ABCG5 p.Arg50Cys
| Predicted by SNAP2: | A: D (85%), C: D (91%), D: D (95%), E: D (91%), F: D (91%), G: D (91%), H: D (80%), I: D (85%), K: D (75%), L: D (85%), M: D (91%), N: D (91%), P: D (91%), Q: D (85%), S: D (91%), T: D (91%), V: D (85%), W: D (91%), Y: D (85%), |
| Predicted by PROVEAN: | A: N, C: D, D: N, E: N, F: D, G: N, H: N, I: D, K: N, L: N, M: N, N: N, P: N, Q: N, S: N, T: N, V: D, W: D, Y: N, |
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[hide] The ABCG family of membrane-associated transporter... Br J Pharmacol. 2010 Dec 22. doi: 10.1111/j.1476-5381.2010.01177.x. Kerr ID, Haider AJ, Gelissen IC
The ABCG family of membrane-associated transporters: you don't have to be big to be mighty.
Br J Pharmacol. 2010 Dec 22. doi: 10.1111/j.1476-5381.2010.01177.x., 2010-12-22 [PMID:21175590]
Abstract [show]
Along with many other mammalian ATP binding cassette (ABC) transporters, members of the ABCG group are involved in the regulated transport of hydrophobic compounds across cellular membranes. In humans, 5 ABCG family members have been identified, encoding proteins ranging from 638 to 678 amino acids in length. All 5 have been the subject of intensive investigation to better understand their physiological roles, expression patterns, interactions with substrates and inhibitors, and regulation at both the transcript and protein level. The principal substrates for at least 4 of the ABCG proteins are endogenous and dietary lipids, with ABCG1 implicated in particular in the export of cholesterol, and ABCG5 and G8 forming a functional heterodimer responsible for plant sterol elimination from the body. ABCG2 has a much broader substrate specificity and its ability to transport numerous diverse pharmaceuticals has implications for the absorption, distribution, metabolism, excretion, and toxicity (ADMETox) profile of these compounds. ABCG2 is one of at least three so-called multidrug resistant (MDR) ABC-transporters expressed in humans, and its activity is associated with decreased efficacy of anticancer agents in several carcinomas. In addition to its role in cancer, ABCG2 also plays a role in the normal physiological transport of urate and haem, the implications of which are described below. We summarize here data on all 5 human ABCG transporters and provide a current perspective on their roles in human health and disease.
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150 The former identified a single locus effect of SNP rs4245791 (in intron 3 of the ABCG8) on total cholesterol levels, whilst the latter identified rs6756629 (resulting in an Arg50Cys change in ABCG5) as being associated with both raised total and LDL‐cholesterol.
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ABCG5 p.Arg50Cys 21175590:150:174
status: VERIFIED182 The former identified a single locus effect of SNP rs4245791 (in intron 3 of the ABCG8) on total cholesterol levels, while the latter identified rs6756629 (resulting in an Arg50Cys change in ABCG5) as being associated with both raised total and low density lipoprotein-cholesterol.
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ABCG5 p.Arg50Cys 21175590:182:172
status: NEW[hide] An ATP-binding cassette gene (ABCG5) from the ABCG... Cytogenet Cell Genet. 2001;92(3-4):204-8. Shulenin S, Schriml LM, Remaley AT, Fojo S, Brewer B, Allikmets R, Dean M
An ATP-binding cassette gene (ABCG5) from the ABCG (White) gene subfamily maps to human chromosome 2p21 in the region of the Sitosterolemia locus.
Cytogenet Cell Genet. 2001;92(3-4):204-8., [PMID:11435688]
Abstract [show]
We characterized a new human ATP-binding cassette (ABC) transporter gene that is highly expressed in the liver. The gene, ABCG5, contains 13 exons and encodes a 651 amino acid protein. The predicted protein is closely related to the Drosophila white gene and a human gene, ABCG1, which is induced by cholesterol. This subfamily of genes all have a single ATP-binding domain at the N-terminus and a single C-terminal set of transmembrane segments. ABCG5 maps to human chromosome 2p21, between the markers D2S117 and D2S119. The abundant expression of this gene in the liver suggests that the protein product has an important role in transport of specific molecule(s) into or out of this tissue.
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52 The only variants detected were the Q609E polymorphism and an arginine to cystine change in codon 50 (R50C).
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ABCG5 p.Arg50Cys 11435688:52:102
status: VERIFIED53 The R50C variant was seen in the father of an affected individual and alters a residue that is con- Fig. 1.
