ABCG5 Q604E and ABCG8 A632V, T400K, D19H and C54Y). Login to comment
244 Interestingly, in 1046 Chinese, Chen et al. [43] observed that the heterozygote of ABCG8 D19H had higher serum total and LDL-C levels than homozygote DD, which is opposite to the effect observed in Caucasian populations. Login to comment
246 No association with ABCG8 C54Y and T400K regarding total and LDL-C levels was observed. Login to comment
254 Recently, in 845 self-identified Puerto Ricans from Boston, Junyent et al. [38] reported that ABCG5/G8 (i7892T.C, rs4131229; 5U145A.C, rs3806471; Y54C; T400K) SNPs were significantly associated with HDL-C concentrations. Login to comment
258 Also, for ABCG8 T400K, smokers, but not nonsmokers, homozygous for the T allele displayed lower HDL-C levels. Login to comment
264 Recently, significant gene-gene interactions for HDL-C were found between ABCG8 (5U145 A.C, T54C A.G, T400K C.A) SNPs and ABCA1_i48168 G.A genetic variant, in which carriers of the 5U145C and 54C alleles, and homozygotes for the T400 allele at ABCG8 genetic variants displayed lower HDL-C concentrations than homozygotes for the 5U145A and T54 alleles, and heterozygotes for the 400K allele at ABCG8 SNPs, only if they were also homozygous for the minor allele (A) at the aforementioned ABCA1 SNP [63]. Login to comment
180 Allele frequencies of the ABCG8 D19H, Y54C, T400K, and A632V SNPs in patients with ischemic vascular diseases showed no significant differences compared with controls. Login to comment
215 The other ABCG5/G8 SNPs (Q604E, Y54C, T400K and A632V) did not show any significant interactions with the CYP7A1 polymorphism. Login to comment
216 No association was observed between ABCG8 T400K and total and LDL-C levels [32-34,36,38-41]. Login to comment
224 The remaining SNPs (Q604E, D19H, Y54C, and T400K) were not associated with plasma lipid levels [60]. Login to comment
239 020 0.062 2.509 0.012 Systolic blood pressure 0.001 0.001 0.066 2.590 0.010 ApoA1/ApoB Waist circumference 20.019 0.002 20.198 27.862 0.000 Age 20.005 0.001 20.089 23.544 0.000 Han TC Waist circumference 0.019 0.005 0.131 3.767 0.000 Age 0.009 0.003 0.126 3.443 0.001 Alcohol consumption 0.302 0.057 0.179 5.286 0.000 Diastolic blood pressure 0.017 0.004 0.168 4.661 0.000 Blood glucose 0.066 0.024 0.095 2.723 0.007 TG Waist circumference 0.075 0.013 0.254 5.661 0.000 Cigarette smoking 0.805 0.165 0.185 4.889 0.000 Blood glucose 0.265 0.049 0.186 5.407 0.000 Diastolic blood pressure 0.030 0.007 0.147 4.120 0.000 Age 20.017 0.005 20.113 23.114 0.002 Alcohol consumption 0.269 0.132 0.078 2.040 0.042 Body mass index 20.065 0.030 20.096 22.157 0.031 HDL-C Waist circumference 20.011 0.002 20.155 24.279 0.000 Gender 0.130 0.046 0.120 2.825 0.005 Alcohol consumption 0.111 0.034 0.138 3.317 0.001 LDL-C Age 0.012 0.002 0.212 6.219 0.000 Body mass index 0.026 0.012 0.101 2.222 0.027 Waist circumference 0.013 0.005 0.115 2.471 0.014 Cigarette smoking 20.310 0.072 20.187 24.227 0.000 hypercholesterolaemic Japanese subjects, Miwa et al. [42] reported that carriers of the ABCG8 M429V or a specific haplotype (wild-type allele of ABCG5 Q604E, and wild-type alleles of ABCG8 C54Y, T400K, and M429V) had higher cholesterol absorption efficiency than non-carriers. Login to comment
240 However, no difference was observed in serum lipid profiles in relation to common SNPs studied previously in Caucasian populations (ABCG5 Q604E and ABCG8 A632V, T400K, D19H and C54Y). Login to comment
252 Recently, in 845 self-identified Puerto Ricans from Boston, Junyent et al. [38] reported that ABCG5/G8 (i7892T.C, rs4131229; 5U145A.C, rs3806471; Y54C; T400K) SNPs were significantly associated with HDL-C concentrations. Login to comment
255 Carriers of the minor alleles at ABCG5/G8 (Q604E, D19H, i14222 A.G, rs6709904) SNPs displayed lower levels of HDL-C only if they were smokers. Login to comment
256 Also, for ABCG8 T400K, smokers, but not nonsmokers, homozygous for the T allele displayed lower HDL-C levels. Login to comment
262 Recently, significant gene-gene interactions for HDL-C were found between ABCG8 (5U145 A.C, T54C A.G, T400K C.A) SNPs and ABCA1_i48168 G.A genetic variant, in which carriers of the 5U145C and 54C alleles, and homozygotes for the T400 allele at ABCG8 genetic variants displayed lower HDL-C concentrations than homozygotes for the 5U145A and T54 alleles, and heterozygotes for the 400K allele at ABCG8 SNPs, only if they were also homozygous for the minor allele (A) at the aforementioned ABCA1 SNP [63]. Login to comment
181 Allele frequencies of the ABCG8 D19H, Y54C, T400K, and A632V SNPs in patients with ischemic vascular diseases showed no significant differences compared with controls. Login to comment
225 The remaining SNPs (Q604E, D19H, Y54C, and T400K) were not associated with plasma lipid levels [60]. Login to comment
251 Recently, in 845 self-identified Puerto Ricans from Boston, Junyent et al. [38] reported that ABCG5/G8 (i7892T.C, rs4131229; 5U145A.C, rs3806471; Y54C; T400K) SNPs were significantly associated with HDL-C concentrations. Login to comment
261 Recently, significant gene-gene interactions for HDL-C were found between ABCG8 (5U145 A.C, T54C A.G, T400K C.A) SNPs and ABCA1_i48168 G.A genetic variant, in which carriers of the 5U145C and 54C alleles, and homozygotes for the T400 allele at ABCG8 genetic variants displayed lower HDL-C concentrations than homozygotes for the 5U145A and T54 alleles, and heterozygotes for the 400K allele at ABCG8 SNPs, only if they were also homozygous for the minor allele (A) at the aforementioned ABCA1 SNP [63]. Login to comment

[hide] Increased plasma plant sterol concentrations and a... Eur J Med Genet. 2011 Jul-Aug;54(4):e458-60. Epub 2011 May 23. Keller S, Prechtl D, Aslanidis C, Ceglarek U, Thiery J, Schmitz G, Jahreis G
Increased plasma plant sterol concentrations and a heterozygous amino acid exchange in ATP binding cassette transporter ABCG5: a case report.
Eur J Med Genet. 2011 Jul-Aug;54(4):e458-60. Epub 2011 May 23., [PMID:21664501]

Abstract [show]
Whilst conducting a scientific study, an elevated plasma plant sterol concentration of 3.07 mg/dL was established in one proband. Similar levels found in his mothers plasma (2.73 mg/dL) were suggestive of a heterozygous sitosterolemia. The resulting gene analysis for ATP binding cassette transporter G5/G8 (ABCG5/G8) revealed a heterozygous polymorphism in ABCG8 (Thr400Lys, rs4148217), which the proband had inherited from his father. However, a heterozygous amino acid exchange (Arg406Gln) in exon 9 of ABCG5 was revealed, which was inherited from his mother. Although not sufficient evidence exists to regard this sequence variation as a mutation, this previously unreleased sequence variation occurred in a "hot spot" area for sitosterolemia of the ABCG5 gene (exon 9) and the similar increased plasma plant sterol concentrations of the heterozygous mother contribute to the notion, that this very likely presents an inactivating mutation.

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3 The resulting gene analysis for ATP binding cassette transporter G5/G8 (ABCG5/G8) revealed a heterozygous polymorphism in ABCG8 (Thr400Lys, rs4148217), which the proband had inherited from his father. Login to comment
50 A heterozygous nucleotide change (c.1199C > A; NM_022437.2) resulting in an amino acid exchange (Thr400Lys, ACG400AAG; NP_071882.1) was found for the ABCG8 gene. Login to comment
53 Koeijvoets et al. [12] did not find an association between the polymorphism Thr400Lys in ABCG8 and cardiovascular endpoints. Login to comment

[hide] Genetic variations at ABCG5/G8 genes modulate plas... Atherosclerosis. 2010 Jun;210(2):486-92. Epub 2010 Jan 22. Garcia-Rios A, Perez-Martinez P, Fuentes F, Mata P, Lopez-Miranda J, Alonso R, Rodriguez F, Garcia-Olid A, Ruano J, Ordovas JM, Perez-Jimenez F
Genetic variations at ABCG5/G8 genes modulate plasma lipids concentrations in patients with familial hypercholesterolemia.
Atherosclerosis. 2010 Jun;210(2):486-92. Epub 2010 Jan 22., [PMID:20172523]

Abstract [show]
OBJECTIVE: To investigate the association of four common single nucleotide polymorphisms (SNPs) at ABCG5 (i7892A>G, i18429C>T, Gln604GluC>G, i11836G>A) and five at ABCG8 (5U145T>G, Tyr54CysA>G, Asp19HisG>C, i14222T>C, and Thr400LysG>T) with plasma lipids concentrations and to explore the interaction between those SNPs and smoking in patients with FH. METHODS AND RESULTS: ABCG5/G8 SNPs were genotyped in 500 subjects with genetic diagnosis of FH. Carriers of the minor A allele at the ABCG5_i11836G>A SNP displayed significantly higher HDL-C concentrations (P=0.023) than G/G subjects. In addition, carriers of the minor G allele at the ABCG5_Gln604GluC>G SNP had significantly lower VLDL-C (P=0.011) and lower TG (P=0.017) concentrations than homozygous C/C. Interestingly, a significant gene-smoking interaction was found, in which carriers of the minor alleles at ABCG5 (i7892A>G, i18429C>T, i11836G>A) SNPs displayed significantly lower HDL-C, higher TC and higher TG respectively, only in smokers. On the other hand, nonsmokers carriers of the minor alleles at ABCG5 (i18429C>T and Gln604GluC>G) SNPs had significantly lower TG concentrations (P=0.012 and P=0.035) compared with homozygous for the major allele. CONCLUSIONS: Our data support the notion that ABCG5/G8 genetic variants modulate plasma lipids concentrations in patients with FH and confirm that this effect could be influenced by smoking. Therefore, these results suggest that gene-environmental interactions can affect the clinical phenotype of FH.

