ABCMdb

ABCA1 p.Val771Met

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Publications

PMID: 21839797 [PubMed] Ota M et al: "A polymorphism of the ABCA1 gene confers susceptibility to schizophrenia and related brain changes."

No. Sentence Comment

25 Previous studies have examined the association between polymorphisms of ABCA1, particularly the non-synonymous single nucleotide polymorphisms (SNPs) of rs2230806 (R219K), rs2066718 (V771M), and rs2230808 (R1587K) and risk for Alzheimer's disease. Login to comment
65 We found only four well-validated SNPs with a heterozygosity value of N0.10 in Asian populations: rs2230806 (R219K), rs2066718 (V771M), rs2066714 (I883M), and rs2230808 (R1587K). Login to comment
123 db SNP ID and aminoacid change Position⁎ Inter-SNP distance (bp) Gender Group N Genotype distribution (frequency) χ2 P Allele count (frequency) χ2 P HWE of Controls (df=1) R/R R/K K/K R K rs2230806 107620867 (-) All Schizophrenia 497 119 (0.24) 241 (0.48) 137 (0.28) 2.77 0.250 479 (0.48) 515 (0.52) 0.01 0.897 χ²=3.73 Arg219Lys exon 7 Controls 932 204 (0.22) 495 (0.53) 233 (0.25) 903 (0.48) 961 (0.52) P=0.053 M Schizophrenia 274 63 (0.23) 137 (0.50) 74 (0.27) 0.47 0.789 263 (0.48) 285 (0.52) 0.45 0.503 χ²=0.05 Controls 330 71 (0.22) 162 (0.49) 97 (0.29) 304 (0.46) 356 (0.54) P=0.827 F Schizophrenia 223 56 (0.25) 104 (0.47) 63 (0.28) 216 (0.48) 230 (0.52) χ²=6.81 Controls 602 133 (0.22) 333 (0.55) 136 (0.23) 599 (0.50) 605 (0.50) P=0.009 V/V V/M M/M V M rs2066718 107589255 31,612 All Schizophrenia 494 438 (0.89) 54 (0.11) 2 (0.00) 1.09 0.580 930 (0.94) 58 (0.06) 0.99 0.319 χ²=0.04 Val771Met exon 16 Controls 936 812 (0.87) 120 (0.13) 4 (0.00) 1744 (0.93) 128 (0.07) P=0.847 M Schizophrenia 273 242 (0.89) 29 (0.11) 2 (0.01) 1.70 0.428 513 (0.94) 33 (0.06) 0.50 0.480 χ²=0.30 Controls 333 287 (0.86) 45 (0.14) 1 (0.00) 619 (0.93) 47 (0.07) P=0.582 F Schizophrenia 221 196 (0.89) 25 (0.11) 0 (0.00) 1.32 0.518 417 (0.94) 25 (0.06) 0.60 0.437 χ²=0.03 Controls 603 525 (0.87) 75 (0.12) 3 (0.00) 1125 (0.93) 81 (0.07) P=0.856 I/I I/M M/M I M rs2066714 107586753 34,114 All Schizophrenia 487 208 (0.43) 212 (0.44) 67 (0.14) 3.86 0.145 628 (0.64) 346 (0.36) 1.75 0.186 χ²=0.91 Ile883Met exon 18 Controls 917 345 (0.38) 446 (0.49) 126 (0.14) 1136 (0.62) 698 (0.38) P=0.339 M Schizophrenia 266 115 (0.43) 116 (0.44) 35 (0.13) 3.23 0.199 346 (0.65) 186 (0.35) 0.87 0.335 χ²=2.40 Controls 330 122 (0.37) 168 (0.51) 40 (0.12) 412 (0.62) 248 (0.38) P=0.122 F Schizophrenia 221 93 (0.42) 96 (0.43) 32 (0.14) 1.23 0.542 282 (0.64) 160 (0.36) 0.62 0.430 χ²=0.002 Controls 587 223 (0.38) 278 (0.47) 86 (0.15) 724 (0.62) 450 (0.38) P=0.966 R/R R/K K/K R K rs2230808 107562804 58,063 All Schizophrenia 491 174 (0.35) 252 (0.51) 65 (0.13) 4.05 0.132 600 (0.61) 382 (0.39) 0.63 0.427 χ²=0.50 Arg1587Lys exon 35 Controls 923 367 (0.40) 422 (0.46) 134 (0.15) 1156 (0.63) 690 (0.37) P=0.478 M Schizophrenia 273 87 (0.32) 148 (0.54) 38 (0.14) 8.51 0.014 322 (0.59) 224 (0.41) 3.68 0.055 χ²=1.17 Controls 327 140 (0.43) 141 (0.43) 46 (0.14) 421 (0.64) 233 (0.36) P=0.278 F Schizophrenia 218 87 (0.40) 104 (0.48) 27 (0.12) 0.79 0.674 278 (0.64) 158 (0.36) 0.60 0.440 χ²=0.01 Controls 596 227 (0.38) 281 (0.47) 88 (0.15) 735 (0.62) 457 (0.38) P=0.945 HWE; Hardy-Weinberg equilibrium. Login to comment
64 We found only four well-validated SNPs with a heterozygosity value of N0.10 in Asian populations: rs2230806 (R219K), rs2066718 (V771M), rs2066714 (I883M), and rs2230808 (R1587K). Login to comment
122 db SNP ID and aminoacid change PositionÌe; Inter-SNP distance (bp) Gender Group N Genotype distribution (frequency) c7;2 P Allele count (frequency) c7;2 P HWE of Controls (df=1) R/R R/K K/K R K rs2230806 107620867 (-) All Schizophrenia 497 119 (0.24) 241 (0.48) 137 (0.28) 2.77 0.250 479 (0.48) 515 (0.52) 0.01 0.897 c7;&#b2;=3.73 Arg219Lys exon 7 Controls 932 204 (0.22) 495 (0.53) 233 (0.25) 903 (0.48) 961 (0.52) P=0.053 M Schizophrenia 274 63 (0.23) 137 (0.50) 74 (0.27) 0.47 0.789 263 (0.48) 285 (0.52) 0.45 0.503 c7;&#b2;=0.05 Controls 330 71 (0.22) 162 (0.49) 97 (0.29) 304 (0.46) 356 (0.54) P=0.827 F Schizophrenia 223 56 (0.25) 104 (0.47) 63 (0.28) 216 (0.48) 230 (0.52) c7;&#b2;=6.81 Controls 602 133 (0.22) 333 (0.55) 136 (0.23) 599 (0.50) 605 (0.50) P=0.009 V/V V/M M/M V M rs2066718 107589255 31,612 All Schizophrenia 494 438 (0.89) 54 (0.11) 2 (0.00) 1.09 0.580 930 (0.94) 58 (0.06) 0.99 0.319 c7;&#b2;=0.04 Val771Met exon 16 Controls 936 812 (0.87) 120 (0.13) 4 (0.00) 1744 (0.93) 128 (0.07) P=0.847 M Schizophrenia 273 242 (0.89) 29 (0.11) 2 (0.01) 1.70 0.428 513 (0.94) 33 (0.06) 0.50 0.480 c7;&#b2;=0.30 Controls 333 287 (0.86) 45 (0.14) 1 (0.00) 619 (0.93) 47 (0.07) P=0.582 F Schizophrenia 221 196 (0.89) 25 (0.11) 0 (0.00) 1.32 0.518 417 (0.94) 25 (0.06) 0.60 0.437 c7;&#b2;=0.03 Controls 603 525 (0.87) 75 (0.12) 3 (0.00) 1125 (0.93) 81 (0.07) P=0.856 I/I I/M M/M I M rs2066714 107586753 34,114 All Schizophrenia 487 208 (0.43) 212 (0.44) 67 (0.14) 3.86 0.145 628 (0.64) 346 (0.36) 1.75 0.186 c7;&#b2;=0.91 Ile883Met exon 18 Controls 917 345 (0.38) 446 (0.49) 126 (0.14) 1136 (0.62) 698 (0.38) P=0.339 M Schizophrenia 266 115 (0.43) 116 (0.44) 35 (0.13) 3.23 0.199 346 (0.65) 186 (0.35) 0.87 0.335 c7;&#b2;=2.40 Controls 330 122 (0.37) 168 (0.51) 40 (0.12) 412 (0.62) 248 (0.38) P=0.122 F Schizophrenia 221 93 (0.42) 96 (0.43) 32 (0.14) 1.23 0.542 282 (0.64) 160 (0.36) 0.62 0.430 c7;&#b2;=0.002 Controls 587 223 (0.38) 278 (0.47) 86 (0.15) 724 (0.62) 450 (0.38) P=0.966 R/R R/K K/K R K rs2230808 107562804 58,063 All Schizophrenia 491 174 (0.35) 252 (0.51) 65 (0.13) 4.05 0.132 600 (0.61) 382 (0.39) 0.63 0.427 c7;&#b2;=0.50 Arg1587Lys exon 35 Controls 923 367 (0.40) 422 (0.46) 134 (0.15) 1156 (0.63) 690 (0.37) P=0.478 M Schizophrenia 273 87 (0.32) 148 (0.54) 38 (0.14) 8.51 0.014 322 (0.59) 224 (0.41) 3.68 0.055 c7;&#b2;=1.17 Controls 327 140 (0.43) 141 (0.43) 46 (0.14) 421 (0.64) 233 (0.36) P=0.278 F Schizophrenia 218 87 (0.40) 104 (0.48) 27 (0.12) 0.79 0.674 278 (0.64) 158 (0.36) 0.60 0.440 c7;&#b2;=0.01 Controls 596 227 (0.38) 281 (0.47) 88 (0.15) 735 (0.62) 457 (0.38) P=0.945 HWE; Hardy-Weinberg equilibrium. Login to comment

PMID: 20800056 [PubMed] Berge KE et al: "Mutations in APOA-I and ABCA1 in Norwegians with low levels of HDL cholesterol."

No. Sentence Comment

59 of patients (het/hom)a Mutation Nucleotide Exon/Intron (i) PolyPhen prediction (score) SNP rs ID, ref.# ABCA1 Missense 8/3 R219K c.656, GNA 7 Benign (0.489) rs2230806 0/1 R282Q c.845, GNA 9 Benign (0.592) Novel 1/0 V399A c.1196, TNC 11 Benign (0.040) rs9282543 1/0 M636V c.1906, ANG 15 Benign (0.418) Novel 3/0 V771M c.2311, GNA 16 Benign (0.931) rs2066718 2/0 V825I c.2473, GNA 17 Benign (0.440) rs2066715 3/1 I883M c.2649, ANG 18 Benign (0.147) rs2066714 1/0 C887F c.2660, GNT 19 Benign (0.888) Novel 3/0 E1172D c.3516, GNC 24 Benign (0.546) rs33918808 1/0 G1216V c.3647, GNT 25 Prob damb (2.154) Ref. [18] 1/0 L1244Q c.3731, TNA 25 Prob dam (2.269) Novel 1/0 C1477F c.4430, TNA 31 Prob dam (3.688) Ref. [17] 14/1 R1587K c.4760, ANT 35 Benign (0.284) rs2230808 1/0 V1674I c.5020, GNA 37 Benign (0.821) Novel 1/0 R1680Q c.5039, GNA 37 Poss damc (1.926) Ref. [17] 1/0 N1800H c.5398, ANC 40 Poss dam (1.845) Ref. [19] Nonsense/splice 1/0 IVS4+1, GNA c.302+1, GNA i4 - 1/0 C1429X c.4287, CNA 31 - 1/0 IVS32+1, GNA c.4559+1, GNA i32 - APOA-I 7/0 R160L c.551, GNT 4 Prob dam (2.491) Ref. [21] 1/0 del182K del c.616-618 AAG 4 - Novel a Het: heterozygote, hom: homozygote. Login to comment
78 Variants R219K, V399A, V771M, V825I, I883M, E1172D, and R1587K have been reported as single nucleotide polymorphisms (SNPs) (Table 1). Login to comment
80 In addition, R219K, V771M, V825I, I883M, E1172D, and R1587K have been found in similar frequencies in patients with low or high HDL cholesterol levels [18], indicating that these variants do not cause low HDL cholesterol levels. Login to comment

PMID: 21130966 [PubMed] Rejeb J et al: "Associations between common polymorphisms of adenosine triphosphate-binding cassette transporter A1 and coronary artery disease in a Tunisian population."