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ABCG5 p.Arg50Cys 11435688:53:4
status: VERIFIED[hide] Stomatocytic haemolysis and macrothrombocytopenia ... Br J Haematol. 2005 Jul;130(2):297-309. Rees DC, Iolascon A, Carella M, O'marcaigh AS, Kendra JR, Jowitt SN, Wales JK, Vora A, Makris M, Manning N, Nicolaou A, Fisher J, Mann A, Machin SJ, Clayton PT, Gasparini P, Stewart GW
Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia.
Br J Haematol. 2005 Jul;130(2):297-309., [PMID:16029460]
Abstract [show]
Phytosterolaemia (sitosterolaemia) is a recessively inherited metabolic condition in which the absorption of both cholesterol and plant-derived cholesterol-like molecules at the gut is unselective and unrestricted. In haematology, Mediterranean stomatocytosis or Mediterranean macrothrombocytopenia is a poorly understood haematological condition that combines stomatocytic haemolysis with the presence of very large platelets. Five pedigrees showing this haematology were identified. Gas chromatography mass spectrometry (GC-MS) showed that all of the patients with this highly specific haematology had grossly elevated levels of phytosterols in the blood, diagnostic of phytosterolaemia. All showed mutations in the ABCG5 and ABCG8 previously linked to phytosterolaemia. Three pedigrees showed five new mutations, while two pedigrees showed the common W361X mutation in ABCG8. We draw the following four conclusions: (i) that Mediterranean stomatocytosis/macrothrombocytopenia is caused by an excess of phytosterols in the blood; (ii) that phytosterolaemia, which does not respond to standard statin treatment, can be diagnosed via the distinctive haematology described here, even when the cholesterol is normal; (iii) that phytosterolaemia should be considered in the differential diagnosis of all patients with large platelets; and (iv) that the platelet size should be noted in patients with hypercholesterolaemia.
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175 Polymorphisms (R50C and Q604E in ABCG5, C54Y in ABCG8) are shown in italics.
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ABCG5 p.Arg50Cys 16029460:175:15
status: VERIFIED176 In a survey of normal donors, we found that the R50C substitution in ABCG5 was present in three of 60 individuals (three of 120 chromosomes) while IVS11+3insT was present in none.
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ABCG5 p.Arg50Cys 16029460:176:48
status: VERIFIED[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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64 Only two loci in ABCG5, R50C and Q604E showed variations in our study population, the remaining 4 SNPs were invariant in all subjects and are not depicted in the haplotype analyses.
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ABCG5 p.Arg50Cys 16507104:64:24
status: VERIFIED177 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.
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ABCG5 p.Arg50Cys 16507104:177:185
status: VERIFIED[hide] Biliary cholesterol secretion: more than a simple ... World J Gastroenterol. 2010 Dec 21;16(47):5936-45. Dikkers A, Tietge UJ
Biliary cholesterol secretion: more than a simple ABC.
World J Gastroenterol. 2010 Dec 21;16(47):5936-45., 2010-12-21 [PMID:21157969]
Abstract [show]
Biliary cholesterol secretion is a process important for 2 major disease complexes, atherosclerotic cardiovascular disease and cholesterol gallstone disease. With respect to cardiovascular disease, biliary cholesterol secretion is regarded as the final step for the elimination of cholesterol originating from cholesterol-laden macrophage foam cells in the vessel wall in a pathway named reverse cholesterol transport. On the other hand, cholesterol hypersecretion into the bile is considered the main pathophysiological determinant of cholesterol gallstone formation. This review summarizes current knowledge on the origins of cholesterol secreted into the bile as well as the relevant processes and transporters involved. Next to the established ATP-binding cassette (ABC) transporters mediating the biliary secretion of bile acids (ABCB11), phospholipids (ABCB4) and cholesterol (ABCG5/G8), special attention is given to emerging proteins that modulate or mediate biliary cholesterol secretion. In this regard, the potential impact of the phosphatidylserine flippase ATPase class I type 8B member 1, the Niemann Pick C1-like protein 1 that mediates cholesterol absorption and the high density lipoprotein cholesterol uptake receptor, scavenger receptor class B type I, is discussed.
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127 With relevance to gallstone disease, recently specific mutations in ABCG5/G8, namely ABCG5 R50C and ABCG8 D19H, have been identified in humans and shown to increase the risk for cholesterol gallstone disease[81-83] .