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22 Another study examined the relationship between SNPs in the ABCG8 gene (D19H and T400K) and plasma cholesterol concentrations in patients with heterozygous FH [12]. Login to comment
145 In this context, Koeijvoets et al. [12] explored the effect of two common ABCG8 (D19H and T400K) SNPs on lipids and CVD in 2,012 patients with heterozygous FH but did not find significant associations with plasma lipid concentrations. Login to comment
150 On the other hand, Miwa et al. [11] reported no significant associations between three ABCG5/G8 (Q604E, C54Y and T400K) SNPs and serum lipid concentrations in 100 Japanese primary hypercholesterolaemic patients. Login to comment
151 Consistent with both studies [11,12] we did not find associations between D19H, T400K and C54Y SNPs and plasma lipid concentrations. Login to comment
152 However, in contrast to Miwa et al. our data showed association between Q604E SNP and VLDL-C and TG concentrations. Login to comment
154 Additionally, Santosa et al. [10] examined the association of four SNPs at ABCG5 (Q604E, i7892, i18429 and M216) and four ABCG8 (C54Y, D19H, i14222 and T400K) with plasma lipids concentrations in 35 young women with mildly hypercholesterolemia. Login to comment
155 They found that C54Y and Q604E SNPs were associated with the response of cholesterol metabolism to weight loss. Login to comment
146 In this context, Koeijvoets et al. [12] explored the effect of two common ABCG8 (D19H and T400K) SNPs on lipids and CVD in 2,012 patients with heterozygous FH but did not find significant associations with plasma lipid concentrations. Login to comment
21 Another study examined the relationship between SNPs in the ABCG8 gene (D19H and T400K) and plasma cholesterol concentrations in patients with heterozygous FH [12]. Login to comment
143 In this context, Koeijvoets et al. [12] explored the effect of two common ABCG8 (D19H and T400K) SNPs on lipids and CVD in 2,012 patients with heterozygous FH but did not find significant associations with plasma lipid concentrations. Login to comment
148 On the other hand, Miwa et al. [11] reported no significant associations between three ABCG5/G8 (Q604E, C54Y and T400K) SNPs and serum lipid concentrations in 100 Japanese primary hypercholesterolaemic patients. Login to comment
149 Consistent with both studies [11,12] we did not find associations between D19H, T400K and C54Y SNPs and plasma lipid concentrations. Login to comment

[hide] The potential influence of genetic variants in gen... Atherosclerosis. 2010 May;210(1):14-27. Epub 2009 Nov 5. Lu Y, Feskens EJ, Boer JM, Muller M
The potential influence of genetic variants in genes along bile acid and bile metabolic pathway on blood cholesterol levels in the population.
Atherosclerosis. 2010 May;210(1):14-27. Epub 2009 Nov 5., [PMID:19932478]

Abstract [show]
The liver is currently known to be the major organ to eliminate excess cholesterol from our body. It accomplishes this function in two ways: conversion of cholesterol molecules into bile acids (BAs) and secretion of unesterified cholesterol molecules into bile. BAs are synthesized in the hepatocytes, secreted into bile and delivered to the lumen of the small intestine where they act as detergents to facilitate absorption of fats and fat-soluble vitamins. About 95% of BAs are recovered in the ileum during each cycle of the enterohepatic circulation. Five percent are lost and replaced by newly synthesized BAs, which amounts to approximately 500 mg/day in adult humans. In contrast to the efficiency of the BAs' enterohepatic circulation, 50% of the 1000 mg of cholesterol secreted daily into bile is lost in feces. It is known that rare human mutations in certain genes in bile acid and bile metabolic pathway influence blood cholesterol levels. With the recent success of genome-wide association studies, we are convinced that common genetic variants also play a role in the genetic architecture of plasma lipid traits. In this review, we summarized the current state of knowledge about genetic variations in bile acid and bile metabolic pathway, and assessed their impact on blood cholesterol levels and cholesterol metabolic kinetics in the population.

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1748 Several polymorphisms in ABCG5 (Q604E, rs6720173) and ABCG8 (T400K, rs4148217; D19H, rs11887534; A632V, rs6544718; and Y54C, rs4148211) have been found to be associated with several facets of cholesterol metabolism, including cholesterol level, cholesterol kinetics, and individual responsiveness of blood cholesterol to dietary and pharmaceutical intervention [41]. Login to comment
1773 No association was observed between T400K of the ABCG8 gene and total and LDL cholesterol levels [44,45,47-50,53,55]. Login to comment
1785 Overall, no consistent results on effects of T400K, A632V and Y54C in ABCG8 gene on blood cholesterol levels and cholesterol metabolic kinetics were reported so far. Login to comment
1787 No modulating effect was observed from T400K, A632V or Y54C on cholesterol lowering response to atorvastatin [25,26]. Login to comment
1795 In 100 hypercholesterolaemic Japanese subjects, Miwa et al. [56] reported that carriers of the M429V variant of ABCG8 or a specific haplotype (wild-type allele of Q604E ABCG5, and wild-type allele of C54Y, wild-type allele of T400K, mutant allele of M429V ABCG8) had higher cholesterol absorption efficiency than non-carriers. Login to comment
1796 However, no difference was observed in serum lipid profiles in relation to common polymorphisms studied previously in Caucasian populations [ABCG5 (Q604E) and ABCG8 (A632V, T400K, D19H and C54Y)]. Login to comment
1800 No association with C54Y and T400K of ABCG8 regarding total and LDL cholesterol levels was observed. Login to comment
1802 Recently, in 845 self-identified Puerto Ricans from Boston, Junyent et al. [47] reported that ABCG5/G8 (i7892T > C, rs4131229; 5U145A > C, rs3806471; Y54C; T400K) SNPs were significantly associated with HDL-C concentrations. Login to comment
1806 Also, for ABCG8 T400K, smokers, but not nonsmokers, homozygous for the T allele displayed lower HDL cholesterol levels. Login to comment
1862 Gylling et al. [45] 262 mildly to moderately hypercholesterolemic Finnish subjects No difference in TC, LDL-C and HDL-C Junyent et al. [47] 845 self-identified Puerto Ricans No difference in TC and LDL-C, but K allele carriers had higher HDL-C than TT Santosa et al. [48] 42 overweight/obese Canadian women No difference in TC, LDL-C and HDL-C Acalovschi et al. [49] 68 Romanian siblings with gallstone disease No difference in TC and HDL-C Plat et al. [50] 112 healthy Dutch volunteers No difference in LDL-C and HDL-C Koeijvoets et al. [53] 2012 Dutch patients with heterozygous familial hypercholesteroemia No difference in TC, LDL-C and HDL-C Chan et al. [55] 47 nonsmoking overweight/obese Australian men No difference in TC, LDL-C and HDL-C Hubacek et al. [46] 285 Czech participants A smaller decrease in TC and LDL-C in K allele carriers than TT after changing dietary habits (less meat and more vegetable) Berge et al. [44] 143 healthy American Caucasians Lower cholesterol absorption marker sterol (serum cholesterol adjusted sitosterol levels) and higher cholesterol synthesis marker sterol (serum cholesterol adjusted desmosterol and lathosterol levels) in K allele carriers than TT Plat et al. [50] 112 healthy Dutch volunteers Higher absorption in campesterol and sitosterol and a stronger inhibitor effect of plant stanol ester on campesterol and sitosterol absorption in TT than K allele carriers Gylling et al. [45] 262 mildly to moderately hypercholesterolemic Finnish subjects No difference in plasma cholesterol absorption and synthesis markers Kajinami et al. [25] 337 hypercholesterolemic subjects, mainly Caucasians No modulating effect from T400K on cholesterol lowering response to atorvastatin Y.Luetal./Atherosclerosis210(2010)14-27 Table 1(Continued). Login to comment

[hide] Long-term consumption of plant stanol and sterol e... Br J Nutr. 2009 Jun;101(11):1688-95. Epub 2008 Nov 19. Gylling H, Hallikainen M, Raitakari OT, Laakso M, Vartiainen E, Salo P, Korpelainen V, Sundvall J, Miettinen TA
Long-term consumption of plant stanol and sterol esters, vascular function and genetic regulation.
Br J Nutr. 2009 Jun;101(11):1688-95. Epub 2008 Nov 19., [PMID:19019257]

Abstract [show]
Polymorphisms of the ABCG5 and ABCG8 genes interfere with cholesterol absorption and synthesis. We determined whether common polymorphisms of these genes regulate the responses of serum cholesterol and vascular function during long-term inhibition of cholesterol absorption. Mildly to moderately hypercholesterolaemic subjects (n 282) completed a 1-year study consuming plant stanol or sterol ester (2 g stanol or sterol) or control spread. Serum cholesterol and non-cholesterol sterols, markers of cholesterol absorption and synthesis, and variables of vascular function and structure were analysed in relation to common polymorphisms of ABCG5 and ABCG8. At baseline, subjects with the 54K allele of ABCG8 had higher brachial endothelial-dependent flow-mediated dilatation than those without it (5.79 (se 0.31) v. 4.46 (se 0.44) %; P = 0.049), and subjects with the 632V allele of ABCG8 had larger brachial artery diameter than those without it. Polymorphisms of ABCG5 and ABCG8 were neither associated with serum cholesterol reduction nor changes in cholesterol metabolism or in vascular function. However, in subjects with the 400K allele of ABCG8, intima media thickness (IMT) was increased in all groups more than in those without it (P < 0.05). In conclusion, serum cholesterol lowering with absorption inhibition was not associated with polymorphic sites of ABCG5 and ABCG8. However, regulation of baseline cholesterol metabolism and vascular function and structure, and IMT progression during 1 year seemed to share some of the common polymorphic sites of these genes, suggesting a gene-regulated interaction between cholesterol metabolism and vascular function and structure.

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155 The present results differ from a previous study conducted in healthy subjects, in whom the serum plant sterol response to stanol esters was associated with the ABCG8 T400K genotype(23) . Login to comment
176 During the intervention the T400K polymorphic site of ABCG8 was associated with the increase in IMT. Login to comment
179 Since at baseline the same T400K polymorphic site of ABCG8 separated subjects with a profile of cholesterol metabolism characteristic for the metabolic syndrome, we assume that low cholesterol absorption and high synthesis as part of the metabolic syndrome is unfavourable for the progression of IMT. Login to comment

[hide] The metabolism of plant sterols is disturbed in po... Metabolism. 2009 Mar;58(3):401-7. Gylling H, Hallikainen M, Rajaratnam RA, Simonen P, Pihlajamaki J, Laakso M, Miettinen TA
The metabolism of plant sterols is disturbed in postmenopausal women with coronary artery disease.
Metabolism. 2009 Mar;58(3):401-7., [PMID:19217458]

Abstract [show]
In postmenopausal coronary artery disease (CAD) women, serum plant sterols are elevated. Thus, we investigated further whether serum plant sterols reflect absolute cholesterol metabolism in CAD as in other populations and whether the ABCG5 and ABCG8 genes, associated with plant sterol metabolism, were related to the risk of CAD. In free-living postmenopausal women with (n = 47) and without (n = 62) CAD, serum noncholesterol sterols including plant sterols were analyzed with gas-liquid chromatography, cholesterol absorption with peroral isotopes, absolute cholesterol synthesis with sterol balance technique, and bile acid synthesis with quantitating fecal bile acids. In CAD women, serum plant sterol ratios to cholesterol were 21% to 26% (P < .05) higher than in controls despite similar cholesterol absorption efficiency. Absolute cholesterol and bile acid synthesis were reduced. Only in controls were serum plant sterols related to cholesterol absorption (eg, sitosterol; in controls: r = 0.533, P < .001; in CAD: r = 0.296, P = not significant). However, even in CAD women, serum lathosterol (relative synthesis marker) and lathosterol-cholestanol (relative synthesis-absorption marker) were related to absolute synthesis and absorption percentage (P range from .05 to <.001) similarly to controls. Frequencies of the common polymorphisms of ABCG5 and ABCG8 genes did not differ between coronary and control women. In conclusion, plant sterol metabolism is disturbed in CAD women; so serum plant sterols only tended to reflect absolute cholesterol absorption. Other relative markers of cholesterol metabolism were related to the absolute ones in both groups. ABCG5 and ABCG8 genes were not associated with the risk of CAD.

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34 Sequence variations in D19H [18,19] and T400K [18] of ABCG8 were associated with low serum plant sterol [18,19] and high serum synthesis marker [19] ratios to cholesterol in earlier studies. Login to comment

[hide] Increased NPC1L1 and ACAT2 expression in the jejun... Biochem Biophys Res Commun. 2009 Jan 30;379(1):49-54. Epub 2008 Dec 9. Jiang ZY, Jiang CY, Wang L, Wang JC, Zhang SD, Einarsson C, Eriksson M, Han TQ, Parini P, Eggertsen G
Increased NPC1L1 and ACAT2 expression in the jejunal mucosa from Chinese gallstone patients.
Biochem Biophys Res Commun. 2009 Jan 30;379(1):49-54. Epub 2008 Dec 9., [PMID:19071091]

Abstract [show]
The incidence of cholesterol gallstones is a very common disease. The aim of this study is to probe for underlying intestinal molecular defects associated with development of gallstones. Twelve Chinese patients with cholesterol gallstone disease (GS) and 31 gallstone-free (GSF) patients were investigated. Quantitation of mRNA levels for individual genes in mucosal biopsies from jejunum was carried out with real-time PCR. The frequency of two SNPs in the ABCG8 gene (Y54C and T400K) was determined by allelic discrimination. The intestinal mRNA expression of NPC1L1 and ACAT2 were significantly higher in GS than GSF (P<0.05). No differences were observed concerning the levels for plasma lipids, plant sterols and 7alpha-hydroxy-4-cholesten-3-one between GS and GSF. No correlations were observed between patients carrying the different genotypes for Y54C or T400K and their mRNA levels for ABCG5 or ABCG8. The increased NPC1L1 and ACAT2 mRNA levels in gallstone patients might indicate an upregulated absorption and esterification of cholesterol in the small intestine.