No. Sentence Comment

68 The genotypes for each ABCA1 polymorphism (G1051A [R219K], G2706A [V771M], G2868A [V825I] and -565C/T [-477C/T]) were determined by polymerase chain reaction-restriction fragment length polymorphism analysis. Login to comment

PMID: 20590502 [PubMed] Stankovic S et al: "Genetic aspects of ischemic stroke: coagulation, homocysteine, and lipoprotein metabolism as potential risk factors."

No. Sentence Comment

383 A study of 244 Hungarian patients suggested a protective role for the ABCA I -R219K and V771M polymorphisms against IS. Login to comment
401 Authors (reference) Year Polymorphism Methodology Phenotype OR 95% ci Andrikovics et al. (434) 2006 R219K V771M Case-control: 244 cases IS Yamada et al. (135) 2006 Arg219Lys (Ile823Met Case-control: 636 cases, 2010 controls IS (atherothrombotic) N.S. N.S. Pasdar et al. (435) 2007 L158L R219K G316G R1587K Case-control: 400 cases, 487controls IS N.S. N.S. N.S. N.S. Yamada et al. (436) 2008 -14C/T (rs1800977) Case-control: 822 cases, 2070 controls IS (atherothrombotic) Dominant-Recessive 1.21 1.75 1.00-1.45 1.22-2.48 Guan et al.,(448) and Xu et al., (450) which reported a relationship with atherosclerotic stroke, and in the prospective cohort study of Morrison et al.,(341) who described a positive association between S447X and asymptomatic stroke lesions, and in that of Kostulas et al.,(449) in which the protective role of the G-allele of LPL S447X polymorphism had a lower frequency in males. Login to comment

PMID: 19596329 [PubMed] Frikke-Schmidt R et al: "Genetic variation in the ABCA1 gene, HDL cholesterol, and risk of ischemic heart disease in the general population."

No. Sentence Comment

2387 Common ABCA1 variants in the general population 5.1. Frequency of common variants in the extreme tails of the HDL distribution Several resequencing studies have identified a number of common non-synonymous variations in ABCA1 [57,58,81-84]: R219K, V771M, V825I, I883M, E1172D and R1587K. Login to comment
2389 In the largest resequencing study to date of Caucasians in the general population, two of the non-synonymous SNPs (V771M and R1587K) and/or their haplotypes differed in frequency between the population extremes of HDL cholesterol levels [52,57]. Login to comment
2395 Frequencies of common variants and association with variation in lipid levels in the general population Frequencies for the most common non-synonymous ABCA1 SNPs (R219K, V825I, I883M, R1587K) are largely similar across studies that partly or as a whole represent general populations [57,58,81,82,86-88], whereas the less common SNPs (V771M, and E1172D) are reported in some [57,58,81,82,86,88], but not in all studies [58,87]. Login to comment
2398 The V771M and V825I SNPs were associated with increases in HDL cholesterol in women, whereas the R1587K SNP was associated with decreased HDL cholesterol levels in both genders. Login to comment
2399 This corresponded well with the findings from the initial screening where V771M and V825I (in women) were overrepresented in the high extreme, and R1587K was overrepresented in the low extreme of HDL cholesterol [57]. Login to comment
2402 The HDL cholesterol and/or apoAI lowering effect of the rare allele of the very common R1587K SNP has now been observed in several different studies [57,81,82], whereas the HDL cholesterol increasing effect of the V771M and V825I/I883M SNPs appears to be confined to specific genders in different populations [57,58,87-89]. Login to comment
2410 Frikke-Schmidt et al. showed for the first time in a large general population sample that three out of six non-synonymous SNPs (V771M, I883M, and E1172D) were independent predictors of IHD risk - risk increases that were not reflected in levels of HDL cholesterol [85]. Login to comment
2411 By stepwise regression, V771M and I883M were shown to be the best predictors in women, whereas I883M and E1172D were most informative in men. Login to comment
2413 Additive effects on IHD risk were present for V771M/I883M and I883M/E1172D pairs with up to three-fold increases in risk for specific subsets of the genotypes (Fig. 4, lower panels) [85]. Login to comment
2441 For V771M, I883M, and E1172D as single sites, heterozygotes and homozygotes for the variant allele were pooled (heterozygotes and homozygotes in red, wildtype in green). Login to comment
2386 Common ABCA1 variants in the general population 5.1. Frequency of common variants in the extreme tails of the HDL distribution Several resequencing studies have identified a number of common non-synonymous variations in ABCA1 [57,58,81-84]: R219K, V771M, V825I, I883M, E1172D and R1587K. Login to comment
2388 In the largest resequencing study to date of Caucasians in the general population, two of the nonsynonymous SNPs (V771M and R1587K) and/or their haplotypes differed in frequency between the population extremes of HDL cholesterol levels [52,57]. Login to comment
2394 Frequencies of common variants and association with variation in lipid levels in the general population Frequencies for the most common non-synonymous ABCA1 SNPs (R219K, V825I, I883M, R1587K) are largely similar across studies that partly or as a whole represent general populations [57,58,81,82,86-88], whereas the less common SNPs (V771M, and E1172D) are reported in some [57,58,81,82,86,88], but not in all studies [58,87]. Login to comment
2397 The V771M and V825I SNPs were associated with increases in HDL cholesterol in women, whereas the R1587K SNP was associated with decreased HDL cholesterol levels in both genders. Login to comment
2401 The HDL cholesterol and/or apoAI lowering effect of the rare allele of the very common R1587K SNP has now been observed in several different studies [57,81,82], whereas the HDL cholesterol increasing effect of the V771M and V825I/I883M SNPs appears to be confined to specific genders in different populations [57,58,87-89]. Login to comment
2409 Frikke-Schmidt et al. showed for the first time in a large general population sample that three out of six non-synonymous SNPs (V771M, I883M, and E1172D) were independent predictors of IHD risk - risk increases that were not reflected in levels of HDL cholesterol [85]. Login to comment
2412 Additive effects on IHD risk were present for V771M/I883M and I883M/E1172D pairs with up to three-fold increases in risk for specific subsets of the genotypes (Fig. 4, lower panels) [85]. Login to comment
2440 For V771M, I883M, and E1172D as single sites, heterozygotes and homozygotes for the variant allele were pooled (heterozygotes and homozygotes in red, wildtype in green). Login to comment

PMID: 18706283 [PubMed] Iatan I et al: "Effect of ABCA1 mutations on risk for myocardial infarction."

No. Sentence Comment

74 To date, the largest study examining ABCA1 single nucleotide polymorphisms (SNPs) and HDL-C is the Copenhagen City Heart Study [24], in which the relationship between six ABCA1 nonsynonymous common SNPs (R219K, V771M, M825I, I883M, E1172D, and R1587K) and HDL-C was analyzed. Login to comment
112 Additional insights into the effects of ABCA1 on MI have recently been described by Frikke-Schmidt et al. [35•] in a study where six nonsynonymous ABCA1 SNPs, R219K, V771M, V825I, I883M, E1172D, and R1587K (identified by resequencing ABCA1 in 190 individuals of Danish ancestry [24]), were genotyped in 9259 individuals from the Copenhagen City Heart Study to assess their risk of CHD (Table 2). Login to comment
115 In addition, to determine which ABCA1 SNPs were independent predictors of CHD and not caused by linkage disequilibrium among SNPs, a stepwise Cox regression approach was performed identifying V771M, I883M, and E1172D as the most important for the final IHD prediction model. Login to comment
116 Additive effects on CHD risk were also observed for the V771M/I883M and I883M/E1172D pairs. Login to comment
149 Genetic variation in ABCA1 and risk of myocardial infarction Study* / year Population screened HDL-C, mmol/L ABCA1 variants Conclusions Andrikovics et al. [45] / 2006 Hungarian patients with ischemic stroke ( n = 244) NA R219K † , V771M † , I883M A higher frequency of R219K and V771M was observed in controls than in Hungarian stroke patients, suggesting a protective role against CHD Hungarian patients with CHD ( n = 150) Controls (n = 193) Benton et al. [46] / 2007 Subgroup of Multi-Ethnic Study of Atherosclerosis study group ( n = 969) R219K genotype: C-565T, R219K † The R219K polymorphism was associated with a 28% lower prevalence of coronary calcifi cation, a measure of subclinical atherosclerosis, and slightly higher HDL-C level RR: 1.34 ± 0.38 RK: 1.29 ± 0.35 KK: 1.37 ± 0.39 Tsai et al. [47] / 2007 Taiwanese patients with CHD ( n = 205) and controls ( n = 201) Cases: 1.04 ± 0.25 I823M The M823 allele was associated with higher HDL-C. Login to comment
152 Cases: 1.70 (1.5-2.0) Ctl: 1.30 (1.1-1.6) Pasdar et al. [49] / 2007 White ischemic stroke patients ( n = 400) Cases: 1.20 ± 0.40 L158L, R219K, G316G, R1587K The ABCA1 gene was not found to be associated with ischemic stroke, but R219K had the greatest impact on lipid profi le, especially on LDL and TG White controls ( n = 487) Ctl: 1.40 ± 0.40 Nebel et al. [50] / 2007 German patients with CHD ( n = 1090) and controls ( n = 728) NA R219K, V771M, I883M † , E1172D, R1587K Only the I883M polymorphism was signifi cantly associated with CHD *Studies reporting the initial molecular and biochemical characterization of fewer than 5 probands with an ABCA1 gene defect and their families were not included in Table 2. Login to comment
155 Genetic variation in ABCA1 and risk of myocardial infarction Study* / year Population screened HDL-C, mmol/L ABCA1 variants Conclusions Frikke-Schmidt et al. [35••] / 2008 Copenhagen City Heart Study: Women: R219K, V771M † , V825I † , I883M † , E1172D † , R1587K † Common genetic variation at the ABCA1 locus predicts IHD risk independently of plasma HDL-C levels. Login to comment
156 The V771M, I883M, and E1172D polymorphisms signifi cantly predicted IHD risk, but their association was not related to HDL-C. Login to comment
161 Taken together, the findings of this study show that three of the six nonsynonymous SNPs (V771M, I883M, and E1172D) in ABCA1 predict risk of IHD in the general population, and that ABCA1 may have proatherosclerosis effects independent of HDL-C levels [35•]. Login to comment

PMID: 18468402 [PubMed] Ergen A et al: "Investigation of ABCA1 C69T and G-191C polymorphisms in coronary artery disease."

No. Sentence Comment

74 They found that the rare alleles of C-14T(C69T) and V771M polymorphisms were associated with higher HDL-C levels in men and, in combination with the rare alleles of R219K and I883M, respectively, with higher HDL-C in both sexes. Login to comment

PMID: 18199144 [PubMed] Slatter TL et al: "Novel rare mutations and promoter haplotypes in ABCA1 contribute to low-HDL-C levels."