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ABCG5 p.Arg50Cys 21157969:127:91
status: VERIFIED[hide] Genetic and functional identification of the likel... Hepatology. 2012 Aug 16. doi: 10.1002/hep.26009. von Kampen O, Buch S, Nothnagel M, Azocar L, Molina H, Brosch M, Erhart W, von Schonfels W, Egberts J, Seeger M, Arlt A, Balschun T, Franke A, Lerch MM, Mayerle J, Kratzer W, Boehm BO, Huse K, Schniewind B, Tiemann K, Jiang ZY, Han TQ, Mittal B, Srivastava A, Fenger M, Jorgensen T, Schirin-Sokhan R, Tonjes A, Wittenburg H, Stumvoll M, Kalthoff H, Lammert F, Tepel J, Puschel K, Becker T, Schreiber S, Platzer M, Volzke H, Krawczak M, Miquel JF, Schafmayer C, Hampe J
Genetic and functional identification of the likely causative variant for cholesterol gallstone disease at the ABCG5/8 lithogenic locus.
Hepatology. 2012 Aug 16. doi: 10.1002/hep.26009., [PMID:22898925]
Abstract [show]
BACKGROUND & AIMS: The sterolin locus (ABCG5/ABCG8) has been solidly shown to confer susceptibility for cholesterol gallstone disease in humans. Both the responsible variant and the molecular mechanism causing an increased incidence of gallstones in these patients have as yet not been identified. METHODS: Genetic mapping utilized patient samples from Germany (2808 cases, 2089 controls), Chile (680 cases, 442 controls), Denmark (366 cases, 766 controls), India (247 cases, 224 controls) and China (280 cases, 244 controls). Analysis of allelic imbalance in cDNA samples from human liver (N=22) was performed using pyrosequencing. Transiently transfected HEK293 cells were used for [3H]-cholesterol export assays, analysis of protein expression and localisation of allelic constructs. RESULTS: Through fine mapping in German and Chilean samples, a approximately 250kB disease-associated interval could be defined for this locus. Lack of allelic imbalance or allelic splicing of the ABCG5 and ABCG8 transcripts in human liver limited the search to coding SNPs. Subsequent mutation detection and genotyping yielded two disease-associated variants ABCG5-R50C (p=4.94x10(-9) ) and ABCG8-D19H (p=1.74x10(-10) ) in high pair-wise LD (r(2) =0.95). [3H]-cholesterol export assays of allelic constructs harbouring these genetic candidate variants demonstrated increased transport activity (3.2-fold, p=0.003) only for the ABCG8-19H variant, which was also superior in nested logistic regression models in German (p=0.018), Chilean (p=0.030) and Chinese (p=0.040) patient samples. CONCLUSION: This variant thus provides a molecular basis for biliary cholesterol hypersecretion as the mechanism for cholesterol gallstone formation thereby drawing a link between "post-genomic" and "pre-genomic" pathophysiological knowledge about this common complex disorder. (HEPATOLOGY 2012.).
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68 SNP rs6756629 (ABCG5-R50C) yielded the second most significant association (p=4.9×10-9 ) of all previously known, non-synonymous variants in ABCG5/8.
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ABCG5 p.Arg50Cys 22898925:68:21
status: NEW121 After extensive genotyping, only two candidate variants remained: ABCG5-R50C and ABCG8-D19H, both with similar allelic odds ratios (Supplementary Table 1, Table 2).
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ABCG5 p.Arg50Cys 22898925:121:72
status: NEW[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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199 The minor T allele of rs6756629 (R50C, C.T) in ABCG5 was reported to be associated with lower levels of TC (P = 1.5610211 ) and LDL-C (P = 2.6610210 ) compared to the major allele [15].
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ABCG5 p.Arg50Cys 22655090:199:33
status: NEW197 The minor T allele of rs6756629 (R50C, C.T) in ABCG5 was reported to be associated with lower levels of TC (P = 1.5610211 ) and LDL-C (P = 2.6610210 ) compared to the major allele [15].
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ABCG5 p.Arg50Cys 22655090:197:33
status: NEW198 The minor T allele of rs6756629 (R50C, C.T) in ABCG5 was reported to be associated with lower levels of TC (P = 1.5610211 ) and LDL-C (P = 2.6610210 ) compared to the major allele [15].
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ABCG5 p.Arg50Cys 22655090:198:33
status: NEW[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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1789 The minor T allele of rs6756629 (R50C, C > T) in ABCG5 was reported to be associated with lower levels of total cholesterol (p = 1.5 × 10-11) and LDL cholesterol (p = 2.6 × 10-10) compared to the major allele [11].
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ABCG5 p.Arg50Cys 19932478:1789:33
status: NEW[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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56 ABCG5 R50C and ABCG8 D19H were in almost complete linkage disequilibrium in Abbreviations and Acronyms ABC = adenosine triphosphate-binding cassette transporter CI = confidence interval LDL = low-density lipoprotein MI = myocardial infarction OR = odds ratio the CCHS (D` &#bc; 0.98; r2 &#bc; 0.94), as previously described (11), and therefore only D19H was genotyped in the CGPS and the CIHDS studies (Online Fig. 1).