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4 The frequency of two SNPs in the ABCG8 gene (Y54C and T400K) was determined by allelic discrimination. Login to comment
7 No correlations were observed between patients carrying the different genotypes for Y54C or T400K and their mRNA levels for ABCG5 or ABCG8. Login to comment
55 Single nucleotide polymorphism (SNP) analysis of the polymorphic sites Y54C and T400K in the ABCG8 gene were determined by allelic discrimination using intestinal cDNA as template. Login to comment
58 T400K: forward primer: GCC TCC CGA GTC CTA CGA A; reverse primer: CGG AAG TCG TTG GAA ATC TGA C. Login to comment
85 for the Y54C and T400K polymorphisms in ABCG8 gene in the GS and GSF patients. Login to comment
86 Previously, T400K had been shown to associate with gallstone disease in Chinese patients [24], but this material was too small to allow a similar evaluation. Login to comment
88 The campesterol and sitosterol levels were lower in subjects heterozygous or homozygous for the Y54C or the T400K polymorphism compared to individuals homozygous for the WT allele, but significance was only obtained for campesterol (Table 1, P < 0.05). Login to comment
101 (D) Comparison between mRNA levels of the genes ABCG5/G8, NPC1L1, and ACCAT2 in the individuals of the total material (GS + GSF) with reference to the T400K polymorphic site in the ABCG8 gene. Login to comment
102 Table 1 Plasma lipid and plant sterol levels in the total material with reference to the polymorphic sites Y54C and T400K in the ABCG8 gene (means ± SEM). Login to comment
126 T400K was overrepresented in a Chinese GS patient material [24], and we also concluded that individuals with this SNP showed lower levels of plasma campesterol. Login to comment

[hide] Association between non-responsiveness to plant st... Appl Physiol Nutr Metab. 2008 Aug;33(4):728-34. Rudkowska I, AbuMweis SS, Nicolle C, Jones PJ
Association between non-responsiveness to plant sterol intervention and polymorphisms in cholesterol metabolism genes: a case-control study.
Appl Physiol Nutr Metab. 2008 Aug;33(4):728-34., [PMID:18641716]

Abstract [show]
Plant sterol (PS) consumption decreases low-density lipoprotein cholesterol (LDL-C) levels; however, high variability of responsiveness of lipid levels to PS intervention has been observed. We hypothesized that common single-nucleotide polymorphisms (SNPs) in the genes for the ATP binding cassette proteins G5 (ABCG5) and G8 (ABCG8), Niemann-Pick C1-like 1 (NPC1L1), or other proteins of the cholesterol pathway, would underline inter-individual variations in response to PS. Twenty-six hyperlipidemic subjects completed a randomized trial of 3 PS phases and a control phase. Three non-responders were identified who failed on 3 consecutive occasions to decrease either total cholesterol or LDL-C level vs. control. It was observed that after 3 PS phases compared with a control phase, cholesterol absorption changed to a lesser degree (-7.7% +/- 10.8%) in the non-responders than in the top 3 responders (-22.1% +/- 8.8%); however, cholesterol synthesis rates did not differ between sub-groups. No common polymorphisms in ABCG8, ABCG5, or NPC1L1 were demonstrated between the 3 top responders and the non-responders. Yet, 1 non-responsive subject did demonstrate a rare SNP in NPC1L1. Results indicate PS intake did not decrease cholesterol absorption rates to the same degree in certain subjects, possibly clarifying the inter-individual variability in the cholesterol-lowering effect; hence, this work should be expanded.

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112 In general, results show that all subjects were homozygous for all ABCG5/G8 polymorphisms, except for 1 non-responder, who was heterozygous for A632V (rs6544718) and T400K (rs414817) in the ABCG8 transporters. Login to comment
114 Hubacek et al. (2004) showed that T400K in the ABCG8 gene associates with changes in lipid levels in males in response to reduced dietary animal fat and cholesterol intake. Login to comment
115 In particular, males had greater reductions of TC with the wild-type allele than with the mutant allele of the T400K in the ABCG8 gene. Login to comment
117 In addition, Plat et al. (2005) showed that cholesterol-standardized serum PS concentrations, as well as changes in serum PS concentrations after consumption of PS, were associated with the ABCG8 T400K genotype. Login to comment
118 However, similar to the present study, no associations were seen between any common variations in T400K with lipids responsiveness to PS intervention (Plat et al. 2005). Login to comment

[hide] ATP binding cassette G8 T400K polymorphism may aff... Clin Chim Acta. 2007 Sep;384(1-2):80-5. Epub 2007 Jun 16. Wang Y, Jiang ZY, Fei J, Xin L, Cai Q, Jiang ZH, Zhu ZG, Han TQ, Zhang SD
ATP binding cassette G8 T400K polymorphism may affect the risk of gallstone disease among Chinese males.
Clin Chim Acta. 2007 Sep;384(1-2):80-5. Epub 2007 Jun 16., [PMID:17612515]

Abstract [show]
BACKGROUND: Supersaturation of bile with cholesterol is a primary step in the formation of cholesterol gallstones. ATP binding cassette (ABC) G5 and G8 play an important role in regulating sterol absorption and secretion. To investigate a possible association between transporter gene polymorphism and gallstone formation, we examined five common polymorphisms in the ABCG5 (Q604E) and ABCG8 (D19H, Y54C, T400K, A632V) genes in patients with gallstone disease (GS). METHODS: Study subjects included 287 patients with GS and 219 gallstone free controls (GSF). Polymorphisms were determined using PCR-RFLP analysis or the Taqman MGB assay. Plasma and biliary lipid levels were measured. RESULTS: 2 SNPs of ABCG8 gene (Y54C and T400K) showed strong linkage disequilibrium (D'=0.824, r2=0.579). Male carriers of the less frequent K allele of ABCG8 T400K had a 2.31-fold elevated risk [95% confidence interval (CI) 1.12 approximately 4.76, P=0.023] for gallstone disease compared to male with the common genotype after the adjustment for age, body mass index. Males with the K allele had lower plasma triglyceride (P=0.044) and biliary phospholipid (P=0.035) levels than TT homozygotes. No such association was found in female or other 4 SNPs. CONCLUSIONS: These findings indicate that the T400K polymorphism in ABCG8 may be associated with the incidence of gallstone disease in males.

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2 To investigate a possible association between transporter gene polymorphism and gallstone formation, we examined five common polymorphisms in the ABCG5 (Q604E) and ABCG8 (D19H, Y54C, T400K, A632V) genes in patients with gallstone disease (GS). Login to comment
6 Results: 2 SNPs of ABCG8 gene (Y54C and T400K) showed strong linkage disequilibrium (D'=0.824, r2 =0.579). Login to comment
7 Male carriers of the less frequent K allele of ABCG8 T400K had a 2.31-fold elevated risk [95% confidence interval (CI) 1.12~4.76, P=0.023] for gallstone disease compared to male with the common genotype after the adjustment for age, body mass index. Login to comment
10 Conclusions: These findings indicate that the T400K polymorphism in ABCG8 may be associated with the incidence of gallstone disease in males. Login to comment
24 Of these variants, it is suggested that 5 non-synonymous single nucleotide polymorphisms (SNPs) in the ABCG5 (Q604E) and ABCG8 (D19H, Y54C, T400K, A632V) coding sequences may effect plasma plant sterol or cholesterol levels [11-14]. Login to comment
41 Four SNP sites in ABCG5 Q604E, ABCG8 Y54C, ABCG8 T400K, and ABCG8 A632V were assayed by PCR amplification and RFLP analysis, as previously described [10,11]. Login to comment
72 Table 2 Linkage disequilibrium in 5 common polymorphisms of ABCG5 and ABCG8 genes D' Locus Q604E D19H Y54C T400K A632V r2 Q604E - 0.368 0.007 0.477 0.087 D19H 0.009 - 0.843 0.718 1.000 Y54C 0.000 0.045 - 0.824 0.211 T400K 0.003 0.000 0.579 - 1.000 A632V 0.000 0.000 0.000 0.001 - D' and r2 were calculated from all 506 subjects in the study. Login to comment
79 Thus, only the Y54C and T400K SNPs showed strong linkage disequilibrium (D'N0.8, r2 N1/3) [19]. Login to comment
85 Table 4 Logistic regression analysis All Male Female OR 95% CI P OR 95% CI P OR 95% CI P T400K 1.17 0.73~1.87 NS 2.31 1.12~4.76 0.023 0.70 0.36~1.34 NS Age 0.99 0.97~1.00 NS 0.98 0.96~1.01 NS 0.98 0.96~1.00 0.074 BMI 1.15 1.08~1.23 b0.001 0.99 0.90~1.09 NS 1.30 1.19~1.43 b0.001 Gender 1.50 1.03~2.17 0.033 - - ABCG8 T400K genotypes were coded as 1=the TT genotype and 2=the TK+KK genotype. Login to comment
90 The risk for GS was 2.31 [95% CI 1.12~4.76; P=0.023] for male carrying the K400 allele of ABCG8 T400K, compared to T400 homozygotes after the adjustment for age and BMI. Login to comment
110 The results indicated that of the five most common polymorphisms in ABCG5 and ABCG8 genes, ABCG8 T400K may be associated with gallstone disease in males. Login to comment
115 A, Concentrations of total plasma cholesterol (T-CH), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C) between the ABCG8 T400K genotypes in males (n=134). Login to comment
116 B, Concentration (A) of biliary total bile acids (BA), phospholipid (PL), and cholesterol (CH) between the ABCG8 T400K genotypes in males (n=37). Login to comment
125 Berge et al. [11] were the first to report that the ABCG8 D19H and T400K polymorphisms were associated with a lower concentration of plant sterols in both parents and their offspring. Login to comment
129 It was suggested that the ABCG8 T400K polymorphism influenced the reduction in total plasma cholesterol and LDL cholesterol levels in males, but not in females. Login to comment
131 Interestingly, our data showed an association of T400K polymorphism with gallstone disease in male only, a similar gender-specific relationship as in the Czech population. Login to comment
147 We speculated that a change from threonine to lysine in the male T400K polymorphism might play a potential role on ABCB4 expression, and thus influence phospholipid secretion. Login to comment
149 In conclusion, we have demonstrated that the T400K polymorphism in ABCG8 may play a role in the lipid metabolism and formation of gallstones, and may help to predict gallstone disease risk in males, at least within the Chinese population. Login to comment
73 Table 2 Linkage disequilibrium in 5 common polymorphisms of ABCG5 and ABCG8 genes D' Locus Q604E D19H Y54C T400K A632V r2 Q604E - 0.368 0.007 0.477 0.087 D19H 0.009 - 0.843 0.718 1.000 Y54C 0.000 0.045 - 0.824 0.211 T400K 0.003 0.000 0.579 - 1.000 A632V 0.000 0.000 0.000 0.001 - D' and r2 were calculated from all 506 subjects in the study. Login to comment
80 Thus, only the Y54C and T400K SNPs showed strong linkage disequilibrium (D'N0.8, r2 N1/3) [19]. Login to comment
86 Table 4 Logistic regression analysis All Male Female OR 95% CI P OR 95% CI P OR 95% CI P T400K 1.17 0.73~1.87 NS 2.31 1.12~4.76 0.023 0.70 0.36~1.34 NS Age 0.99 0.97~1.00 NS 0.98 0.96~1.01 NS 0.98 0.96~1.00 0.074 BMI 1.15 1.08~1.23 b0.001 0.99 0.90~1.09 NS 1.30 1.19~1.43 b0.001 Gender 1.50 1.03~2.17 0.033 - - ABCG8 T400K genotypes were coded as 1=the TT genotype and 2=the TK+KK genotype. Login to comment
91 The risk for GS was 2.31 [95% CI 1.12~4.76; P=0.023] for male carrying the K400 allele of ABCG8 T400K, compared to T400 homozygotes after the adjustment for age and BMI. Login to comment
111 The results indicated that of the five most common polymorphisms in ABCG5 and ABCG8 genes, ABCG8 T400K may be associated with gallstone disease in males. Login to comment
117 B, Concentration (A) of biliary total bile acids (BA), phospholipid (PL), and cholesterol (CH) between the ABCG8 T400K genotypes in males (n=37). Login to comment
126 Berge et al. [11] were the first to report that the ABCG8 D19H and T400K polymorphisms were associated with a lower concentration of plant sterols in both parents and their offspring. Login to comment
130 It was suggested that the ABCG8 T400K polymorphism influenced the reduction in total plasma cholesterol and LDL cholesterol levels in males, but not in females. Login to comment
132 Interestingly, our data showed an association of T400K polymorphism with gallstone disease in male only, a similar gender-specific relationship as in the Czech population. Login to comment
148 We speculated that a change from threonine to lysine in the male T400K polymorphism might play a potential role on ABCB4 expression, and thus influence phospholipid secretion. Login to comment
150 In conclusion, we have demonstrated that the T400K polymorphism in ABCG8 may play a role in the lipid metabolism and formation of gallstones, and may help to predict gallstone disease risk in males, at least within the Chinese population. Login to comment