No. Sentence Comment

20 The C-14T promoter SNP (17), and the R1587K coding SNP (9) have been associated with low HDL-C, while the V771M (9), V825I (9, 10) and I883M (10, 18) coding SNPs have been associated with elevated HDL-C. Login to comment
41 Genotyping of ABCA1 SNPs by RFLP Fourteen SNPs including five promoter SNPs (C-564T, G-407C, G-278C, G-99C, and C-14T), one 5#-UTR SNP [-76(-75) insG], six non-synonymous coding SNPs (R219K, V771M, V825I, I883M, E1172D, and R1587K) and two 3#-UTR SNPs [A-960G -383(-381)delGTT] were genotyped in the low-, mid-, and high-HDL-C groups by restriction fragment length polymorphism (RFLP) analysis. Login to comment
55 Six of the non-synonymous variants were previously reported SNPs (R219K, V771M, V825I, I883M, E1172D and R1587K). Login to comment
105 a Coding haplotypes were derived from the following six non-synonymous SNPs (left to right): R219K (G.A), V771M (G.A), V825I (G.A), I883M (A.G), E1172D (G.C), and R1587K (G.A). Login to comment

PMID: 17951323 [PubMed] Frikke-Schmidt R et al: "Genetic variation in ABCA1 predicts ischemic heart disease in the general population."

No. Sentence Comment

7 Two SNPs (V771M and V825I) were previously associated with increases in HDL-C, 1 (R1587K) with decreased HDL-C, whereas 3 (R219K, I883M and E1172D) did not affect HDL-C levels. Login to comment
8 Despite this, 5 out of 6 SNPs (V771M, V825I, I883M, E1172D, R1587K) predicted increased risk of IHD. Login to comment
10 A stepwise regression approach identified V771M, I883M, and E1172D as the most important predictors of IHD and additive effects on IHD risk were present for V771M/I883M and I883M/E1172D pairs. Login to comment
16 In the present study we included 9259 individuals from the 1991 to 1994 examination, whom we genotyped for all nonsynonymous SNPs (R219K, V771M, V825I, I883M, E1172D, R1587K) identified by resequencing ABCA1 in 190 individuals of Danish ancestry.8 Information on diagnosis of IHD (nϭ1170; World Health Organization; International Classification of Diseases, 8th edition: codes 410 to 414; 10th edition: codes I20-I25) was collected and verified until 31st December 2000 by reviewing all hospital admissions and diagnoses entered in the national Danish Patient Registry, all causes of death entered in the national Danish Causes of Death Registry, and medical records from hospitals and general practitioners. Login to comment
29 The cohort was participants in The Copenhagen City Heart Study who attended the 1991 to 1994 examination, and for whom combined genotypes for all 6 nonsynonymous SNPs (R219K, V771M, V825I, I883M, E1172D, R1587K) were available as well as all clinical and biochemical data (nϭ9028 out of nϭ9259; Table 1). Login to comment
38 SNP Genotyping The ABI PRISM 7900HT Sequence Detection System (Applied Biosystem Inc) was used to genotype for all 6 nonsynonymous SNPs (R219K, V771M, V825I, I883M, E1172D, R1587K) identified by resequencing ABCA1 in 190 individuals, as previously described.8 Biochemical Analyses Colorimetric and turbidimetric assays (Hitachi autoanalyzer) were used to measure plasma levels of total cholesterol, HDL-C, triglycerides, and apolipoproteins B and -AI (all Boehringer Mannheim GmbH). Login to comment
55 Frikke-Schmidt et al ABCA1 and Ischemic Heart Disease 181 the entire ABCA1 gene in 190 individuals of Danish descent were: 0.26 (R219K), 0.03 (V771M), 0.03 (E1172D), 0.06 (V825I), 0.12 (I883M), and 0.24 (R1587K).8 Similar allele frequencies have been reported for other White populations.14 Please see Data Supplements, Expanded Results for description of Hardy-Weinberg equilibrium. Login to comment
57 A strong positive DЈ was present for R219K/V771M, M825I/I883M, and E1172D/ R1587K (DЈϾ0.9), whereas a strong negative DЈ was present for R219K/V825I, V771M/V825I, and V771M/I883M (DЈϽ-0.9). Login to comment
60 Risk of IHD Prospective Study The cumulative incidence of IHD as a function of age was increased for V771M (GAϩAA versus GG, borderline Pϭ0.06), V825I (GAϩAA versus GG; Pϭ0.02), I883M (AGϩGG versus AA, Pϭ0.01), E1172D (GCϩCC versus GG, Pϭ0.03), and for R1587K (AA versus GG, borderline Pϭ0.06), but not for R219K (Figure 2). Login to comment
61 The age adjusted hazard ratios (HRs) for IHD were: V771M (GAϩAA versus GG) 1.2 (95% confidence interval [CI] 1.0 to 1.5), V825I (GAϩAA versus GG) 1.2 (1.0 to 1.5), I883M (AGϩGG versus AA) 1.2 (1.0 to 1.4), E1172D (GCϩCC versus GG) 1.3 (1.0 to 1.6) and R1587K (AA versus GG) 1.2 (1.0 to 1.6), respectively (Table 2). Login to comment
68 Probability values are for overall log-rank tests. For V771M, V825I, I883M, and E1172D, heterozygotes and homozygotes for the variant allele were pooled (combined genotype in red, common genotype in green). Login to comment
71 There was evidence for a statistically significant interaction between gender and V771M (Pϭ0.04) in the prediction of IHD, whereas the remaining 5 SNPs did not interact with gender (all probability values Ͼ0.52). Login to comment
74 The age-adjusted odds ratios (ORs) were: V771M (GAϩAA versus GG) 1.2 (0.9 to 1.5), V825I (GAϩAA versus GG) 1.2 (0.9 to 1.4), I883M (AGϩGG versus AA) 1.2 (1.0 to 1.4), E1172D (GCϩCC versus GG) 1.1 (0.8 to 1.4), and R1587K (GA versus GG) 1.2 (1.0 to 1.4). Login to comment
77 The final prediction model included the 3 noncorrelated SNPs, V771M, I883M, and E1172D (HRs: V771M, 1.2 [1.0 to 1.6]; I883M, 1.2 [1.0 to 1.4]; E1172D, 1.2 [1.0 to 1.6]). Login to comment
78 Performing gender specific stepwise regression, V771M and I883M were the best predictors in women (HRs: V771M, 1.6 [1.2 to 2.3]; I883M, 1.3 [1.1 to 1.6]), whereas I883M and E1172D were best in men (HRs: I883M, 1.1 (1.0 to 1.4); E1172D, 1.3 (1.0 to 1.7). Login to comment
81 ABCA1 SNPs and HDL-C Levels In genders combined, V771M and V825I were associated with increases in HDL-C of 0.04 and 0.05 mmol/L, respectively (Figure 3, upper panel). Login to comment
85 Risk of Ischemic Heart Disease as a Function of ABCA1 Genotype in the Prospective Study n, % Number of Events Incidence Rate (95% CI) per 10 000 Person-Years Hazard Ratio (95% CI) Observed Expected Age Adjusted HDL-C Adjusted Multifactorially Adjusted R219K GG 4863 (54) 603 603 64 (59-70) 1 1 1 GA 3461 (39) 429 426 64 (58-71) 1.0 (0.9-1.1) 1.0 (0.9-1.1) 1.0 (0.9-1.2) AA 641 (7) 75 79 64 (50-80) 1.0 (0.8-1.2) 1.0 (0.8-1.2) 1.0 (0.8-1.3) V771M GG 8379 (93) 1023 1040 64 (60-68) 1 1 1 GAϩAA 586 (7) 84 69 75 (60-93)* 1.2 (1.0-1.5) 1.3 (1.0-1.6) 1.2 (1.0-1.5) M825I GG 7959 (89) 962 988 63 (59-67) 1 1 1 GAϩAA 1006 (11) 145 122 76 (64-89)† 1.2 (1.0-1.5) 1.2 (1.0-1.5) 1.2 (1.0-1.4) I883M AA 6934 (77) 827 864 62 (58-66) 1 1 1 AGϩGG 2031 (23) 280 245 72 (64-81)† 1.2 (1.0-1.4) 1.2 (1.1-1.4) 1.2 (1.1-1.4) E1172D GG 8469 (94) 1026 1045 63 (59-67) 1 1 1 GCϩCC 496 (6) 81 64 86 (68-106)† 1.3 (1.0-1.6) 1.3 (1.0-1.6) 1.3 (1.0-1.6) R1587K GG 5216 (58) 626 645 62 (58-67) 1 1 1 GA 3213 (36) 399 396 65 (58-71) 1.0 (0.9-1.2) 1.0 (0.9-1.2) 1.0 (0.9-1.2) AA 536 (6) 82 68 82 (65-102)* 1.2 (1.0-1.6) 1.2 (1.0-1.5) 1.3 (1.0-1.6) Nonincident cases (nϭ63) were excluded, leaving 8965 individuals for the survival analyses and Cox regression. Login to comment
89 Rs numbers: R219K (rs2230806); V771M (rs2066718); V825I (rs2066715); I883M (rs4149313); E1172D (rs33918808); R1587K (rs2230808). Login to comment
102 The fact that the stepwise regression approach identified the V771M, I883M, and E1172D SNPs, which have very weak association between rare alleles (low r2 or negative DЈ), as important for the final IHD prediction model, supports that the observed findings for these 3 SNPs are not caused by LD. Login to comment
1 Two SNPs (V771M and V825I) were previously associated with increases in HDL-C, 1 (R1587K) with decreased HDL-C, whereas 3 (R219K, I883M and E1172D) did not affect HDL-C levels. Login to comment
2 Despite this, 5 out of 6 SNPs (V771M, V825I, I883M, E1172D, R1587K) predicted increased risk of IHD. Login to comment
4 A stepwise regression approach identified V771M, I883M, and E1172D as the most important predictors of IHD and additive effects on IHD risk were present for V771M/I883M and I883M/E1172D pairs. Login to comment
23 The cohort was participants in The Copenhagen City Heart Study who attended the 1991 to 1994 examination, and for whom combined genotypes for all 6 nonsynonymous SNPs (R219K, V771M, V825I, I883M, E1172D, R1587K) were available as well as all clinical and biochemical data (nafd;9028 out of nafd;9259; Table 1). Login to comment
32 SNP Genotyping The ABI PRISM 7900HT Sequence Detection System (Applied Biosystem Inc) was used to genotype for all 6 nonsynonymous SNPs (R219K, V771M, V825I, I883M, E1172D, R1587K) identified by resequencing ABCA1 in 190 individuals, as previously described.8 Biochemical Analyses Colorimetric and turbidimetric assays (Hitachi autoanalyzer) were used to measure plasma levels of total cholesterol, HDL-C, triglycerides, and apolipoproteins B and -AI (all Boehringer Mannheim GmbH). Login to comment
49 Frikke-Schmidt et al ABCA1 and Ischemic Heart Disease 181 at Semmelweis University (Egyetem) on December 3, 2015 http://atvb.ahajournals.org/ Downloaded from the entire ABCA1 gene in 190 individuals of Danish descent were: 0.26 (R219K), 0.03 (V771M), 0.03 (E1172D), 0.06 (V825I), 0.12 (I883M), and 0.24 (R1587K).8 Similar allele frequencies have been reported for other White populations.14 Please see Data Supplements, Expanded Results for description of Hardy-Weinberg equilibrium. Login to comment
51 A strong positive Db18; was present for R219K/V771M, M825I/I883M, and E1172D/ R1587K (Db18;b0e;0.9), whereas a strong negative Db18; was present for R219K/V825I, V771M/V825I, and V771M/I883M (Db18;b0d;afa;0.9). Login to comment
54 Risk of IHD Prospective Study The cumulative incidence of IHD as a function of age was increased for V771M (GAaf9;AA versus GG, borderline Pafd;0.06), V825I (GAaf9;AA versus GG; Pafd;0.02), I883M (AGaf9;GG versus AA, Pafd;0.01), E1172D (GCaf9;CC versus GG, Pafd;0.03), and for R1587K (AA versus GG, borderline Pafd;0.06), but not for R219K (Figure 2). Login to comment
62 Probability values are for overall log-rank tests. For V771M, V825I, I883M, and E1172D, heterozygotes and homozygotes for the variant allele were pooled (combined genotype in red, common genotype in green). Login to comment
65 There was evidence for a statistically significant interaction between gender and V771M (Pafd;0.04) in the prediction of IHD, whereas the remaining 5 SNPs did not interact with gender (all probability values b0e;0.52). Login to comment
72 Performing gender specific stepwise regression, V771M and I883M were the best predictors in women (HRs: V771M, 1.6 [1.2 to 2.3]; I883M, 1.3 [1.1 to 1.6]), whereas I883M and E1172D were best in men (HRs: I883M, 1.1 (1.0 to 1.4); E1172D, 1.3 (1.0 to 1.7). Login to comment
75 ABCA1 SNPs and HDL-C Levels In genders combined, V771M and V825I were associated with increases in HDL-C of 0.04 and 0.05 mmol/L, respectively (Figure 3, upper panel). Login to comment
79 Risk of Ischemic Heart Disease as a Function of ABCA1 Genotype in the Prospective Study n, % Number of Events Incidence Rate (95% CI) per 10 000 Person-Years Hazard Ratio (95% CI) Observed Expected Age Adjusted HDL-C Adjusted Multifactorially Adjusted R219K GG 4863 (54) 603 603 64 (59-70) 1 1 1 GA 3461 (39) 429 426 64 (58-71) 1.0 (0.9-1.1) 1.0 (0.9-1.1) 1.0 (0.9-1.2) AA 641 (7) 75 79 64 (50-80) 1.0 (0.8-1.2) 1.0 (0.8-1.2) 1.0 (0.8-1.3) V771M GG 8379 (93) 1023 1040 64 (60-68) 1 1 1 GAaf9;AA 586 (7) 84 69 75 (60-93)* 1.2 (1.0-1.5) 1.3 (1.0-1.6) 1.2 (1.0-1.5) M825I GG 7959 (89) 962 988 63 (59-67) 1 1 1 GAaf9;AA 1006 (11) 145 122 76 (64-89)ߤ 1.2 (1.0-1.5) 1.2 (1.0-1.5) 1.2 (1.0-1.4) I883M AA 6934 (77) 827 864 62 (58-66) 1 1 1 AGaf9;GG 2031 (23) 280 245 72 (64-81)ߤ 1.2 (1.0-1.4) 1.2 (1.1-1.4) 1.2 (1.1-1.4) E1172D GG 8469 (94) 1026 1045 63 (59-67) 1 1 1 GCaf9;CC 496 (6) 81 64 86 (68-106)ߤ 1.3 (1.0-1.6) 1.3 (1.0-1.6) 1.3 (1.0-1.6) R1587K GG 5216 (58) 626 645 62 (58-67) 1 1 1 GA 3213 (36) 399 396 65 (58-71) 1.0 (0.9-1.2) 1.0 (0.9-1.2) 1.0 (0.9-1.2) AA 536 (6) 82 68 82 (65-102)* 1.2 (1.0-1.6) 1.2 (1.0-1.5) 1.3 (1.0-1.6) Nonincident cases (nafd;63) were excluded, leaving 8965 individuals for the survival analyses and Cox regression. Login to comment
83 Rs numbers: R219K (rs2230806); V771M (rs2066718); V825I (rs2066715); I883M (rs4149313); E1172D (rs33918808); R1587K (rs2230808). Login to comment
96 The fact that the stepwise regression approach identified the V771M, I883M, and E1172D SNPs, which have very weak association between rare alleles (low r2 or negative Db18;), as important for the final IHD prediction model, supports that the observed findings for these 3 SNPs are not caused by LD. Login to comment