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ABCG5 p.Arg50Cys 24657701:56:6
status: NEW[hide] Future therapeutic targets for the treatment and p... Eur J Pharmacol. 2015 Oct 15;765:366-74. doi: 10.1016/j.ejphar.2015.08.045. Epub 2015 Sep 7. Castro-Torres IG, Cardenas-Vazquez Rde J, Velazquez-Gonzalez C, Ventura-Martinez R, De la O-Arciniega M, Naranjo-Rodriguez EB, Martinez-Vazquez M
Future therapeutic targets for the treatment and prevention of cholesterol gallstones.
Eur J Pharmacol. 2015 Oct 15;765:366-74. doi: 10.1016/j.ejphar.2015.08.045. Epub 2015 Sep 7., [PMID:26358204]
Abstract [show]
The formation of cholesterol gallstones involves very complex imbalances, such as alterations in the secretion of biliary lipids (which involves the ABCG5, ABCG8, ABCB4 and ABCB11 transporters), biochemical and immunological reactions in the gallbladder that produce biliary sludge (mucins), physicochemical changes in the structure of cholesterol (crystallization), alterations in gallbladder motility, changes in the intestinal absorption of cholesterol (ABCG5/8 transporters and Niemann-Pick C1L1 protein) and alterations in small intestine motility. Some of these proteins have been studied at the clinical and experimental levels, but more research is required. In this review, we discuss the results of studies on some molecules involved in the pathophysiology of gallstones that may be future therapeutic targets to prevent the development of this disease, and possible sites for treatment based mainly on the absorption of intestinal cholesterol (Niemann-Pick C1L1 and ABCG5/8 proteins).
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1442 In the latter two countries, genetic mapping identified segments of about 250 kilobases, which can be mapped to the locus of ABCG5/8, ABCG5-R50C (p&#bc;4.94 10(9)) and ABCG8-D19H (p&#bc;1.74 10(10)).
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ABCG5 p.Arg50Cys 26358204:1442:140
status: NEW[hide] Lipid trait-associated genetic variation is associ... BMC Med Genet. 2013 Nov 21;14:120. doi: 10.1186/1471-2350-14-120. Goodloe R, Brown-Gentry K, Gillani NB, Jin H, Mayo P, Allen M, McClellan B Jr, Boston J, Sutcliffe C, Schnetz-Boutaud N, Dilks HH, Crawford DC
Lipid trait-associated genetic variation is associated with gallstone disease in the diverse Third National Health and Nutrition Examination Survey (NHANES III).
BMC Med Genet. 2013 Nov 21;14:120. doi: 10.1186/1471-2350-14-120., [PMID:24256507]
Abstract [show]
BACKGROUND: Gallstone disease is one of the most common digestive disorders, affecting more than 30 million Americans. Previous twin studies suggest a heritability of 25% for gallstone formation. To date, one genome-wide association study (GWAS) has been performed in a population of European-descent. Several candidate gene studies have been performed in various populations, but most have been inconclusive. Given that gallstones consist of up to 80% cholesterol, we hypothesized that common genetic variants associated with high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) would also be associated with gallstone risk. METHODS: To test this hypothesis, the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study as part of the Population Architecture using Genomics and Epidemiology (PAGE) study performed tests of association between 49 GWAS-identified lipid trait SNPs and gallstone disease in non-Hispanic whites (446 cases and 1,962 controls), non-Hispanic blacks (179 cases and 1,540 controls), and Mexican Americans (227 cases and 1,478 controls) ascertained for the population-based Third National Health and Nutrition Examination Survey (NHANES III). RESULTS: At a liberal significance threshold of 0.05, five, four, and four SNP(s) were associated with disease risk in non-Hispanic whites, non-Hispanic blacks, and Mexican Americans, respectively. No one SNP was associated with gallstone disease risk in all three racial/ethnic groups. The most significant association was observed for ABCG5 rs6756629 in non-Hispanic whites [odds ratio (OR) = 1.89; 95% confidence interval (CI) = 1.44-2.49; p = 0.0001). ABCG5 rs6756629 is in strong linkage disequilibrium with rs11887534 (D19H), a variant previously associated with gallstone disease risk in populations of European-descent. CONCLUSIONS: We replicated a previously associated variant for gallstone disease risk in non-Hispanic whites. Further discovery and fine-mapping efforts in diverse populations are needed to fully describe the genetic architecture of gallstone disease risk in humans.
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90 Replication in European-descent populations ABCG5 rs6756629 (R50C) is in strong linkage disequilibrium with rs11887534 (D19H), a variant previously associated with gallstone disease risk in populations of European-descent [20].
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ABCG5 p.Arg50Cys 24256507:90:61
status: NEW