[hide] Cholesterol synthesis prevails over absorption in ... Transl Res. 2007 Jun;149(6):310-6. Epub 2007 May 23. Gylling H, Hallikainen M, Kolehmainen M, Toppinen L, Pihlajamaki J, Mykkanen H, Agren JJ, Rauramaa R, Laakso M, Miettinen TA
Cholesterol synthesis prevails over absorption in metabolic syndrome.
Transl Res. 2007 Jun;149(6):310-6. Epub 2007 May 23., [PMID:17543849]

Abstract [show]
The objective of this study was to investigate cholesterol metabolism and its association with glucose metabolism and genetic regulation in metabolic syndrome. Overall, 74 subjects with clinically defined metabolic syndrome and sex and age-matched controls (n=74) were recruited. Cholesterol metabolism was assayed with serum non-cholesterol sterols, surrogate markers of synthesis, and fractional absorption of cholesterol and was related to variables of glucose and insulin action and to the common polymorphisms of the ABCG5 and ABCG8 genes. Serum squalene and non-cholesterol sterols were analyzed with gas-liquid chromatography (GLC) and presented as ratios to cholesterol. Also, synthesis marker/absorption marker ratios were calculated. The subjects with metabolic syndrome had higher cholesterol synthesis marker ratios, including squalene, and lower absorption marker ratios than controls. When adjusted with body mass index (BMI) and waist circumference, differences in some of the absorption markers (plant sterols), but not in the synthesis markers, disappeared. Plasma glucose, serum triglycerides, and homeostasis model assessment (HOMA) index were positively associated with cholesterol synthesis/absorption marker ratios (r=0.264 to 0.353, P<0.05 for all). In multivariate analysis, the serum squalene ratio was the best variable of those of cholesterol metabolism explaining the presence of metabolic syndrome. The polymorphisms of ABCG5 and ABCG8 genes did not differ between the cases and controls. In conclusion, cholesterol synthesis prevails over absorption in metabolic syndrome. The high serum squalene ratio turned out to be associated with the prevalence of metabolic syndrome. The perturbations of cholesterol metabolism seem to be related to abdominal obesity, and weight reduction might normalize cholesterol metabolism.

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111 Polymorphisms of the different genes tested were evenly distributed between MBO and controls (heterozygotesϩhomozygotes/wild type: ABCG8: D19H, MBO 16/56, controls 13/61; T400K, MBO 29/ 43, controls 26/48; A632V, MBO 27/45, controls 27/ 47; ABCG5: Q604E, MBO 16/56, controls 16/58). Login to comment
110 Polymorphisms of the different genes tested were evenly distributed between MBO and controls (heterozygotesaf9;homozygotes/wild type: ABCG8: D19H, MBO 16/56, controls 13/61; T400K, MBO 29/ 43, controls 26/48; A632V, MBO 27/45, controls 27/ 47; ABCG5: Q604E, MBO 16/56, controls 16/58). Login to comment

[hide] Are plasma lipid levels related to ABCG5/ABCG8 pol... Eur J Intern Med. 2006 Nov;17(7):490-4. Acalovschi M, Ciocan A, Mostean O, Tirziu S, Chiorean E, Keppeler H, Schirin-Sokhan R, Lammert F
Are plasma lipid levels related to ABCG5/ABCG8 polymorphisms? A preliminary study in siblings with gallstones.
Eur J Intern Med. 2006 Nov;17(7):490-4., [PMID:17098593]

Abstract [show]
BACKGROUND: The role of ABCG5 and ABCG8 genes in the determination of plasma lipid levels is currently under intensive investigation. The aim of this study was to evaluate plasma lipid levels in sibling pairs with gallstones and to assess their correlation with common gene polymorphisms in the ABCG5/ABCG8 genes. METHODS: Plasma levels of cholesterol, HDL-cholesterol, and triglycerides were measured in 68 patients belonging to 34 sibling pairs with gallstones (affected sibling pairs, mean age 56.3 years) and in 68 gallstone carriers with stone-free siblings (age/gender-matched controls in a ratio of 2:1 with the index patients of the study group). Four and one non-synonymous sequence variants in ABCG8 and ABCG5 genes, respectively, were determined in the affected sibling pairs, employing allelic discrimination with 5' nuclease assays. RESULTS: Plasma triglyceride levels were higher and HDL-cholesterol levels lower in the index patients than in controls. Plasma lipid levels were correlated in the members of the affected sibling pairs. Triglyceride levels were higher in carriers of the common alleles for ABCG5 Q604E and ABCG8 D19H sequence variants, and HDL-cholesterol was lower in carriers of the common alleles for ABCG5 Q604E than in carriers of the rare alleles. CONCLUSIONS: The significantly different plasma lipid levels in siblings with gallstones versus controls, as well as the correlation of plasma lipids in affected sibling pairs, confirm the genetic influence in gallstone disease. Polymorphisms in ABCG5/ABCG8 genes might contribute to the genetic variation in plasma lipid levels and in cholesterol saturation of the bile.

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54 Genotype analysis The patients were genotyped for the ABCG5 single nucleotide polymorphism (SNP) Q604E and the ABCG8 SNPs D19H, Y54C, T400K, and A632V [5,11,12] by TaqMan allelic discrimination. Login to comment
109 Variation in plasma concentrations of non-cholesterol sterols has been demonstrated to be highly heritable, and D19H and T400K polymorphisms in ABCG8 have been found to contribute to genetic variations in the plasma concentrations of plant sterols [10]. Login to comment
110 Other polymorphisms in ABCG8 (A632V [10], T400K, and Y54C [27]) and in ABCG5 (Q604E [28]) have been suggested to be associated with plasma cholesterol levels. Login to comment
119 Plasma lipids in affected siblings Table 4 Plasma triglycerides, cholesterol, and HDL-cholesterol in the 68 siblings with gallstones in relation to ABCG5/G8 genotypes (bold indicates pb0.05) Triglycerides (mg/dl) Cholesterol (mg/dl) HDL cholesterol (mg/dl) ABCG8 A632V CT/TT=28 155.5±57.3 205.7±32.6 48.1±13.2 CC=44 154.1±67.3 204.6±39.2 45.6±18.2 T400K CA/AA=30 168.5±76.9 209.9±37.5 46.0±17.3 CC=42 144.7±50.1 201.5±35.8 48.2±14.4 Y54C AG/GG=44 144.5±58.4 202.7±39.6 44.9±17.0 AA=28 170.6±68.3 210.3±32.8 48.0±15.6 D19H GC/CC=12 130.9±52.6 192.5±27.3 49.0±19.5 GG=60 159.4±64.5 208.3±38.4 46.0±16.0 ABCG5 Q604E CG/GG=24 127.4±51.9 191.7±35.1 55.9±12.9 CC=48 168.2±64.5 212.7±36.3 42.7±15.7 did not correlate with those in controls. Login to comment
53 Genotype analysis The patients were genotyped for the ABCG5 single nucleotide polymorphism (SNP) Q604E and the ABCG8 SNPs D19H, Y54C, T400K, and A632V [5,11,12] by TaqMan allelic discrimination. Login to comment
108 Variation in plasma concentrations of non-cholesterol sterols has been demonstrated to be highly heritable, and D19H and T400K polymorphisms in ABCG8 have been found to contribute to genetic variations in the plasma concentrations of plant sterols [10]. Login to comment
118 Plasma lipids in affected siblings Table 4 Plasma triglycerides, cholesterol, and HDL-cholesterol in the 68 siblings with gallstones in relation to ABCG5/G8 genotypes (bold indicates pb0.05) Triglycerides (mg/dl) Cholesterol (mg/dl) HDL cholesterol (mg/dl) ABCG8 A632V CT/TT=28 155.5&#b1;57.3 205.7&#b1;32.6 48.1&#b1;13.2 CC=44 154.1&#b1;67.3 204.6&#b1;39.2 45.6&#b1;18.2 T400K CA/AA=30 168.5&#b1;76.9 209.9&#b1;37.5 46.0&#b1;17.3 CC=42 144.7&#b1;50.1 201.5&#b1;35.8 48.2&#b1;14.4 Y54C AG/GG=44 144.5&#b1;58.4 202.7&#b1;39.6 44.9&#b1;17.0 AA=28 170.6&#b1;68.3 210.3&#b1;32.8 48.0&#b1;15.6 D19H GC/CC=12 130.9&#b1;52.6 192.5&#b1;27.3 49.0&#b1;19.5 GG=60 159.4&#b1;64.5 208.3&#b1;38.4 46.0&#b1;16.0 ABCG5 Q604E CG/GG=24 127.4&#b1;51.9 191.7&#b1;35.1 55.9&#b1;12.9 CC=48 168.2&#b1;64.5 212.7&#b1;36.3 42.7&#b1;15.7 did not correlate with those in controls. Login to comment

[hide] Interactions between common genetic polymorphisms ... Atherosclerosis. 2004 Aug;175(2):287-93. Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ
Interactions between common genetic polymorphisms in ABCG5/G8 and CYP7A1 on LDL cholesterol-lowering response to atorvastatin.
Atherosclerosis. 2004 Aug;175(2):287-93., [PMID:15262185]

Abstract [show]
Cholesterol excretion by ATP binding cassette transporters G5 and G8 (ABCG5/G8) and bile acid biosynthesis by cholesterol 7alpha-hydroxylase (CYP7A1) are major pathways for the removal of cholesterol into bile. To investigate the interactions between common polymorphisms in ABCG5/G8 and CYP7A1 and statin response, we examined the relationships between five non-synonymous polymorphisms in ABCG5/G8 (Q604E, D19H, Y54C, T400K, and A632V) and a promoter variant in CYP7A1 (A-204C) in 337 hypercholesterolemic patients treated with atorvastatin 10mg. The ABCG8 H19 allele was significantly associated with a greater LDL cholesterol reduction relative to the wild type D19 allele (39.6% versus 36.6%, P = 0.043). This difference was enhanced in non-carriers of the CYP7A1 promoter polymorphism (42.7% versus 38.2%, P = 0.048), and was diminished in accordance with the number of CYP7A1 variant alleles (1.8% in heterozygotes and 0.2% in homozygotes). Combination analysis of these polymorphisms explained a greater percentage of LDL cholesterol response variation (8.5% difference across subgroups) than did single polymorphism analysis (4.2% in CYP7A1 and 3.0% in ABCG8 D19H). The other ABCG5/G8 polymorphisms did not show any significant interactions with the CYP7A1 polymorphism. We conclude that the ABCG8 H19 and CYP7A1 C-204 alleles appear to interact in a dose-dependent manner on atorvastatin response.