PMID: 17070530 [PubMed] Nebel A et al: "Common coding polymorphisms in the ABCA1 gene and risk of early-onset coronary heart disease in northern Germany."

No. Sentence Comment

7 In the present study, we have examined the potential association between the five known coding polymorphisms R219K, V771M, I883M, E1172D and R1587K in the ABCA1 gene and early-onset CHD in a large ethnically homogeneous sample from the northernmost province in Germany. Login to comment
25 We examined the five known ABCA1 polymorphisms R219K, V771M, I883M, E1172D and R1587K in early-onset 0021-9150/$ - see front matter (c) 2006 Elsevier Ireland Ltd. Login to comment
27 doi:10.1016/j.atherosclerosis.2006.09.022 Letter to the Editor / Atherosclerosis 193 (2007) 458-460 Table 1 Summary association statistics for common ABCA1 coding SNPs in German CHD patients and controls ABCA1 variant MAFa CHD MAFa control Pallele Pgenotype Pcarrier b ORcarrier c 95% CIcarrier d R219K (rs2230806)e 0.265 0.258 0.656 0.582 0.438 1.08 0.89-1.30 V771M (rs2066718)e 0.026 0.034 0.188 0.255 0.222 0.78 0.53-1.16 I883M (rs4149313)e 0.138 0.112 0.023 0.068 0.021 1.31 1.04-1.64 E1172D (hCV25924149)e 0.025 0.025 0.914 0.714 0.983 1.00 0.65-1.55 R1587K (rs2230808)e 0.261 0.234 0.067 0.197 0.097 1.18 0.97-1.42 a MAF, minor allele frequency. Login to comment
31 e R219K, V771M, I883M, E1172D and R1587K were typed using TaqMan® SNP Assays (Applied Biosystems, Foster City, USA). Login to comment
36 However, additional studies have indicated no relevant effects for the I883M genotype on CHD or HDH-C levels [8,10,11]. Login to comment
37 The other four SNPs R219K, V771M, E1172D and R1587K exhibited no clear effects in the German CHD samples investigated here. Login to comment
46 Table 2 Logistic regression analysis for five coding SNPs in the ABCA1 gene in German CHD patients and controls Predictora ORb 95% CIc P Gender 1.05 0.81-1.36 0.721 R219K 1.20 0.99-1.47 0.066 V771M 0.90 0.57-1.41 0.645 I883M 1.28 1.02-1.61 0.034 E1172D 0.78 0.52-1.19 0.253 R1587K 1.10 0.90-1.34 0.361 a Each marker binary classified for carriership of rare allele, gender was included as a predictive variable, logistic regression analysis was performed with the R-package [14]. Login to comment
26 doi:10.1016/j.atherosclerosis.2006.09.022 Letter to the Editor / Atherosclerosis 193 (2007) 458-460 Table 1 Summary association statistics for common ABCA1 coding SNPs in German CHD patients and controls ABCA1 variant MAFa CHD MAFa control Pallele Pgenotype Pcarrier b ORcarrier c 95% CIcarrier d R219K (rs2230806)e 0.265 0.258 0.656 0.582 0.438 1.08 0.89-1.30 V771M (rs2066718)e 0.026 0.034 0.188 0.255 0.222 0.78 0.53-1.16 I883M (rs4149313)e 0.138 0.112 0.023 0.068 0.021 1.31 1.04-1.64 E1172D (hCV25924149)e 0.025 0.025 0.914 0.714 0.983 1.00 0.65-1.55 R1587K (rs2230808)e 0.261 0.234 0.067 0.197 0.097 1.18 0.97-1.42 a MAF, minor allele frequency. Login to comment
30 e R219K, V771M, I883M, E1172D and R1587K were typed using TaqMan&#ae; SNP Assays (Applied Biosystems, Foster City, USA). Login to comment
45 Table 2 Logistic regression analysis for five coding SNPs in the ABCA1 gene in German CHD patients and controls Predictora ORb 95% CIc P Gender 1.05 0.81-1.36 0.721 R219K 1.20 0.99-1.47 0.066 V771M 0.90 0.57-1.41 0.645 I883M 1.28 1.02-1.61 0.034 E1172D 0.78 0.52-1.19 0.253 R1587K 1.10 0.90-1.34 0.361 a Each marker binary classified for carriership of rare allele, gender was included as a predictive variable, logistic regression analysis was performed with the R-package [14]. Login to comment

PMID: 17556888 [PubMed] Klos KL et al: "Genetic determinants of HDL: monogenic disorders and contributions to variation."

No. Sentence Comment

81 Sequence analyses, most notably of the ABCA1 region, suggest that both common variants and rare mutations contribute to interindividual variation in Genetic determinants of HDL Klos and Kullo 347 Table1Commonpolymorphisms(minorallelefrequency>5%)reportedtobeassociatedwithplasmaHDL-Cinmorethanonestudy;thereporteddirectionofeffectoftheless commonallele,andtheircontributionstocovariate-adjustedHDL-Cvariationaloneandincombinationwithotherpolymorphismsofthesamegene GenesymbolGenenamePolymorphismEffecta Single-sitevariationMultisitevariation ABCA1ATP-bindingcassette,sub-familyA (ABC1),member1 596G>A"HDL-C[52,53]4%[52] R219K"HDL-C[28,29 ,30 ]6%[54] V771M"HDL-C[30 ,33] V825I/V825L"HDL-C[30 ];#HDL-C[32 ] APOA5ApolipoproteinA-VÀ1131T>C#HDL-C[55-57] APOC3ApolipoproteinC-III482C>T#HDL-C[55,58 ]0.2-1.4%[58 ]1-6%[58 ,59] SstIS2allelewith#HDL-C[60,61] APOEApolipoproteinEÀ219G>T#HDL-C[27 ,62] e2/e3/e40.8-6.5%[63,64 ]8.3-15.3%[65] ARAndrogenreceptorEx1CAGrepeat"HDL-Cwithlength[66] CETPCholesterol-estertransferproteinÀ1946VNTR"HDL-Cwiththeshortallele[36,67] À629C>A"HDL-C[36,38,39,67-69]4.6-5.2%[39,64 ]5.5-9.8%[39,68] Taq1B"HDL-C[35]3.9%[39]5.5-15%[39,54] MspIin8#HDL-C[36,67] A373P/R451Q#HDL-C[67,68]8%[70] I405V"HDL-C[35] LIPCHepaticlipaseÀ514C>T"HDL-C[45]Upto31%[54] À250G>A"HDL-C[41,43]4.7%[67] LIPGEndotheliallipaseT111I"HDL-C[72,73 ];#HDL-C[74] LPLLipoproteinlipaseHindIII#HDL-CwiththeHþallele[49,75] N291S#HDL-C[50 ] S447X"HDL-C[48,75]0.8%[64 ]3%[35] PON1Paraoxonase1À107T>C"HDL-C[76-78] Q192R"HDL-C[77,79 ];#HDL-C[79 ] PPARDPeroxisomeproliferatorsactivatedreceptordelta294T>C#HDL-C[80] PPARGPeroxisomeproliferatorsactivatedreceptorgammaPro12Ala"HDL-C[81,82] SCARB1ScavengerreceptorclassB,member1A350A"HDL-C[64 ,83]1.3%[64 ] IVS5/A350A(/IVS10)haplotype#HDL-C[84 ] a Citationsrepresentaselectionofavailablestudiesprioritizedbasedonmeta-analysesofassociationresultsinnumerousstudygroups,andrecentstudiescontainingcomprehensivereviewsofpreviously reportedassociations. Login to comment

PMID: 17553166 [PubMed] Pasdar A et al: "The effect of ABCA1 gene polymorphisms on ischaemic stroke risk and relationship with lipid profile."

No. Sentence Comment

33 The only published study in ischaemic stroke on 244 Hungarian patients [25] suggests a protective role for the ABCA1-R219K and V771M polymorphisms. Login to comment

PMID: 17303779 [PubMed] Kiss RS et al: "Genetic etiology of isolated low HDL syndrome: incidence and heterogeneity of efflux defects."