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43 The set of polymorphisms in ABCG5/G8 (Q604E, D19H, Y54C, T400K, and A632V) and CYP7A1 (A-204C) was examined in 337 subjects from the atorvastatin (10 mg per day) arm. The means (±S.D.) of age and BMI were 58 ± 11 years old and 27.0 ± 3.0 kg/m2, respectively [15]. Login to comment
76 K.Kajinamietal./Atherosclerosis175(2004)287-293291 Table 3 Associations between ABCG5 Q604E, ABCG8 T400K, ABCG8 A632V/CYP7A1 A-204C and the LDL-lowering response to atorvastatin* ABCG5/G8 All subjects CYP7A1 P-values among CYP7A1 genotype† Unadjusted Adjusted AA AC CC Additive Dominant Recessive ABCG5 Q604E QQ 36.9 ± 10.1 37.0, 35.7-38.2 (212) 39.4, 37.0-41.8 (57) 36.6, 34.8-38.4 (104) 35.0, 32.4-37.5 (51) 0.055 0.031 0.080 QE 37.1 ± 9.5 36.9, 35.1-38.6 (111) 37.6, 34.7-40.5 (39) 37.3, 34.8-39.9 (54) 33.9, 29.6-38.2 (18) 0.321 0.646 0.131 EE 36.9 ± 9.3 37.8, 32.9-42.7 (14) 44.3, 35.1-53.4 (4) 36.9, 30.0-43.7 (7) 31.0, 20.5-41.5 (3) 0.159 0.081 0.164 ABCG8 T400K TT 37.3 ± 10.3 37.4, 36.2-38.8 (197) 37.5, 34.4-40.6 (62) 36.4, 34.4-38.4 (92) 34.1, 30.4-37.7 (43) 0.022 0.030 0.019 TK 36.5 ± 8.6 36.2, 34.6-37.9 (128) 38.7, 36.2-41.3 (33) 36.4, 34.1-38.8 (67) 35.4, 32.5-38.4 (28) 0.611 0.726 0.320 KK 35.8 ± 13.5 36.0, 30.7-41.3 (12) 42.4, 37.9-46.9 (5) 39.1, 35.7-42.5 (6) 31.9, 26.1-37.6 (1) 0.157 0.046 0.988 ABCG8 A632V AA 36.5 ± 10.0 36.4, 35.2-37.6 (224) 39.8, 37.4-42.1 (65) 37.4, 35.6-39.3 (116) 34.3, 31.4-37.1 (43) 0.005 0.004 0.020 AV 38.0 ± 9.6 38.3, 36.4-40.2 (97) 36.7, 33.5-39.8 (28) 36.6, 34.4-38.8 (41) 34.9, 31.6-38.3 (28) 0.288 0.794 0.126 VV 36.9 ± 7.3 36.2, 31.7-40.8 (16) 42.4, 34.3-50.5 (7) 30.4, 23.0-37.8 (8) 37.0, 18.9-55.1 (1) 0.697 0.992 0.397 In testing the effects of ABCG5 (Q604E) or ABCG8 (T400K and A632V) genotype on LDL-lowering response, none of P-values reached statistical significance. Login to comment
78 Corresponding values between ABCG8 T400K and CYP7A1 were 0.439, 0.709, and 0.641, and those between ABCG8 A632V and CYP7A1 were 0.267, 0.593, and 0.279, respectively. Login to comment
44 The set of polymorphisms in ABCG5/G8 (Q604E, D19H, Y54C, T400K, and A632V) and CYP7A1 (A-204C) was examined in 337 subjects from the atorvastatin (10 mg per day) arm. The means (&#b1;S.D.) of age and BMI were 58 &#b1; 11 years old and 27.0 &#b1; 3.0 kg/m2, respectively [15]. Login to comment
80 Corresponding values between ABCG8 T400K and CYP7A1 were 0.439, 0.709, and 0.641, and those between ABCG8 A632V and CYP7A1 were 0.267, 0.593, and 0.279, respectively. Login to comment

[hide] Two genes that map to the STSL locus cause sitoste... Am J Hum Genet. 2001 Aug;69(2):278-90. Epub 2001 Jul 9. Lu K, Lee MH, Hazard S, Brooks-Wilson A, Hidaka H, Kojima H, Ose L, Stalenhoef AF, Mietinnen T, Bjorkhem I, Bruckert E, Pandya A, Brewer HB Jr, Salen G, Dean M, Srivastava A, Patel SB
Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively.
Am J Hum Genet. 2001 Aug;69(2):278-90. Epub 2001 Jul 9., [PMID:11452359]

Abstract [show]
Sitosterolemia is a rare autosomal recessive disorder characterized by (a) intestinal hyperabsorption of all sterols, including cholesterol and plant and shellfish sterols, and (b) impaired ability to excrete sterols into bile. Patients with this disease have expanded body pools of cholesterol and very elevated plasma plant-sterol species and frequently develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. In previous studies, we have mapped the STSL locus to human chromosome 2p21. Recently, we reported that a novel member of the ABC-transporter family, named "sterolin-1" and encoded by ABCG5, is mutated in 9 unrelated families with sitosterolemia; in the remaining 25 families, no mutations in sterolin-1 could be identified. We identified another ABC transporter, located <400 bp upstream of sterolin-1, in the opposite orientation. Mutational analyses revealed that this highly homologous protein, termed "sterolin-2" and encoded by ABCG8, is mutated in the remaining pedigrees. Thus, two highly homologous genes, located in a head-to-head configuration on chromosome 2p21, are involved as causes of sitosterolemia. These studies indicate that both sterolin-1 and sterolin-2 are indispensable for the regulation of sterol absorption and excretion. Identification of sterolin-1 and sterolin-2 as critical players in the regulation of dietary-sterol absorption and excretion identifies a new pathway of sterol transport.

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169 OF IDENTIFIED POLYMORPHISMS HARDY-WEINBERG EQUILIBRIUM?ϩ/ϩ ϩ/- -/- ABCG5: 167CrT (Pro9Pro) Gain of BstNI … … … … 1950CrG (Gln604Glu) Loss of SmlI 46 25 1 Yes ABCG8: Exon 1 141CrT (Pro17Pro) … 49 1 0 Yes Exon 1 145GrC (Asp19His) Loss of BaeI 74 3 1 No Exon 2 251GrA (Cys54Tyr) Gain of SexAI 21 23 23 No Exon 6 802GrA (Glu238Lys) … 10 1 0 Yes Exon 6 866CrT (Ala259Val) Loss of HaeIII 0 5 0 … Exon 8 1289CrA (Thr400Lys) Gain of MseI 116 53 4 Yes Exon 11 1785CrT (Ala565Ala) Loss of MnlI 20 7 1 Yes Exon 11 1813GrC (Gly575Arg) Gain of HhaI 188 6 4 No Exon 13 1984CrT (Ala632Val) Loss of StyI 107 50 13 No 5 UTR -15ArC Gain of BstEII 47 4 0 Yes 5 UTR -19TrG Loss of Tsp451 38 42 29 No 5 UTR -41CrT Loss of DdeI 7 2 4 No Intron 1 -7CrT Loss of BsmAI 21 23 4 Yes Intron 1 -21CrA Loss of MnlI 20 23 4 Yes Intron 9 -19CrT … 1 3 4 … Intron 10 IVS10 ϩ34delCC … 3 1 4 … Intron 10 -50CrT … 4 4 2 … cohort of patients with sitosterolemia. Login to comment
170 af9;/af9; af9;/afa; afa;/afa; ABCG5: 167CrT (Pro9Pro) Gain of BstNI ߪ ߪ ߪ ߪ 1950CrG (Gln604Glu) Loss of SmlI 46 25 1 Yes ABCG8: Exon 1 141CrT (Pro17Pro) ߪ 49 1 0 Yes Exon 1 145GrC (Asp19His) Loss of BaeI 74 3 1 No Exon 2 251GrA (Cys54Tyr) Gain of SexAI 21 23 23 No Exon 6 802GrA (Glu238Lys) ߪ 10 1 0 Yes Exon 6 866CrT (Ala259Val) Loss of HaeIII 0 5 0 ߪ Exon 8 1289CrA (Thr400Lys) Gain of MseI 116 53 4 Yes Exon 11 1785CrT (Ala565Ala) Loss of MnlI 20 7 1 Yes Exon 11 1813GrC (Gly575Arg) Gain of HhaI 188 6 4 No Exon 13 1984CrT (Ala632Val) Loss of StyI 107 50 13 No 5 UTR afa;15ArC Gain of BstEII 47 4 0 Yes 5 UTR afa;19TrG Loss of Tsp451 38 42 29 No 5 UTR afa;41CrT Loss of DdeI 7 2 4 No Intron 1 afa;7CrT Loss of BsmAI 21 23 4 Yes Intron 1 afa;21CrA Loss of MnlI 20 23 4 Yes Intron 9 afa;19CrT ߪ 1 3 4 ߪ Intron 10 IVS10 af9;34delCC ߪ 3 1 4 ߪ Intron 10 afa;50CrT ߪ 4 4 2 ߪ cohort of patients with sitosterolemia. Login to comment
171 af9;/af9; af9;/afa; afa;/afa; ABCG5: 167CrT (Pro9Pro) Gain of BstNI ߪ ߪ ߪ ߪ 1950CrG (Gln604Glu) Loss of SmlI 46 25 1 Yes ABCG8: Exon 1 141CrT (Pro17Pro) ߪ 49 1 0 Yes Exon 1 145GrC (Asp19His) Loss of BaeI 74 3 1 No Exon 2 251GrA (Cys54Tyr) Gain of SexAI 21 23 23 No Exon 6 802GrA (Glu238Lys) ߪ 10 1 0 Yes Exon 6 866CrT (Ala259Val) Loss of HaeIII 0 5 0 ߪ Exon 8 1289CrA (Thr400Lys) Gain of MseI 116 53 4 Yes Exon 11 1785CrT (Ala565Ala) Loss of MnlI 20 7 1 Yes Exon 11 1813GrC (Gly575Arg) Gain of HhaI 188 6 4 No Exon 13 1984CrT (Ala632Val) Loss of StyI 107 50 13 No 5 UTR afa;15ArC Gain of BstEII 47 4 0 Yes 5 UTR afa;19TrG Loss of Tsp451 38 42 29 No 5 UTR afa;41CrT Loss of DdeI 7 2 4 No Intron 1 afa;7CrT Loss of BsmAI 21 23 4 Yes Intron 1 afa;21CrA Loss of MnlI 20 23 4 Yes Intron 9 afa;19CrT ߪ 1 3 4 ߪ Intron 10 IVS10 af9;34delCC ߪ 3 1 4 ߪ Intron 10 afa;50CrT ߪ 4 4 2 ߪ cohort of patients with sitosterolemia. Login to comment

[hide] Association of ATP binding cassette transporter G8... Lipids Health Dis. 2012 May 1;11:46. Li Q, Wei XL, Yin RX
Association of ATP binding cassette transporter G8 rs4148217 SNP and serum lipid levels in Mulao and Han nationalities.
Lipids Health Dis. 2012 May 1;11:46., [PMID:22548731]

Abstract [show]
BACKGROUND: The association of ATP binding cassette transporter G8 gene (ABCG8) rs4148217 single nucleotide polymorphism (SNP) and serum lipid profiles is still controversial in diverse racial/ethnic groups. Mulao nationality is an isolated minority in China. The aim of this study was to evaluate the association of ABCG8 rs4148217 SNP and several environmental factors with serum lipid levels in the Guangxi Mulao and Han populations. METHODS: A total of 634 subjects of Mulao nationality and 717 participants of Han nationality were randomly selected from our previous samples. Genotyping of the ABCG8 rs4148217 SNP was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. RESULTS: The genotypic and allelic frequencies of ABCG8 rs4148217 SNP were different between the two nationalities (P < 0.01 for each), the frequency of A allele was higher in Mulao than in Han. The A allele carriers in Han had lower high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (Apo) A1 levels than the A allele noncarriers (P < 0.05 for each), whereas the A allele carriers in Mulao had lower ApoA1 levels than the A allele noncarriers (P < 0.05). Subgroup analyses showed that the A allele carriers in Han had lower HDL-C and higher triglyceride (TG) levels in females but not in males than the A allele noncarriers (P < 0.05 for each), and the A allele carriers in Mulao had lower ApoA1 levels in females but not in males than the A allele noncarriers (P < 0.05). The levels of TG and HDL-C in Han, and ApoA1 in Mulao were associated with genotypes in females but not in males (P < 0.05-0.01). Serum lipid parameters were also correlated with several environmental factors (P < 0.05-0.001). CONCLUSIONS: The ABCG8 rs4148217 SNP is associated with serum TG, HDL-C and ApoA1 levels in our study populations, but this association is different between the Mulao and Han populations. There is a sex (female)-specific association in both ethnic groups.

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31 Thus, the aim of the present study was to detect the association of ABCG8 rs4148217 (T400K) SNP and several environmental factors with serum lipid profiles in the Mulao and Han populations. Login to comment
272 Wang Y, Jiang ZY, Fei J, Xin L, Cai Q, Jiang ZH, Zhu ZG, Han TQ, Zhang SD: ATP binding cassette G8 T400K polymorphism may affect the risk of gallstone disease among Chinese males. Login to comment
32 Thus, the aim of the present study was to detect the association of ABCG8 rs4148217 (T400K) SNP and several environmental factors with serum lipid profiles in the Mulao and Han populations. Login to comment

[hide] ABCG8 gene polymorphisms, plasma cholesterol conce... Atherosclerosis. 2009 Jun;204(2):453-8. Epub 2008 Sep 27. Koeijvoets KC, van der Net JB, Dallinga-Thie GM, Steyerberg EW, Mensink RP, Kastelein JJ, Sijbrands EJ, Plat J
ABCG8 gene polymorphisms, plasma cholesterol concentrations, and risk of cardiovascular disease in familial hypercholesterolemia.
Atherosclerosis. 2009 Jun;204(2):453-8. Epub 2008 Sep 27., [PMID:18977479]

Abstract [show]
Elevated plasma plant sterol concentrations may be a risk factor of cardiovascular disease (CVD). Polymorphisms in the ABCG8 gene have been identified that contribute to the variation in plasma concentrations of plant sterols. However, data on the direct relationship of ABCG8 gene polymorphisms with CVD are lacking. Therefore, we examined associations between the D19H and T400K polymorphisms in the ABCG8 gene and CVD in a large cohort study of 2012 patients with heterozygous familial hypercholesterolemia (FH). A total of 244 individuals carried one or two alleles of the D19H variant and 568 individuals the T400K variant. During 94,809 person years, 648 (32.2%) individuals developed CVD of which coronary heart disease (CHD) was the most frequent cardiovascular event (N=553). In a Cox proportional hazard regression model adjusted for relevant cardiovascular risk factors, the D19H polymorphism was not associated with total CVD risk (p=0.2), but there was evidence of an association with higher risk of CHD (RR 1.42, CI 1.04-1.95; p=0.03). We observed no relationship between the T400K polymorphism and cardiovascular endpoints (p>0.1). However, FH individuals carrying the risk genotype for both ABCG8 variants had an increased risk of CVD (RR 1.57, 95% CI 1.13-2.18; p=0.01) and CHD (RR 1.72, 95% CI 1.23-2.41; p=0.002). In conclusion, our data suggest that genetic variation in the ABCG8 gene may influence the burden of atherosclerosis.

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3 Therefore, we examined associations between the D19H and T400K polymorphisms in the ABCG8 gene and CVD in a large cohort study of 2012 patients with heterozygous familial hypercholesterolemia (FH). Login to comment
4 A total of 244 individuals carried one or two alleles of the D19H variant and 568 individuals the T400K variant. Login to comment
7 We observed no relationship between the T400K polymorphism and cardiovascular endpoints (p > 0.1). Login to comment
42 Since the D19H and T400K polymorphisms in the ABCG8 gene showed the strongest relationship with cholesterol standardized serum plant sterol concentrations [15,16], we decided to evaluate associations with these ABCG8 variants. Login to comment
69 This resulted in the selection of two polymorphisms in ABCG8: D19H (substitution of histidine for aspartic acid at amino acid 19 in exon 1) and T400K (substitution of thyrosine for lysine at amino acid 400 in exon 8) that resulted both in lower cholesterol standardized plasma plant sterol concentrations [15,16]. Login to comment
71 Taqman SNP Genotyping Assay ID for the D19H was C 26135643 10 and for the T400K C 375061 10 (Applied Biosystems). Login to comment
76 Genotyping was successful in 2053 (95.7%) patients for the T400K polymorphism, and in 2065 (96.3%) patients for the D19H polymorphism. Login to comment
86 The association between the D19H and T400K polymorphisms in ABCG8 and the occurrence of CVD or CHD was assessed using a Cox proportional hazard regression analysis. Login to comment
99 For the T400K polymorphism, 45 (2.2%) patients were homozygous (KK), 523 (26.0%) patients were heterozygous (TK), and in 1444 (71.8%) patients the homozygous wild type allele (TT) was detected. Login to comment
101 Using chi-square analyses, ABCG8 genotype distributions were similar between individuals without and with a history of CVD (D19H, p = 0.9; T400K, p = 0.1) 3.2. Login to comment
102 ABCG8 genotypes and plasma cholesterol concentrations Plasma cholesterol concentrations according to D19H and T400K genotypes are presented in Table 3. Login to comment
103 No significant differences in plasma lipid concentrations among D19H and T400K genotypes were found. Login to comment
105 Patients homozygous or heterozygous for the T400K polymorphism had significantly less often hypertension compared to carriers of the wild type alleles (7.0% vs. 9.8%; p = 0.03). Login to comment
109 The percentage of D19H and T400K carriers that were Table 2 Genotype and allele distributions for D19H and T400K polymorphisms in ABCG8. Login to comment
110 D19H T400K Total CVD- CVD+ Total CVD- CVD+ N (%) N (%) N (%) N (%) N (%) N (%) Genotypes Wild type (DD or TT) 1768 (87.9) 1198 (87.8) 570 (88.0) 1444 (71.8) 965 (70.7) 479 (73.9) Heterozygous (DH or TK) 237 (11.8) 161 (11.8) 76 (11.7) 523 (26.0) 372 (27.3) 151 (23.3) Homozygous (HH or KK) 7 (0.3) 5 (0.4) 2 (0.3) 45 (2.2) 27 (2.0) 18 (2.8) Total 2012 (100.0) 1364 (100.0) 648 (100.0) 2012 (100.0) 1364 (100.0) 648 (100.0) Alleles Wild type allele (D or T) 3773 (93.8) 2557 (93.7) 1216 (93.8) 3411 (84.8) 2302 (84.4) 1109 (85.6) Minor allele (H or K) 251 (6.2) 171 (6.3) 80 (6.2) 613 (15.2) 426 (15.6) 187 (14.4) Total 4024 (100.0) 2728 (100.0) 1296 (100.0) 4024 (100.0) 2728 (100.0) 1296 (100.0) CVD+ indicates history of cardiovascular disease, CVD- indicates no cardiovascular disease. Login to comment
111 Table 3 Plasma cholesterol concentrations according to D19H and T400K genotypes. Login to comment
112 Polymorphism Genotype Total cholesterol LDL cholesterol HDL cholesterol Triglycerides D19H DD 9.50 (±1.99) 7.32 (±1.91) 1.22 (±0.36) 1.81 (±1.04) DH/HH 9.50 (±1.92) 7.40 (±1.87) 1.22 (±0.36) 1.75 (1;1.04) T400K TT 9.50 (±2.00) 7.32 (±1.91) 1.21 (±0.34) 1.82 (±1.04) TK/KK 9.51 (±1.94) 7.36 (±1.92) 1.24 (±0.39) 1.78 (±1.07) LDL indicates low-density lipoprotein HDL indicates high-density lipoprotein. Login to comment
121 As shown in Table 5, we found no evidence for associations of the D19H or T400K polymorphisms with total CVD risk. Login to comment
124 Although we found no significant relationship between the ABCG8 variants and CVD overall, the effect estimates seemed opposite for the D19H and T400K polymorphisms (Table 5). Login to comment
126 The risk genotype for the D19H variant was the DH/HH genotype ("carriers" of the D19H polymorphism) and the risk genotype for the T400K variant was the frequent TT genotype ("non-carriers" of the T400K polymorphism). Login to comment
138 We found no significant relationship of the T400K polymorphism with susceptibility of CHD. Login to comment
144 Model 1 Model 2 Model 3 Polymorphism RR (95% CI) p RR (95% CI) p RR (95% CI) p ABCG8 D19H CVD 1.13 (0.89-1.46) 0.3 1.26 (0.93-1.71) 0.1 1.27 (0.93-1.72) 0.1 CHD 1.27 (0.98-1.64) 0.07 1.42 (1.04-1.95) 0.03 1.42 (1.04-1.95) 0.03 ABCG8 T400K CVD 0.88 (0.73-1.05) 0.2 0.87 (0.70-1.08) 0.2 0.87 (0.69-1.08) 0.2 CHD 0.87 (0.72-1.06) 0.2 0.84 (0.66-1.06) 0.1 0.83 (0.65-1.05) 0.1 RR indicates relative risk, CI indicates confidence interval, CVD indicates cardiovascular disease, CHD indicates coronary heart disease. Login to comment
152 We observed no significant association between the T400K polymorphism and plasma cholesterol levels or cardiovascular endpoints. Login to comment
168 We found no association between the T400K polymorphism and any cardiovascular event nor with plasma cholesterol concentrations. Login to comment
170 In line with our observations, none of these studies found a significant relationship between the T400K variant and plasma cholesterol levels. Login to comment
190 In conclusion, in this large, multicenter, cohort study amongst high-risk individuals with FH, we found a modest effect of the ABCG8 D19H gene variant on risk of CHD, but we did not observe a relationship between the ABCG8 T400K polymorphism and cardiovascular endpoints. Login to comment

[hide] Genetics of biliary lithiasis from an ethnic persp... Clin Res Hepatol Gastroenterol. 2013 Apr;37(2):119-25. doi: 10.1016/j.clinre.2012.09.002. Epub 2013 Jan 20. Krawczyk M, Miquel JF, Stokes CS, Zuniga S, Hampe J, Mittal B, Lammert F
Genetics of biliary lithiasis from an ethnic perspective.
Clin Res Hepatol Gastroenterol. 2013 Apr;37(2):119-25. doi: 10.1016/j.clinre.2012.09.002. Epub 2013 Jan 20., [PMID:23340007]

Abstract [show]
Gallstone disease represents one of the most common gastroenterological disorders worldwide. Gallstones affect over 15% of adults in Europe and 25-30% of Hispanic populations in Central and South America. The heritability of gallstones varies considerably according to ethnicity, with Native Americans and Hispanics with Amerindian admixture being the most susceptible populations. Genetic factors have been shown to account for 25-30% of total gallstone risk in Europe, however, in Hispanic populations, this risk percentage may increase to 45-65%. Recent genome-wide association and candidate gene studies have identified common polymorphisms in enterohepatic transporters (ABCG5/8, SLC10A2) and the Gilbert syndrome UGT1A1 variant as genetic determinants of gallstone formation. Together, these polymorphisms cover a significant proportion of the previously predicted genetic background of gallstones in European populations. New lithogenic genes need to be discovered in future studies in high-risk populations. In this review, we address the latest developments in the genetic analysis of gallstones and discuss the ethnic background of this condition in European, Central and South American and Asian populations.