No. Sentence Comment

47 In ABCA1, a total of 19 nonsynonymous coding sequence variants; some of these we reported previously.22 Of these, 9 sequence variants were common polymorphisms (ie, reported in the literature as common or of similar prevalence in control subjects): P85L, P85A, R219K, V399A, V771M, V825I, I883M, E1172D, R1587K.14,32-35 Another 5 sequence variants, identified here, were previously reported to be disease causing: W590L (reported as W590S)14; C1477F (reported as C1477R)13; S1731C (only found in French-Canadian populations)36; N1800H32; and 1851X.37 Five sequence variants were novel: K199F, H551D, R965C, E1386Q, and D1706N. Login to comment
42 In ABCA1, a total of 19 nonsynonymous coding sequence variants; some of these we reported previously.22 Of these, 9 sequence variants were common polymorphisms (ie, reported in the literature as common or of similar prevalence in control subjects): P85L, P85A, R219K, V399A, V771M, V825I, I883M, E1172D, R1587K.14,32-35 Another 5 sequence variants, identified here, were previously reported to be disease causing: W590L (reported as W590S)14; C1477F (reported as C1477R)13; S1731C (only found in French-Canadian populations)36; N1800H32; and 1851X.37 Five sequence variants were novel: K199F, H551D, R965C, E1386Q, and D1706N. Login to comment

PMID: 17430597 [PubMed] Wahrle SE et al: "Apolipoprotein E levels in cerebrospinal fluid and the effects of ABCA1 polymorphisms."

No. Sentence Comment

40 In particular, studies have implicated the following SNPs in affecting levels of plasma HDL-C: rs2230806 (R219K) [33], rs2066718 (V771M) [31,32], rs2066715 (V825I) [31], rs4149313 (I883M) [34], rs2230808 (R1587K) [31]. Login to comment
70 The subjects for whom we had CSF apoE data were genotyped for the following ABCA1 SNPs: rs2230806 (R219K), rs2066718 (V771M), rs2066715 (V825I), rs4149313 (I883M), rs2230808 (R1587K), rs1883025 (intron), rs2275544 (intron), rs2777799 (intron), rs3904999 (intron) and rs6479283 (intron). Login to comment
149 Genotyping The following SNPS in ABCA1 were genotyped in the Washington University sample of 168 subjects: rs2230806 (R219K), rs2066718 (V771M), rs2066715 (V825I), rs4149313 (I883M), rs2230808 (R1587K), rs1883025 (intron), rs2275544 (intron), rs2777799 (intron), rs3904999 (intron) and rs6479283 (intron). Login to comment

PMID: 17324514 [PubMed] Wavrant-De Vrieze F et al: "ABCA1 polymorphisms and Alzheimer's disease."

No. Sentence Comment

20 doi:10.1016/j.neulet.2007.02.010 The SNPs used were rs2230806 (also designated as rs2234884) which encodes variant R219K (c.969A > G, numbering according to GenBank reference NM 005502) with a reported ~25% minor allele frequency in Caucasian populations [5,7], rs2066718 which is a V771M (c.2624A > G) variant with a reported ~3% minor allele frequency [5,7], rs2230808 which encodes a R1587K (c.5073A > G) variant with a reported 26% minor allele frequency [5,7] and finally rs2422493 which is a 5 UTR polymorphism located at -477 in the promoter with a reported 46% minor allele frequency [23,25]. Login to comment
41 These previous findings emphasize the Table 1 Genotype frequency of ABCA1 polymorphisms in USA sibpair series SNP ID (function) Total (Nf = 331) ApoE-␧4- (Nf = 76) ApoE-␧4+ (Nf = 227) Fam Freq p-Value Fam Freq p-Value Fam Freq p-Value rs2422493 (promoter) C/C 45 0.266 0.62 5 0.245 N/A 25 0.284 0.62 T/C 79 0.494 0.17 14 0.494 0.29 38 0.489 0.35 T/T 44 0.241 0.02* 10 0.261 0.30 21 0.227 0.08 rs2230806 (R219K) A/A 17 0.095 0.93 2 0.058 N/A 10 0.111 0.86 A/G 66 0.399 0.23 12 0.483 0.01* 31 0.388 0.70 G/G 56 0.507 0.21 11 0.459 0.02* 25 0.500 0.59 rs2066718 (V771M) A/A 0 0 N/A 0 0 N/A 0 0 N/A A/G 14 0.100 0.69 2 0.162 N/A 6 0.102 N/A G/G 14 0.900 0.69 2 0.838 N/A 6 0.898 N/A rs2230808 (R1587K) A/A 15 0.066 0.06 5 0.044 N/A 8 0.064 N/A A/G 62 0.426 0.69 14 0.505 0.64 32 0.420 0.90 G/G 56 0.509 0.55 13 0.451 0.57 29 0.515 0.67 Fam, number of informative families; Freq, frequency; Nf, number of nuclear families; N/A, non-applicable. Login to comment

PMID: 17383594 [PubMed] Mantaring M et al: "Genotypic variation in ATP-binding cassette transporter-1 (ABCA1) as contributors to the high and low high-density lipoprotein-cholesterol (HDL-C) phenotype."

No. Sentence Comment

3 Carrier frequencies of common ABCA1 polymorphisms, R219K, V771M, V825I, I883M, E1172D, and R1587K were also assessed. Login to comment
36 DNA was PCR amplified and digested using standard methods and the frequency of the 6 common polymorphisms (R219K, V771M, V825I, I883M, E1172D, and R1587K) in ABCA1, which was determined as described by Clee et al.8 Sequencing of PCR-amplified DNA. Login to comment
54 The prevalence of 6 common ABCA1 polymorphisms, R219K, V771M, V825I, I883M, E1172D, and R1587K was also evaluated. Login to comment
57 Very high HDL-C was associated with a higher genotype frequency of R219K (RK and KK, 68.2%; Ptrend ϭ 0.04) although allele frequency was not materially different. Login to comment
58 Mild differences in allele frequency were also identified between the highest and lowest HDL-C groups for V771M (23% vs 10%; Ptrend ϭ 0.04) and I883M (36% vs 20%; Ptrend ϭ 0.05). Login to comment
77 Genotype and allele frequencies for 6 common ABCA1 polymorphisms in subgroups with HDL-C defined as very high (n ϭ 22), high (n ϭ 34), average (n ϭ 36), or low (n ϭ 32) R219K Genotype frequencies P value Allele frequencies P valueR/R R/K K/K R K Very high 31.8% 45.5% 22.7% 0.04 0.55 0.45 0.20 High 45.7% 51.4% 2.9% 0.71 0.29 Average 43.2% 56.8% 0.0% 0.72 0.28 Low 50.0% 40.0% 10.0% 0.70 0.30 V771M V/V V/M M/M V M Very high 59.0% 36.0% 4.5% 0.11 0.77 0.23 0.04 High 85.7% 14.3% 0.0% 0.93 0.07 Average 86.1% 13.9% 0.0% 0.93 0.07 Low 80.0% 20.0% 0.0% 0.90 0.10 V825I V/V V/I I/I V I Very high 77.3% 22.7% 0.0% 0.58 0.89 0.11 0.62 High 88.6% 11.4% 0.0% 0.94 0.06 Average 88.9% 11.1% 0.0% 0.94 0.06 Low 82.8% 17.2% 0.0% 0.92 0.08 I883M I/I I/M M/M I M Very high 40.9% 45.5% 13.6% 0.29 0.64 0.36 0.05 High 60.0% 34.3% 5.7% 0.78 0.22 Average 73.0% 24.3% 2.7% 0.85 0.15 Low 66.7% 26.7% 6.7% 0.80 0.20 E1172D E/E E/D D/D E D Very high 68.2% 31.8% 0.0% 0.0004 0.82 0.18 0.0002 High 94.3% 5.7% 0.0% 0.97 0.03 Average 94.6% 5.4% 0.0% 0.97 0.03 Low 100.00% 0.0% 0.0% 1.00 0.00 R1587K R/R R/K K/K R K Very high 31.8% 50.0% 18.2% 0.16 0.57 0.43 0.07 High 65.6% 25.0% 9.4% 0.78 0.22 Average 55.6% 41.7% 2.8% 0.76 0.24 Low 51.9% 33.3% 14.8% 0.69 0.31 of R219K may have a basis for reduced CVD risk as previously suggested.8-11,24 CONCLUSION The data extend previous findings that novel mutations in ABCA1 are associated with the low rather than the high HDL-C (FHA) phenotype. Login to comment
35 DNA was PCR amplified and digested using standard methods and the frequency of the 6 common polymorphisms (R219K, V771M, V825I, I883M, E1172D, and R1587K) in ABCA1, which was determined as described by Clee et al.8 Sequencing of PCR-amplified DNA. Login to comment
53 The prevalence of 6 common ABCA1 polymorphisms, R219K, V771M, V825I, I883M, E1172D, and R1587K was also evaluated. Login to comment

PMID: 16806540 [PubMed] Saleheen D et al: "A novel haplotype in ABCA1 gene effects plasma HDL-C concentration."

No. Sentence Comment

7 R219K, A399V and V771M polymorphisms did not show any association with levels of HDL-C, LDL-C, cholesterol and triglycerides. Login to comment
50 Subjects were classified as having diabetes mellitus if he or she already Table 1 Methods for restriction fragment length polymorphism for screening of ABCA1 SNPs Variant Forward oligo (5VY3V), reverse oligo (5VY3V) Annealing temperature Enzyme Product (bp), wild-type allele, variant allele R219K (G1051A) ''aaagacttcaaggacccagctt``, ''cctcacattccgaaagcatta`` 62.5 -C EcoNI 309, 184, 125 V399A (T1591C) ''ctcattgtctgtgcttctcctc``, ''gtgaccagaaactcacctctcc`` 64.0 -C HphI 117, 71, 48, 188, 48 V771M (G2706A) ''tacaagtgagtgcttgggattg``, ''cccattggaaaagacaatcatc`` 60.0 -C BsaAI 254, 137, 391 V825L (G2868A) ''ttctgcaccttatgattgatcc``, ''agcacaaagaaaggacatcagc`` 62.5 -C BsaI 265, 127, 392 Polymerase chain reaction (PCR) was carried out using a Perkin Elmer GeneAmp PCR system 2400 (Perkin Elmer Corp., Applied Biosystems Division, USA). Login to comment
77 R219K, V399A and V771M polymorphisms did not show any association with levels of HDL-C, LDL-C, cholesterol and triglycerides. Login to comment
80 R219K, V399A and T774P polymorphisms followed the HWE however V825L and V771M showed a departure from HWE. Login to comment
82 Linkage disequilibrium and haplotype analysis R219K polymorphism was in significant linkage disequilibrium (LD) with V825L and V771M (DV=0.50; P-value<10À3 ). Login to comment
87 D. Saleheen et al. / International Journal of Cardiology 115 (2007) 7-13 9 polymorphism was in complete linkage equilibrium with T774P, V825L and V771M polymorphisms. Login to comment
97 South Asian populations (from Pakistan, India, Bangladesh and Sri Lanka) represent a quarter of the developing world and harbor thirty percent of the global Table 4 Haplotype association analysis of the ABCA1 gene polymorphisms in relation with the HDL-C levels Haplotype Haplotype frequencies Haplotypic additive effects [95% CI] P-value R219K RV 0.47 + V825L RL 0.18 À0.12 [À0.22 to À0.03] 0.001 KV 0.28 À0.04 [À0.10 to 0.01] 0.15 KL 0.06 0.08 [À0.06 to 0.22] 0.25 T774P TV 0.21 0.03 [À0.05 to 0.12] 0.41 V825L TL 0.09 0.10 [À0.06 to 0.27] 0.22 PV 0.47 + PL 0.21 0;0.06 [À0.14 to 0.02] 0.15 R219K RM 0.55 + V771M RV 0.07 À0.13 [À0.45 to 0.19] 0.41 KM 0.34 À0.02 [À0.09 to 0.05] 0.54 KV 0.04 0.07 [À0.12 to 0.27] 0.46 Table 3 Mean HDL-C levels (S.D.) for the genotypes and alleles of the studied polymorphisms Frequencies HDL-C (S.D.) b (95% CI) P-value R219K RR 39.8 1.06 (0.30) À0.02 (À0.16 to 0.13) 0.85 RK 46.0 1.10 (0.28) 0.00 (À0.14 to 0.14) 0.99 KK 14.3 1.10 (0.31) + R 62.7 1.08 (0.26) 0.01 (À0.05 to 0.07) 0.79 K 37.3 1.09 (0.31) V399A AA 6.0 1.01 (0.23) À0.03 (À0.24 to 0.16) 0.70 AV 34.7 1.11 (0.28) 0.10 (À0.04 to 0.16) 0.22 VV 59.3 1.04 (0.31) + A 23.3 1.09 (0.28) À0.03 (À0.10 to 0.05) 0.58 V 76.7 1.04 (0.31) T774P PP 9.6 1.10 (0.31) 0.20 (0.01 to 0.40) 0.03 PT 37.5 1.03 (0.32) 0.13 (À0.03 to 0.20) 0.14 TT 52.9 0.97 (0.28) + P 28.4 1.05 (0.32) À0.15 (À0.18 to À0.02) 0.01 T 71.6 0.99 (0.29) V771M MM 6.1 1.09 (0.30) 0.01 (À0.24 to 0.25) VM 10.1 0.98 (0.24) À0.07 (À0.27 to 0.12) 0.46 VV 83.8 1.07 (0.29) + 0.94 M 11.1 1.04 (0.27) 0.03 (À0.10 to 0.15) 0.71 V 88.9 1.07 (0.29) V825L LL 9.8 0.89 (0.299) À0.17 (À0.32 to À0.19) 0.02 LV 32.8 1.06 (0.265) À0.03 (À0.11 to 0.076) 0.70 VV 57.5 1.07 (0.30) + L 26.1 1.07 (0.29) 0.10 (À0.00 to .13) 0.05 V 73.9 1.00 (0.28) P-values are adjusted for age and gender. Login to comment
115 Similarly, a lack of association of V399A and V771M polymorphisms is consistent with the published literature [28]. Login to comment