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39 For this study, common ABCG5 (p.Q604E) and ABCG8 (p.D19H, p.Y54C, p.T400K, p.A632V) variants were selected and the nonparametric linkage (NPL) as well as case-control analyses were performed. Login to comment

[hide] ABCG5/ABCG8 in cholesterol excretion and atheroscl... Clin Chim Acta. 2014 Jan 20;428:82-8. doi: 10.1016/j.cca.2013.11.010. Epub 2013 Nov 16. Yu XH, Qian K, Jiang N, Zheng XL, Cayabyab FS, Tang CK
ABCG5/ABCG8 in cholesterol excretion and atherosclerosis.
Clin Chim Acta. 2014 Jan 20;428:82-8. doi: 10.1016/j.cca.2013.11.010. Epub 2013 Nov 16., [PMID:24252657]

Abstract [show]
Cholesterol is essential for the growth and function of all mammalian cells, but abnormally increased blood cholesterol is a major risk factor for atherosclerotic cardiovascular disease. ATP-binding cassette (ABC) transporters G5 (ABCG5) and G8 (ABCG8) form an obligate heterodimer that limits intestinal absorption and facilitates biliary secretion of cholesterol and phytosterols. Consistent with their function, ABCG5 and ABCG8 are located on the apical membrane of enterocytes and hepatocytes. Liver X receptor is the major positive regulator of ABCG5 and ABCG8 expression. Mutations in either of the two genes cause sitosterolemia, a condition in which cholesterol and plant sterols accumulate in the circulation leading to premature cardiovascular disease. Overexpression of ABCG5 and ABCG8 in mice retards diet-induced atherosclerosis because of reduced circulating and hepatic cholesterol. In the current review, we summarize recent developments and propose a future framework that provides new perspectives on the regulation of cholesterol metabolism and treatment of atherosclerotic cardiovascular disease.

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749 A recent report in a heterozygous familial hypercholesterolemia cohort indicates that the T400K polymorphism in the ABCG8 gene has an increased risk of cardiovascular disease but is not associated with cardiovascular endpoints [31]. Login to comment

[hide] Association of three common single nucleotide poly... PLoS One. 2014 Jan 30;9(1):e87200. doi: 10.1371/journal.pone.0087200. eCollection 2014. Jiang ZY, Cai Q, Chen EZ
Association of three common single nucleotide polymorphisms of ATP binding cassette G8 gene with gallstone disease: a meta-analysis.
PLoS One. 2014 Jan 30;9(1):e87200. doi: 10.1371/journal.pone.0087200. eCollection 2014., [PMID:24498041]

Abstract [show]
BACKGROUND: In this study, we evaluated the association between these polymorphisms and gallstone disease using meta-analysis and compared the hepatic ABCG5/G8 mRNA expression and biliary lipids composition in patients with different genotypes of T400K and Y54C. METHODS: Data were analyzed using the Stata/SE 11.0 software and a random- effects model was applied irrespective of between-study heterogeneity. Hepatic mRNA expression of ABCG5/G8 genes in 182 patients with gallstone disease and 35 gallstone-free patients who underwent cholecystectomy were determined using real-time PCR. Genotypes of Y54C and T400K in the ABCG8 gene were determined by allelic discrimination using either genomic DNA or hepatic cDNA as template by Taqman assays. Biliary compostion in gallbladder bile was assayed in these patients as well. RESULTS: Ten papers including 13 cohorts were included for the final analysis. In the genotype model, the overall association between genotype with gallstone was significant for D19H (OR = 2.43, 95%CI: 2.23-2.64, P<0.001), and for Y54C (OR = 1.36, 95%CI: 1.01-1.83, P = 0.044), or T400K (OR = 1.17, 95%CI: 0.96-1.43. P = 0.110). In allele model, minor alleles of D19H polymorphism (allele D: OR = 2.25, 95%CI: 2.10-2.42, P<0.001) and of T400K polymorphism (allele K: OR = 1.18, 95%CI: 1.06-1.31, P<0.001) were related with an increased risk of gallstone disease. However, minor allele of Y54C polymorphism (allele Y, OR = 1.08, 95%CI: 0.96-1.21, P = 0.146) was not related with gallstone disease. I(2) statistics indicated no significant between-study heterogeneity for all genetic models for any of the three polymorphisms. Funnel plot and Egger's test suggested the absence of publication bias as well. However, no association of T400K and Y54C polymorphism with hepatic ABCG8/G5 mRNA expression or biliary lipids composition was found. CONCLUSIONS: Our study showed strong association of D19H polymorphism with gallstone disease. T400K and Y54C polymorphism, though to a less extent, may also relate with gallstone disease.

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2 Genotypes of Y54C and T400K in the ABCG8 gene were determined by allelic discrimination using either genomic DNA or hepatic cDNA as template by Taqman assays. Login to comment
5 In the genotype model, the overall association between genotype with gallstone was significant for D19H (OR = 2.43, 95%CI: 2.23-2.64, P,0.001), and for Y54C (OR = 1.36, 95%CI: 1.01-1.83, P = 0.044), or T400K (OR = 1.17, 95%CI: 0.96-1.43. Login to comment
7 In allele model, minor alleles of D19H polymorphism (allele D: OR = 2.25, 95%CI: 2.10-2.42, P,0.001) and of T400K polymorphism (allele K: OR = 1.18, 95%CI: 1.061.31, P,0.001) were related with an increased risk of gallstone disease. Login to comment
11 However, no association of T400K and Y54C polymorphism with hepatic ABCG8/G5 mRNA expression or biliary lipids composition was found. Login to comment
13 T400K and Y54C polymorphism, though to a less extent, may also relate with gallstone disease. Login to comment
32 The most studied loci are D19H, T400K and Y54C. Login to comment
37 The aims of our study are: 1) to evaluate the association between polymorphisms at D19H, T400K and Y54C and gallstone disease using meta-analysis; 2) to compare the hepatic ABCG5/G8 mRNA expression and biliary lipids composition in patients with different genotypes of T400K and Y54C. Methods Literature Search Publication were searched via public database PubMed (http:// www.ncbi.nlm.nih. Login to comment

[hide] The ABCG5/8 cholesterol transporter and myocardial... J Am Coll Cardiol. 2014 May 27;63(20):2121-8. doi: 10.1016/j.jacc.2013.12.055. Epub 2014 Mar 19. Stender S, Frikke-Schmidt R, Nordestgaard BG, Tybjaerg-Hansen A
The ABCG5/8 cholesterol transporter and myocardial infarction versus gallstone disease.
J Am Coll Cardiol. 2014 May 27;63(20):2121-8. doi: 10.1016/j.jacc.2013.12.055. Epub 2014 Mar 19., [PMID:24657701]

Abstract [show]
OBJECTIVES: The study sought to test the hypothesis that genetic variation in ABCG5/8, the transporter responsible for intestinal and hepatobiliary cholesterol efflux, may simultaneously influence plasma and biliary cholesterol levels, and hence risk of myocardial infarction (MI) and gallstone disease in opposite directions. BACKGROUND: High plasma levels of low-density lipoprotein (LDL) cholesterol are a causal risk factor for MI, whereas high levels of biliary cholesterol promote gallstone formation. METHODS: A total of 60,239 subjects from Copenhagen were included, including 5,647 with MI and 3,174 with symptomatic gallstone disease. Subjects were genotyped for 6 common, nonsynonymous and functional variants in ABCG5/8, and a combined weighted genotype score was calculated. RESULTS: Combined, weighted genotype scores were associated with stepwise decreases in LDL cholesterol of up to 5.9% (0.20 mmol/l) for individuals with a score >/=8.0 (prevalence = 11%) versus <2.0 (prevalence = 9%; p for trend across 5 groups = 2 x 10E-35). The cumulative incidences of MI and gallstone disease as a function of age and increasing genotype score were decreased and increased (log-rank ps for trend: 6 x 10E-4 and 9 x 10E-45), respectively. The multifactorially adjusted odds ratios were 0.83 (95% confidence interval: 0.73 to 0.94) for MI and 2.85 (95% confidence interval: 2.39 to 3.39) for symptomatic gallstone disease for individuals with a genotype score >/=8.0 versus <2.0. CONCLUSIONS: Genetic variation in ABCG5/8, which associates with decreased levels of plasma LDL cholesterol protects against MI, but increases the risk of symptomatic gallstone disease. These results suggest that MI and gallstones, 2 seemingly unrelated diseases, are intrinsically linked via the function of the ABCG5/8 cholesterol transporter.

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22 We genotyped all common nonsynonymous variants (minor allelefrequency >5%) inABCG5/ 8 (ABCG8D19H, Y54C, T400K, A632V; ABCG5 Q604E) and a functional intronic variant (ABCG8 IVS3&#fe;981) in 2 prospective studies of the Danish general population, CGPS (Copenhagen General Population Study) and CCHS (Copenhagen City Heart Study), and in a case-control study, CIHDS (Copenhagen Ischemic Heart Disease Study), totaling 60,239 participants, including 5,647 with MI and 3,174 with symptomatic gallstone disease. Login to comment
40 From the 5 genotypes that were individually associated with reductions in LDL cholesterol levels, we generated combined, weighted genotype scores based on the percentage reductions in LDL cholesterol compared to the reference genotype: ABCG8 D19H, DD &#bc; 0, DH &#bc; 2.7, HH &#bc; 5.8; IVS3&#fe;981 T>C, CC &#bc; 0, TC &#bc; 2.5, TT &#bc; 4.5; Y54C, YY &#bc; 0, YC &#bc; 0.2, CC &#bc; 1.1; T400K, TT &#bc; 0, TK &#bc; 0.9, KK &#bc; 2.9; A632V, VV &#bc; 0, AV &#bc; 0.9, AA &#bc; 1.1. Login to comment
45 In analyses stratified on ABCG8 D19H, a weighted genotype score without D19H was constructed (i.e., including IVS3&#fe;981, Y54C, T400K, and A632V). Login to comment
78 For the individual genotypes, ORs for MI ranged from 0.83 (95% CI: 0.76 to 0.92) for IVS3&#fe;981 TT to 1.07 (95% CI: 0.91 to 1.25) for T400K KK versus noncarriers, while ORs for gallstone disease ranged from 3.82 (95% CI: 2.66 to 5.49) for D19H HH to 1.11 (95% CI: 0.99 to 1.23) for Y54C CC versus noncarriers (Online Fig. 3). Login to comment
87 The corresponding multifactorially adjusted ORs for MI and symptomatic gallstone disease were 0.88 (95% CI: 0.80 to 0.98), and 1.74 (95% CI: 1.48 to 2.05), respectively (p for trend Figure 2 Lipid and Lipoprotein Levels as a Function of ABCG5/8 Genotypes, Individually and Combined The genotype score was constructed by summation of weighted low-density lipoprotein (LDL) cholesterol lowering genotypes of adenosine triphosphate-binding cassette transporter G8 (ABCG8) D19H, IVS3&#fe;981, T400K, Y54C, and A632V. The p values are for trend tests by Cuzick`s extension of a Wilcoxon rank sum test. Login to comment
105 Figure 3 Cumulative Incidence of Myocardial Infarction and Symptomatic Gallstone Disease as a Function of Age and ABCG5/8 Genotype Score The genotype score was constructed by summation of weighted low-density lipoprotein cholesterol lowering genotypes of adenosine triphosphate-binding cassette transporter G8 (ABCG8) D19H, IVS3&#fe;981, T400K, Y54C, and A632V. The p values are by log-rank trend test. Login to comment
122 For instance, a common intronic ABCG8 variant was recently used together with Figure 4 Risk of Myocardial Infarction and Symptomatic Gallstone Disease as a Function of ABCG5/8 Genotype Score The genotype score was constructed by summation of weighted low-density lipoprotein (LDL) cholesterol lowering genotypes of adenosine triphosphate-binding cassette transporter G8 (ABCG8) D19H, IVS3&#fe;981, T400K, Y54C, and A632V. The p values are for trend tests by Cuzick`s extension of a Wilcoxon rank sum test, or for trend tests of odds ratios (ORs). Login to comment
137 Although 3 smaller studies (287 gallstone cases) have reported associations for ABCG5 Q604E and ABCG8 T400K with risk of gallstone disease, the large genome-wide association study (n &#bc; 2,280 cases) that initially identified ABCG8 D19H did not report other risk variants in ABCG5/8 (27-30). Login to comment
138 However, re-evaluating the thorough fine-mapping of variants in the ABCG5/8-region performed in this genome-wide association study revealed that ABCG8 IVS&#fe;981 and T400K, as well as ABCG5 Q604E, were indeed associated with gallstone disease, but that the associations did not reach the stringent requirements for statistical significance and/or replication (30). Login to comment
139 We found that ABCG8 IVS&#fe;981 and T400K, as well as ABCG5 Q604E, were individually associated with risk of symptomatic gallstone disease independent of D19H genotype. Login to comment
142 For ABCG8 IVS3&#fe;981 and T400K, the gallstone risk alleles were also associated with decreased levels of plasma LDL cholesterol. Login to comment
143 This resembles the association seen for D19H, suggesting that gain-of-function effects similar to the H-allele of D19H might underlie the associations for IVS3&#fe;981 and T400K. Login to comment
159 However, other cohorts with measurements of both LDL cholesterol and plant sterols may be better suited to directly assess the LDL cholesterol Figure 6 Risk of Myocardial Infarction and Symptomatic Gallstone Disease as a Function of ABCG5/8 Genotype Score on a D19H DD Background The genotype score was constructed by summation of weighted low-density lipoprotein (LDL) cholesterol lowering alleles of adenosine triphosphate-binding cassette transporter G8 (ABCG8) IVS3&#fe;981, T400K, Y54C, and A632V. The p values are for trend tests by Cuzick`s extension of a Wilcoxon rank sum test, or for trend tests of odds ratios (ORs). Login to comment