PMID: 16704350 [PubMed] Brunham LR et al: "Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis."

No. Sentence Comment

605 Many of these variants have been studied in relationship to their association with HDL cholesterol levels and atherosclerosis (11, 15, 22, 27, 28, 38, TABLE 4 Nonsynonymous single-nucleotide polymorphisms (SNPs) in ABCA1 SNP id Nucleotidea Amino acidb Observed heterozygosity rs2230806 G969A R219K 0.488 rs9282541 C1001T R230C 0.029 rs9282543 T1509C V399A 0.020 rs4131108 A1556C M415L - rs13306068 A1949G I546V - rs2066718 G2624A V771M 0.074 rs2472458 G2804A D831N - rs4149313 A2962G I883M - rs2482437 C3326T E1005K - rs13306072 G3473A V1054I - rs13306073 G3599A V1096I - rs1997618 T4977C I1555T - rs2230808 A5073G K1587R 0.480 rs1883024 T5256C L1648P - - C5505G S1731C - a Nucleotide position is with respect to NM 005502. b Amino acid position is with respect to NP 005493. Login to comment
612 The V825I and V771M SNPs were associated with increased HDL cholesterol in one, but not both, genders. Login to comment

PMID: 16446539 [PubMed] Andrikovics H et al: "Decreased frequencies of ABCA1 polymorphisms R219K and V771M in Hungarian patients with cerebrovascular and cardiovascular diseases."

No. Sentence Comment

0 Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Original Paper Cerebrovasc Dis 2006;21:254-259 DOI: 10.1159/000091223 Decreased Frequencies of ABCA1 Polymorphisms R219K and V771M in Hungarian Patients with Cerebrovascular and Cardiovascular Diseases Hajnalka Andrikovicsa Endre Pongráczb Ákos Kalinac Anikó Szilvásia Charalampos Aslanidisd Gerd Schmitzd Attila Tordaia a Department of Molecular Genetics, National Medical Center, b Neurology Department, Central Hospital, Ministry of Interior, and c Hospital of the National Railways, Budapest, Hungary; d Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Germany and 0 8 1.6%, respectively) were decreased. Login to comment
1 V771M was almost exclusively (35/36) found in individuals carrying the R219K allele. Login to comment
2 Conclusions: Our data confirm earlier observations that ABCA1 R219K and V771M polymorphisms may be associated with a protective role against CHD and extend those to another important pathologic condition, namely stroke. Login to comment
7 Methods: We investigated 244 unrelated, consecutively enrolled patients with ischemic stroke, 150 patients with coronary heart disease (CHD) and 193 blood donors for allele frequencies (AFs) of three common ABCA1 polymorphisms (R219K, V771M and I883M). Login to comment
8 Results: Compared to controls (30.8 8 4.7 and 4.9 8 2.2%, respectively), decreased AFs were found in both patient groups for R219K and V771M (28.7 8 4.1 and 3.1 8 1.6% in stroke, and 25.7 8 5.0%; 1.3 8 1.3% in CHD patients, respectively). Login to comment
10 Similarly, among CHD patients younger than 60, AFs of R219K and V771M (22.6 8 7.5 Received: July 25, 2005 Accepted: October 12, 2005 Published online: January 27, 2006 Attila Tordai Department of Molecular Genetics National Medical Center, Diószegi út 64 HU-1113 Budapest (Hungary) Tel./Fax +36 1 385 2255, E-Mail tordai@biomembrane.hu (c) 2006 S. Karger AG, Basel 1015-9770/06/0214-$23.50/0 Accessible online at: www.karger.com/ced To date, the ABCA1 gene proved to be highly polymorphic with large numbers of sequence variations leading to amino acid changes or affecting the putative promoter region [8] (see also http://www.abca1 mutants.all.at). Login to comment
28 DNA Isolation and Detection of ABCA1 R219K, V771M and I883M Alleles with LightCycler Hybridization Probe Technique DNA isolation was performed from anticoagulated peripheral blood with the standard 'salting-out` procedure. Login to comment
29 The following ABCA1sequencevariantswerestudied:R219K(exon7,c.969A]G, substitution of Arg219 by Lys); V771M (exon 16, c.2624G]A, substitution of Val771 by Met), and I883M (exon 18, c.2962A]G, substitution of Ile883 by Met). Login to comment
53 2006;21:254-259256 Results Genotyping for R219K, V771M and I883M ABCA1 Allelic Variants Using genomic DNA samples, simultaneous genotyping was carried out in the control blood donor and the stroke- and CHD-affected patient groups by PCR and fluorescent allelic discrimination techniques. Login to comment
55 In the control group, AF figures (30.8 8 4.7, 4.9 8 2.2 and 12.4 8 4.5%) were found in the expected range for R219K, V771M and I883M, respectively. Login to comment
56 Decreased AFs were found in both patient groups for R219K and V771M variants (28.9 8 4.1 and 3.3 8 1.6% in stroke, and 25.7 8 5.0% and 1.3 8 1.3% in CHD, respectively). Login to comment
57 In the CHD group, the decrease in V771M AF was significant (p = 0.009) by univariate analyses. Login to comment
59 In a subset of stroke patients with disease onset before 50 (n = 114), both variants occurred in significantly lower frequencies compared to the control group [R219K: 22.4 8 5.5%, p = 0.013, crude OR = 0.55 (0.34-0.88); V771M: 1.8 8 1.7%, p = 0.045, crude OR = 0.33 (0.111.00)]. Login to comment
60 A similar tendency was observed in the CHD group in a subset of patients younger than 60 (n = 62) for R219K and V771M, but only the V771M AF decrease was significant [22.6 8 3.6%, p 1 0.05; and 0 8 1.6%, p = 0.005, crude OR = 0.07 (0.004-1.2)]. Login to comment
62 Figure 1 further illustrates the tendency of R219K and V771M AF decreases following stratification of the patient groups by age at onset. Login to comment
63 Multivariate analyses (logistic regression) also showed that the R219K and V771M variants are protective factors against stroke, independently from age and sex [R219K: p = 0.032, adjusted OR: 0.68 (0.48-0.97); V771M: p = 0.017, adjusted OR: 0.34 (0.14-0.82)]. Login to comment
64 In the CHD group, only V771M proved to be a significant independent protective factor [p = 0.027, adjusted OR: 0.08 (0.01-0.75), table 1]. Login to comment
66 Similarly to results of the entire stroke group, R219K AF reduction was 27.4 8 4.9%, p = 0.015, adjusted OR: 0.59 (0.39-0.91), and V771M AF reduction was 3.3 8 2.0%, p = 0.042, adjusted OR: 0.36 (0.13-0.97) compared to control. Login to comment
67 We also observed significant R219K and V771M AF reduction in patients with CT-proven ischemic stroke [n = 124; R219K: 24.6 8 5.5%, p = 0.049, adjusted OR: 0.64 (0.41-0.99), and V771M: 1.2 8 1.4%, p = 0.021, adjusted OR: 0.19 (0.05-0.78)] compared to control. Login to comment
70 Genotyping results and statistical analyses for three common ABCA1 polymorphisms (R219K, V771M and I883M) in the control and patient groups Polymorphism AF % (895% CI) Heterozygous individuals n (%) Homozygous individuals n (%) p value Adjusted OR (95% CI) R219K Controls (n = 193) 30.8 (4.7) 73 (37.8) 23 (11.9) Patients with stroke (n = 244) 28.9 (4.1) 84 (34.1) 29 (11.8) 0.032 0.68 (0.48-0.97) Patients with CHD (n = 150) 25.7 (5.0) 55 (36.7) 11 (7.3) NS NS V771M Controls (n = 193) 4.9 (2.2) 19 (9.8) 0 Patients with stroke (n = 244) 3.3 (1.6) 14 (5.7) 1 (0.4) 0.017 0.34 (0.14-0.82) Patients with CHD (n = 150) 1.3 (1.3) 4 (2.7) 0 0.027 0.08 (0.01-0.75) I883M Controls (n = 105) 12.4 (4.5) 24 (22.9) 1 (1.0) Patients with stroke (n = 244) 15.2 (3.2) 61 (24.8) 7 (2.9) NS NS Patients with CHD (n = 150) 12.3 (3.8) 29 (19.3) 4 (2.6) NS NS AF = Allele frequency; CI = confidence interval; NS = nonsignificant. Login to comment
72 showed that R219K and V771M variants also play a protective role against stroke independently from age and sex in the stroke patient subgroup without ischemic heart disease [R219K: p = 0.040, adjusted OR: 0.69 (0.48-0.98), and V771M: p = 0.034, adjusted OR: 0.39 (0.16-0.93)]. Login to comment
73 These results indicate that the protective role of R219K and V771M in the stroke group cannot be explained with the frequent coexistence of CHD. Login to comment
78 We observed lower R219K and V771M AFs in the low-risk group (R219K: 27.4 8 5.2 vs. 30.6 8 6.6%, and V771M: 2.1 8 1.7 vs. 4.6 8 3.0%, respectively), but the differences were not significant. Login to comment
84 The V771M allele was almost exclusively found in individuals carrying the R219K allele (36/37 V771M carriers were positive for R219K). Login to comment
86 0.0005 by the Arlequin software) was observed between V771M and R219K. Login to comment
92 No significant linkage disequilibrium was observed between V771M and I883M. Login to comment
94 Comparisons of AFs of the ABCA1 R219K and V771M variants in the control and patient groups. Login to comment
96 AF values and 95% CIs (bars) are presented for the R219K (a) and V771M (b) variants. Login to comment
103 However, V771M carriers of the stroke group (n = 9) had higher plasma HDL levels than non-carriers [n = 104; 1.00 (0.90-1.30) vs. 1.60 (1.05-1.80) mM; p = 0.053]. Login to comment
116 Although we could only demonstrate significant AF decreases for the V771M variant comparing the entire CHD-affected group to the blood donor group, a trend toward an AF decrease could be demonstrated for both SNPs in both patient groups. Login to comment
119 However, upon subgroup analyses, among patients affected by both diseases with younger ages at onset, both variants R219K and V771M showed significantly decreased AFs (fig. 1). Login to comment
120 Clee et al. [9] reported that the ABCA1 V771M variant also plays a protective role against CHD. Login to comment
121 They explained this observation with the linkage disequilibrium between the R219K and V771M variants. Login to comment
122 In our study, the V771M variant, or compound heterozygosity for V771M and R219K, showed significant AF reduction in the patient groups, in spite of the fact that our controls were relatively younger than our patients with stroke or CHD. Login to comment
128 Our data confirm earlier observations that ABCA1 R219K and V771M polymorphisms may play a protective role against CHD and extend those to another frequently occurring pathologic condition, namely stroke. Login to comment

PMID: 16372134 [PubMed] Katzov H et al: "Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-beta 1-42 and plasma apolipoprotein levels."

No. Sentence Comment

127 The number of individuals in each category is shown in parenthesis. Comparisons were performed by ANOVATC total cholesterol, LDL-C low density lipoprotein cholesterol Traits KK RK RR F value P value APOA1a (g/l) 1.46±0.02 (157) 1.48±0.01 (966) 1.47±0.01 (1,439) 0.23 0.79 APOB (g/l) 1.64±0.03 (157) 1.53±0.01 (966) 1.55±0.01 (1,439) 5.4 0.0046 HDL-C (mmol/l) 1.16±0.26 (156) 1.20±0.01 (961) 1.20±0.01 (1,427) 1.1 0.34 LDL-C (mmol/l) 4.26±0.86 (154) 4.08±0.03 (951) 4.05±0.03 (1,415) 0.26 0.038 TC (mmol/l) 6.24±0.09 (157) 6.04±0.04 (969) 6.01±0.03 (1,439) 3.02 0.049 TGa (mmol/l) 1.87±0.11 (157) 1.71±0.04 (969) 1.72±0.03 (1,441) 1.38 0.25 a Log-transformed traits k.embl-heidelberg.de/PolyPhen/) (Ramensky et al. 2002) for five coding SNPs (cSNPs) in ABCA1 (R219K rs2230806; V771M rs2066718; V825I rs4149312; I883M rs2066714; R1587K rs2230808) (Frikke-Schmidt et al. 2004). Login to comment
129 The number of individuals in each category is shown in parenthesis. Comparisons were performed by ANOVATC total cholesterol, LDL-C low density lipoprotein cholesterol Traits KK RK RR F value P value APOA1a (g/l) 1.46&#b1;0.02 (157) 1.48&#b1;0.01 (966) 1.47&#b1;0.01 (1,439) 0.23 0.79 APOB (g/l) 1.64&#b1;0.03 (157) 1.53&#b1;0.01 (966) 1.55&#b1;0.01 (1,439) 5.4 0.0046 HDL-C (mmol/l) 1.16&#b1;0.26 (156) 1.20&#b1;0.01 (961) 1.20&#b1;0.01 (1,427) 1.1 0.34 LDL-C (mmol/l) 4.26&#b1;0.86 (154) 4.08&#b1;0.03 (951) 4.05&#b1;0.03 (1,415) 0.26 0.038 TC (mmol/l) 6.24&#b1;0.09 (157) 6.04&#b1;0.04 (969) 6.01&#b1;0.03 (1,439) 3.02 0.049 TGa (mmol/l) 1.87&#b1;0.11 (157) 1.71&#b1;0.04 (969) 1.72&#b1;0.03 (1,441) 1.38 0.25 a Log-transformed traits k.embl-heidelberg.de/PolyPhen/) (Ramensky et al. 2002) for five coding SNPs (cSNPs) in ABCA1 (R219K rs2230806; V771M rs2066718; V825I rs4149312; I883M rs2066714; R1587K rs2230808) (Frikke-Schmidt et al. 2004). Login to comment

PMID: 16207707 [PubMed] Hirsch-Reinshagen V et al: "The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease."

No. Sentence Comment

336 Katzov et al. (75) reported significant associations with the R219K, R1587K, and V771M on AD in single marker and haplotype analyses conducted on European subjects. Login to comment
337 Katzov et al. (75) reported significant associations with the R219K, R1587K, and V771M on AD in single marker and haplotype analyses conducted on European subjects. Login to comment

PMID: 15935359 [PubMed] Hodoglugil U et al: "Common polymorphisms of ATP binding cassette transporter A1, including a functional promoter polymorphism, associated with plasma high density lipoprotein cholesterol levels in Turks."