[hide] ABCG5/8 variants are associated with susceptibilit... Mol Med Rep. 2014 Jun;9(6):2512-20. doi: 10.3892/mmr.2014.2098. Epub 2014 Apr 1. Wu G, Li GB, Yao M, Zhang DQ, Dai B, Ju CJ, Han M
ABCG5/8 variants are associated with susceptibility to coronary heart disease.
Mol Med Rep. 2014 Jun;9(6):2512-20. doi: 10.3892/mmr.2014.2098. Epub 2014 Apr 1., [PMID:24691589]

Abstract [show]
ATP-binding cassette sub-family G member 5 (ABCG5) and ABCG8 are members of an ATP-binding cassette transporter superfamily. ABCG5 and ABCG8 variants affected serum levels of cholesterol and were considered as risk factors for coronary heart disease (CHD). The present control study analyzed ABCG5 and ABCG8 variants in a population for association with the risk of CHD. A total of 417 CHD patients and 267 controls were recruited for genotyping of four single nucleotide polymorphisms (SNPs; i.e. i7892T>C in ABCG5 and Tyr54CysA>G, Thr400LysC>A and 5U145A>C in ABCG8) using quantitative PCR high-resolution melting (qPCR-HRM). Serum lipid levels were measured using an automatic biochemical analyzer. The association of ABCG5/8 variants with lipid levels was analyzed using a Chi-square test. The impact of candidate ABCG5/8 SNPs on CHD was evaluated in a dominant genetic model with stepwise multiple regression analysis. Subgroup analyses were performed with regard to these SNPs, tobacco smoking status, alcohol consumption and gender. Genotypic and allelic frequencies of ABCG8 Thr400LysC>A were significantly different (P<0.05) between CHD patients and controls. CC homozygotes of the ABCG8 Thr400LysC>A SNP had greater triglyceride levels than CA/AA carriers with CHD. Logistic analysis revealed CHD risk was significantly higher in CC homozygotes of ABCG8 Thr400LysC>A than in carriers of the A allele (adjusted P=0.048; OR=2.034; 95% CI=0.983-4.207). Furthermore, there was a significant gene-tobacco smoking interaction. CC homozygotes of ABCG8 Thr400LysC>A SNP had significantly higher triglyceride concentrations (P=0.012) and an increased risk of CHD than tobacco smoking carriers of the A allele. The data from the current study suggested that ABCG8 Thr400LysC>A SNP genetic variants modulated plasma triglyceride levels and thereby affected CHD risk in the population studied. The genetic variant of ABCG8 also contributed to CHD risk through interaction with tobacco smoking.

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105 Genotype All participants Tobacco smoke Non-smokers Male Female Alcohol drinking Non-drinkers Thr400Lys C>A (allele) OR (95%CI) 2.107 2.700 1.625 2.059 2.108 2.722 1.926 (1.068-4.157) (1.024-7.120) (0.597-4.421) (0.774-5.476) (0.816-5.447) (0.612-12.101) (0.895-4.143) P-value 0.032 0.045 0.342 0.148 0.124 0.188 0.094 Adjusted log-dominant model OR (95%CI) 2.034 2.663 1.472 2.220 1.975 2.152 1.972 (0.983-4.207) (0.973-7.286) (0.467-4.640) (0.746-6.608) (0.717-5.439) (0.359-12.914) (0.873-4.454) P-value 0.048 0.049 0.509 0.152 0.188 0.402 0.102 CI is adjusted for age, smoking, diabetes and HDL-C. Login to comment
158 Several other studies have also demonstrated a significant association between baseline TG levels and the p.T400K polymorphism (16,32,33). Login to comment
159 Notably, several association studies have also demonstrated that there is no significant association between the T400K polymorphism and plasma levels of TG (28,29,34,35). Login to comment
161 Furthermore, neither ABCG8 T400K nor D19H polymorphisms are independently associated with the risk of CHD in a cohort containing 2,012 heterozygous FH patients (37). Login to comment
166 In the current study, ABCG8 CC homozygotes had >two-fold risk of CHD compared with A allele carriers, which may imply that ABCG8 T400K variants are a novel gene marker for CHD risk in the northern Han Chinese population. Login to comment
167 Indeed, the T400K variant is a missense mutation that changes the amino acid residue at position 400 from arginine to histidine in ABCG8. Login to comment
172 Thus, it may be expected that the expression of the ABCG5/8 gene, in C allele carriers at Thr400Lys, is able to increase markedly while consuming a high fat diet to limit cholesterol absorption but promote hepatic secretion. Login to comment

[hide] ABCG8 polymorphisms and renal disease in type 2 di... Metabolism. 2015 Jun;64(6):713-9. doi: 10.1016/j.metabol.2015.03.005. Epub 2015 Mar 14. Nicolas A, Fatima S, Lamri A, Bellili-Munoz N, Halimi JM, Saulnier PJ, Hadjadj S, Velho G, Marre M, Roussel R, Fumeron F
ABCG8 polymorphisms and renal disease in type 2 diabetic patients.
Metabolism. 2015 Jun;64(6):713-9. doi: 10.1016/j.metabol.2015.03.005. Epub 2015 Mar 14., [PMID:25804128]

Abstract [show]
BACKGROUND AND AIM: Sterols, bile acids and their receptors have been involved in diabetic nephropathy. The ATP-binding cassette transporters G5 and G8 (ABCG5 and ABCG8) play an important role in intestinal sterol absorption and bile acid secretion. The aim of our study was to assess the associations between two ABCG8 coding polymorphisms, T400K and D19H, and the incidence of renal events in type 2 diabetic subjects. METHODS: Participants were the 3137 French type 2 diabetic subjects with micro- or macro-albuminuria from the genetic substudy of the DIABHYCAR trial. The mean duration of follow-up was 4years. Renal events were defined as a doubling of serum creatinine concentration or end-stage renal disease at follow-up. We then used a second population (DIAB2NEPHROGENE) of 2140 type 2 diabetic patients for the purpose of validation. RESULTS: In DIABHYCAR, the 400K allele was significantly associated with a higher risk of incident renal events in a multiple adjusted model (HR: 1.75 [95% CI 1.20-2.56], P=0.003). This association was still significant after further adjustments for baseline values of estimated glomerular filtration rate and urinary albumin excretion. In the validation population, the 400K allele was associated with the prevalence of end-stage renal disease (OR=2.01 [95% CI 1.15-3.54], P=0.015). No significant association was found between the D19H polymorphism and the risk of diabetic nephropathy. CONCLUSIONS: A polymorphism of the sterol transporter ABCG8 has been associated with the prevalence of end-stage renal disease and with the incidence of new renal events in type 2 diabetic patients.

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2 The ATP-binding cassette transporters G5 and G8 (ABCG5 and ABCG8) play an important role in intestinal sterol absorption and bile acid secretion. The aim of our study was to assess the associations between two ABCG8 coding polymorphisms, T400K and D19H, and the incidence of renal events in type 2 diabetic subjects. Login to comment
33 In particular, the variants of ABCG8 D19H (rs11887534, G>C, exon 1) and ABCG8 T400K (rs4148217, C>A, exon 8) have been the most frequently reported to be associated with phenotypic variability. Login to comment
35 In the present investigation, we assessed associations of D19H and T400K variants in the coding region of ABCG8 with the incidence of severe kidney outcomes in the prospective DIABHYCAR cohort of French type 2 diabetic patients [27-30]. Login to comment
54 Polymorphism determination Polymorphisms T400K (rs4148217, C>A, exon 8) and D19H (rs11887534, G>C, exon 1) were genotyped using the Kaspar method (LGC Genomics, Hoddesdon, UK). Login to comment
71 The characteristics of participants at baseline according to the incidence of renal events during 714 M E T A B O L I S M C L I N I C A L A N D E X P E R I M E N T A L 6 follow-upareshowninTable1.Thegenotypeswerenotsignificantly associated with any of the baseline characteristics of the patients, except a trend for an association between T400K and eGFR, the K allele being associated with a lower rate (eGFR in ml/mn/1.73 m2 : 81.7 (65.4-102.5), 81.1 (63.8-101.5) and 77.8 (63.6-96.7) for the TT, TK and KK genotypes, respectively, P = 0.08). Login to comment
77 Validation population In order to validate our findings, we tested the ABCG8 T400K polymorphism in the DIAB2NEPHROGENE population. Login to comment
107 Since FXR is a bile acid receptor, it might interact with ABCG8 involved in bile acid secretion. The D19H polymorphism was not significantly associated with renal disease in our study, although its effects on plasma plant sterols and bile acid secretion seem of greater magnitude than those of T400K [22]. Login to comment
111 Polymorphism Renal event Statistics Without, n (%) With, n (%) Incidence, % P c7;2 unadjusted Hazard ratio (95% CI) Model 1 Model 2 a T400K (C>A) TT 1948 (64.9) 39 (52.0) 2.0 2 df: 0.018 Additive: 0.007 Dominant (CA + AA vs CC): 0.022 1.75 (1.20-2.56), P = 0.003 1.52 (1.05-2.21), P = 0.03 TK 953 (31.8) 30 (40.0) 3.1 KK 100 (3.3) 6 (8.0) 5.7 MAF 0.192 0.280 D19H (G>C) DD 2,615 (87.2) 69 (93.2) 2.6 2 df: 0.29 Additive: 0.13 Dominant (GC + CC vs GG): 0.14 0.53 (0.21-1.31), P = 0.16 0.53 (0.21-1.33), P = 0.18 DH 372 (12.4) 5 (6.8) 1.3 HH 11 (0.4) 0 (0) 0.0 MAF 0.066 0.034 MAF: minor allele frequency. a Cox regression analysis for the additive model, model 1: adjustment for sex, age, BMI, TG, total and HDL cholesterol, CRP, HbA1c, glycemia, diabetes duration, and prior myocardial infarction; model 2: idem + eGFR, UAE, SBP, DBP at baseline. Login to comment
122 Nevertheless, the association of ABCG8 T400K polymorphism with renal disease was validated in the DIAB2NEPHROGENE population of patients with type 2 diabetes. Login to comment
145 M. Marre (Bichat Hospital, Paris, France); steering committee: Table 4 - ABCG8 T400K (C>A) polymorphism genotype frequencies according to end-stage renal disease prevalence in DIAB2NEPHROGENE. Login to comment
146 T400K (C>A) End-stage renal disease Statistics Without, n (%) With, n (%) Prevalence, % P c7;2 unadjusted Odds ratio (95% CI) a TT 1366 (65.5) 26 (49.1) 1.9 2 df: 0.028; additive: 0.05 Dominant (CA + AA vs CC): 0.015 Additive model 1 1.54 (0.99-2.38), P = 0.055 Additive model 2 1.63 (1.05-2.54), P = 0.03 TK 627 (30.0) 25 (47.2) 3.8 KK 94 (4.5) 2 (3.8) 2.1 MAF 0.195 0.273 Dominant model 1 2.01 (1.15-3.54), P = 0.015 Dominant model 2 2.22 (1.25-3.94), P = 0.007 MAF: minor allele frequency. a Logistic regression analysis, model 1: adjusted for sex, age, BMI, total cholesterol, HbA1c, diabetes duration and prior myocardial infarction. Login to comment