No. Sentence Comment

3 The rare alleles of C-14T and V771M polymorphisms were associated with higher HDL-C levels in men and, in combination with the rare alleles of R219K and I883M, respectively, with higher HDL-C in both sexes. Login to comment
4 Rare alleles of the C-14T and V771M polymorphisms were more frequent in the high HDL-C (≥40 mg/dl) than in the low HDL-C group (≤30 mg/dl) in men (P < 0.05). Login to comment
9 Analysis of the coding region structure revealed that the rare M allele of V771M was distributed predominantly among three common haplotypes, but the sum of their frequencies comprise only two-thirds of the frequency of the M allele. Login to comment
10 The rare alleles of the V771M and the I883M polymorphisms do not exist together on any of the common haplotypes. Login to comment
11 In conclusion, we describe a functional promoter polymorphism (C-14T) and a coding sequence variant (V771M) of ABCA1 and their interactions with two other variants (R219K and I883M) on plasma HDL-C levels in Turks. Login to comment
24 Recently, it was shown that some polymorphisms of ABCA1 were associated with increases (V771M and V825I) or decreases (R1587K) in HDL-C in women and with some consistent trends in men in a large random Danish population [17]. Login to comment
104 The G-803A Table 2 ABCA1 polymorphisms Nucleotide changea Carrier of rare allele (%) Rare allele (%) nb Referencesc Frequency in 5 and promoter regions G-803A ~10 92/141 [19] T-564C 72.7 47.7 728/1268 [18] G-407C 62.5 40.7 220/233 [18] G-99C 42.2 24.2 875/1130 [46] C-14T 61.2 37.7 916/1416 [46] InsG 319 26.6 14.2 848/1288 [46] Nucleotide changed Amino acid change Exon Carrier of rare allele (%) Rare allele (%) nb Referencesc Frequency in coding sequence Nonsynonymous G(70943)A R219K 7 62.3 38.5 996/1466 db 2230806 G(102555)A V771M 16 10.0 5.1 981/1477 db 2066718 G(103777)A V825I 17 12.3 6.2 960/1145 db 4149312 A(105057)G I883M 18 38.1 21.8 1084/1448 db 4149313 G(112177)C E1172D 24 9.0 4.6 1001/1237 [12,13] A(116887)G Q1328R 28 0.003e 0.0015 172/156 NR G(129004)A R1587K 35 55.1 33.0 937/1351 db 2230808 T(133402)C Y1767H 39 ~1.0e 40/55 NR G(133420)A V1773M 39 ~1.0e 40/55 NR Synonymous C(100538)A I620I 15 ~4.0 40/55 NR C(109469)T V990V 21 ~3.0 87/90 [17] T(109861)G V1053V 22 ~1.0 90/90 [12] C(109868)T L1056L 22 ~5.0 90/90 NR C(109906)T R1068R 22 ~3.0 90/90 NR A(113280)G E1211E 25 ~4.0 40/55 [17] A(116879)G T1325T 28 ~1.0 40/55 NR T(137043)C Y1921Y 43 ~1.0 40/55 NR Nucleotide changed Intron Carrier of rare allele (%) Intronic location nb Referencesc Frequency in noncoding sequence G(23816)A 1 ~1.0 11 bp 5 exon 1b 94 NR G(23819)C 1 42 8 bp 5 exon 1b 94 NR A(22997)T 1 46 90 bp 5 exon 1d 91 NR A(23004)G 1 ~1.0 83 bp 5 exon 1d 91 NR G(23058)C 1 46 29 bp 5 exon 1d 91 NR G(40504)A 3 2.6 26 bp 3 of exon 3 192 NR C(45217)T 4 0.7 64 bp 3 of exon 4 142 NR T(98628)A 14 35-40 24 bp 3 of exon 14 190 db 4743763 C(100332)T 14 4.3 59 bp 5 of exon 15 90 db 2066717 C(108020)T 19 0.7 3 bp 5 of exon 20 144 NR DelTTT(134503-6) 39 7.0 20-23 bp 5 of exon 40 90 NR C(142026)T 46 8.6 34 bp 5 of exon 47 116 NR A(142751)G 48 15.9 13 bp 3 of exon 48 107 NR a Relative to transcriptional start. Login to comment
109 Table 3 ABCA1 polymorphisms and mean plasma HDL-C levels (mg/dl ± S.D.) in a random Turkish population Females Males AAa AB BB AAa AB BB Promoter and 5 region T-564C 40.4 ± 8.4 (205) 41.0 ± 7.9 (365) 39.9 ± 7.6 (158) 35.6 ± 7.4 (339) 35.5 ± 6.5 (635) 34.9 ± 6.5 (294) G-407C 41.3 ± 11.2 (82) 40.7 ± 7.7 (101) 40.7 ± 12.2 (37) 35.7 ± 6.9 (88) 35.3 ± 6.7 (96) 35.4 ± 7.4 (49) G-99C 40.7 ± 7.5 (505) 41.0 ± 7.2 (317) 41.3 ± 8.4 (53) 35.1 ± 6.5 (654) 35.0 ± 6.3 (405) 34.9 ± 6.5 (71) C-14T 41.3 ± 9.0 (361) 41.0 ± 9.0 (417) 41.0 ± 9.4 (138) 34.8 ± 7.0b (547) 35.5 ± 7.5 (675) 36.7 ± 8.1b (194) InsG 319 41.3 ± 8.1 (641) 40.5 ± 7.7 (193) 43.1 ± 8.0 (14) 35.3 ± 6.4 (933) 34.7 ± 6.4 (332) 34.5 ± 6.5 (23) Nonsynonymous R219K 41.2 ± 9.4 (364) 40.8 ± 8.6 (480) 41.2 ± 10 (152) 35.2 ± 7.3 (574) 35.3 ± 7.3 (688) 35.2 ± 7.6 (204) V771M 40.9 ± 9.2 (896) 42.8 ± 9.3 (82) 38.7 ± 10 (3) 35.1 ± 7.2c (1330) 37.1 ± 8.0c (144) 45.7 ± 10.7 (3) V825I 40.6 ± 9.4 (842) 38.9 ± 8.5 (117) 42 (1) 35.8 ± 8.7 (1005) 37.1 ± 9.5 (140) (-) I883M 41.1 ± 9.5 (643) 40.8 ± 8.4 (372) 41.4 ± 9.1 (69) 35.0 ± 7.0 (922) 35.7 ± 8.0 (457) 35.6 ± 7.4 (69) E1172D 40.5 ± 8.8 (907) 40.5 ± 7.6 (93) 29 (1) 34.6 ± 7.3 (1129) 35.4 ± 7.6 (105) 30.7 ± 8.7 (3) R1587K 41.1 ± 9.4 (410) 40.8 ± 9.6 (433) 41.0 ± 10.1 (94) 35.9 ± 8.1 (617) 35.1 ± 7.6 (579) 35.3 ± 8.6 (155) Numbers of subjects are shown in parenthesis. Login to comment
116 Informative associations between HDL-C levels and the R219K, V771M, and I883M polymorphisms will be discussed. Login to comment
149 Of these, only the V771M polymorphism appeared to be associated with altered HDL-C levels in males (Table 3). Login to comment
150 Since the V771M polymorphism was present in the Turkish population with an allelic frequency of 5.1% (n = 2458), the rare 771MM homozygous genotype (BB) occurred infrequently (three males and three females). Login to comment
152 Analysis of covariance revealed that the V771M polymorphism was primarily associated with plasma HDL-C, not with triglycerides, in Turkish males (P < 0.05). Login to comment
154 The V771M polymorphism had no significant effect on HDL-C levels in females (Table 3). Login to comment
155 Further stratification of the V771M polymorphism by age, BMI, smoking, alcohol consumption, and apoE genotype yielded no additional information. Login to comment
156 The association of the V771M polymorphism with HDL-C levels was confirmed in the randomly divided subpopulations of Turkish males (Supplemental Table II). Login to comment
163 Genotypic (left) and allelic (right) frequencies of the ABCA1 V771M polymorphism in males with low (≤30 mg/dl), moderate (30-40 mg/dl), or high (≥40 mg/dl) levels of HDL-C. Login to comment
170 In contrast, the combinations of C-14T with R219K and of V771M with I883M were associated with altered HDL-C levels. Login to comment
177 To assess the combined effect of the V771M and I883M polymorphisms on HDL-C levels, subjects were stratified by the I883M genotype (II, IM, or MM) versus V771M. Login to comment
181 Separate haplotype blocks of ABCA1 In order to assess whether the length of the ABCA1 locus could be treated as a single haplotype block, haplotypes were constructed and significant LDs between polymorphisms were calculated using 10 common ABCA1 polymorphisms Table 4 Interactive effects of ABCA1 polymorphisms on mean plasma HDL-C levels (mg/dl ± S.D.) R219K C-14T Females Males RR CC 41.4 ± 8.5 (128) 34.7 ± 6.7 (207) CT 41.6 ± 9.8 (150) 35.7 ± 7.6 (253) TT 41.3 ± 8.9 (55) 36.3 ± 7.8 (84) RK CC 41.8 ± 8.3 (169) 34.8 ± 7.4 (261) CT 39.9 ± 8.3 (203) 35.5 ± 6.8 (309) TT 39.5 ± 9.0 (60) 36.8 ± 8.5 (84) KK CC 39.8 ± 11.2 (60) 34.0 ± 6.2 (69) CT 41.1 ± 9.0 (60) 35.7 ± 8.4 (102) TT 44.7 ± 9.8a (22) 37.1 ± 7.8a (22) I883M V771M II VV 40.9 ± 9.8 (499) 34.8 ± 6.8 (797) VM 41.4 ± 8.3 (74) 36.7 ± 8.3b (112) IM VV 40.3 ± 8.0 (313) 35.1 ± 8.1 (427) VM 44.2 ± 11.5b (17) 37.3 ± 7.4b (26) MM VV 41.6 ± 9.2 (60) 35.6 ± 7.5 (67) Numbers of subjects are shown in parenthesis. Login to comment
190 Many of the rare single nucleotide polymorphisms, such as V771M, were not well represented on the 26 common haplotypes and therefore existed only on the remaining rare haplotypes. Login to comment
204 However, further analysis Table 5 Allele frequency and significant (P < 0.01) pair-wise linkage disequilibrium coefficients between the ABCA1 polymorphisms in a random Turkish population Position Allele % T-564C G-99C C-14T InsG 319 R219K V771M V825I I883M E1172D R1587K T-564C 52.3/47.7 - G-99C 75.8/24.2 0.36 - C-14T 62.3/37.7 -0.96 -0.98 - InsG 319 85.8/14.2 - - - - R219K 61.5/38.5 - - - - V771M 94.9/5.1 - - - 0.99 - V825I 93.8/6.2 -0.40 -0.69 - - -0.76 - - I883M 78.2/21.8 - -0.42 - - 0.20 -0.79 0.91 - E1172D 95.4/4.6 - - - - - 0.34 - - - R1587K 67.0/33.0 - - -0.23 - - 0.56 - - 0.87 - Table 6 Common haplotypes of promoter and coding regions of ABCA1 gene in a random Turkish population Promoter region haplotypes % T-564C G-99C C-14T InsG 319 1 31.7 0 0 1 0 2 20.1 1 1 0 0 3 19.9 1 0 0 0 4 12.7 0 0 0 0 5 4.6 0 0 1 1 6 4.2 1 1 0 1 7 3.2 1 0 0 1 8 2.5 0 0 0 1 Sum 98.9 Coding region haplotypes % R219K V771M V825I I883M E1172D R1587K 1 39.3 0 0 0 0 0 0 2 12.6 1 0 0 0 0 0 3 12.0 0 0 0 0 0 1 4 8.7 1 0 0 1 0 0 5 8.3 1 0 0 0 0 1 6 4.0 0 0 1 1 0 0 7 3.4 0 0 0 0 1 1 8 1.6 1 0 0 1 0 1 9 1.3 1 1 0 0 0 0 10 1.3 0 1 0 0 1 1 11 1.3 0 0 1 1 0 1 12 1.1 1 1 0 0 0 1 Sum 95.1 0: common allele; 1: rare allele. Login to comment
215 Haplotype structure and haplotype-phenotype association of polymorphisms in the coding region of ABCA1 When the haplotype structure of the coding region was constructed using six polymorphisms (R219K, V771M, V825I, I883M, E1172D, and R1587K; Table 6), 12 haplotypes with a frequency >1% accounted for 95.1% of all haplotypes. Login to comment
219 The rare allele frequency of the V771M polymorphism, which was associated with high HDL-C in males, was 5.1% (Table 2). Login to comment
221 Those remaining must be distributed among the rare (<1%) haplotypes, and this distribution may explain the lack of association for the V771M on haplotype analysis. Login to comment
222 We observed an interaction between the V771M and I883M polymorphisms (Table 4). Login to comment
230 (rare allele in LD with rare allele) was observed between pairs of V771M and InsG 319, V825I and I883M, and R1587K and E1172D. Login to comment
231 There was negative LD (rare allele to common allele) between I883M and V771M as seen in Table 4. Login to comment
232 The R219K, C-14T, and V771M polymorphisms were not in LD in the Turkish population. Login to comment
279 In the analysis of covariance, where the sources of variance on plasma HDL-C levels were examined, introduction of interaction variables (smoking or alcohol consumption) × (C-14T or V771M) to the model showed that neither parameter modulated (P > 0.05) the effect of polymorphisms on HDL-C levels in males or females or when data for both genders were pooled. Login to comment
289 In Turks, the interaction of C-14T and R219K may play a role in altering plasma HDL-C levels and possibly CAD risk. Login to comment
290 In Turkish males but not females, the M allele of the V771M polymorphism was associated with high plasma HDL-C levels. After stratification by HDL-C levels, the M allele was significantly more frequent in the high than in the low HDL-C group, further supporting an association with high plasma HDL-C levels. Login to comment
295 The V771M polymorphism was associated with high HDL-C in females and consistent trends in males [17], whereas male subjects with the 771M allele had decreased focal atherosclerosis without alterations in plasma lipid levels [12]. Login to comment
299 In contrast, the M allele of the I883M polymorphism was associated with increased progression of atherosclerosis [12]. Login to comment
300 The combination of V771M and I883M alone or with other factors may modulate plasma HDL-C levels and CAD risk. Login to comment
304 A functional promoter polymorphism, C-14T, and a coding sequence polymorphism, V771M, in the ABCA1 gene appeared to affect HDL-C levels in Turks and these results could be replicated when our entire data set was randomly divided in two different subsets (Supplemental Table II). Login to comment
305 Two combinations of rare alleles-C-14T with R219K and V771M with I883M-were associated with high HDL-C in both males and females. Login to comment
103 The G-803A Table 2 ABCA1 polymorphisms Nucleotide changea Carrier of rare allele (%) Rare allele (%) nb Referencesc Frequency in 5 and promoter regions G-803A ~10 92/141 [19] T-564C 72.7 47.7 728/1268 [18] G-407C 62.5 40.7 220/233 [18] G-99C 42.2 24.2 875/1130 [46] C-14T 61.2 37.7 916/1416 [46] InsG 319 26.6 14.2 848/1288 [46] Nucleotide changed Amino acid change Exon Carrier of rare allele (%) Rare allele (%) nb Referencesc Frequency in coding sequence Nonsynonymous G(70943)A R219K 7 62.3 38.5 996/1466 db 2230806 G(102555)A V771M 16 10.0 5.1 981/1477 db 2066718 G(103777)A V825I 17 12.3 6.2 960/1145 db 4149312 A(105057)G I883M 18 38.1 21.8 1084/1448 db 4149313 G(112177)C E1172D 24 9.0 4.6 1001/1237 [12,13] A(116887)G Q1328R 28 0.003e 0.0015 172/156 NR G(129004)A R1587K 35 55.1 33.0 937/1351 db 2230808 T(133402)C Y1767H 39 ~1.0e 40/55 NR G(133420)A V1773M 39 ~1.0e 40/55 NR Synonymous C(100538)A I620I 15 ~4.0 40/55 NR C(109469)T V990V 21 ~3.0 87/90 [17] T(109861)G V1053V 22 ~1.0 90/90 [12] C(109868)T L1056L 22 ~5.0 90/90 NR C(109906)T R1068R 22 ~3.0 90/90 NR A(113280)G E1211E 25 ~4.0 40/55 [17] A(116879)G T1325T 28 ~1.0 40/55 NR T(137043)C Y1921Y 43 ~1.0 40/55 NR Nucleotide changed Intron Carrier of rare allele (%) Intronic location nb Referencesc Frequency in noncoding sequence G(23816)A 1 ~1.0 11 bp 5 exon 1b 94 NR G(23819)C 1 42 8 bp 5 exon 1b 94 NR A(22997)T 1 46 90 bp 5 exon 1d 91 NR A(23004)G 1 ~1.0 83 bp 5 exon 1d 91 NR G(23058)C 1 46 29 bp 5 exon 1d 91 NR G(40504)A 3 2.6 26 bp 3 of exon 3 192 NR C(45217)T 4 0.7 64 bp 3 of exon 4 142 NR T(98628)A 14 35-40 24 bp 3 of exon 14 190 db 4743763 C(100332)T 14 4.3 59 bp 5 of exon 15 90 db 2066717 C(108020)T 19 0.7 3 bp 5 of exon 20 144 NR DelTTT(134503-6) 39 7.0 20-23 bp 5 of exon 40 90 NR C(142026)T 46 8.6 34 bp 5 of exon 47 116 NR A(142751)G 48 15.9 13 bp 3 of exon 48 107 NR a Relative to transcriptional start. Login to comment
108 Table 3 ABCA1 polymorphisms and mean plasma HDL-C levels (mg/dl &#b1; S.D.) in a random Turkish population Females Males AAa AB BB AAa AB BB Promoter and 5 region T-564C 40.4 &#b1; 8.4 (205) 41.0 &#b1; 7.9 (365) 39.9 &#b1; 7.6 (158) 35.6 &#b1; 7.4 (339) 35.5 &#b1; 6.5 (635) 34.9 &#b1; 6.5 (294) G-407C 41.3 &#b1; 11.2 (82) 40.7 &#b1; 7.7 (101) 40.7 &#b1; 12.2 (37) 35.7 &#b1; 6.9 (88) 35.3 &#b1; 6.7 (96) 35.4 &#b1; 7.4 (49) G-99C 40.7 &#b1; 7.5 (505) 41.0 &#b1; 7.2 (317) 41.3 &#b1; 8.4 (53) 35.1 &#b1; 6.5 (654) 35.0 &#b1; 6.3 (405) 34.9 &#b1; 6.5 (71) C-14T 41.3 &#b1; 9.0 (361) 41.0 &#b1; 9.0 (417) 41.0 &#b1; 9.4 (138) 34.8 &#b1; 7.0b (547) 35.5 &#b1; 7.5 (675) 36.7 &#b1; 8.1b (194) InsG 319 41.3 &#b1; 8.1 (641) 40.5 &#b1; 7.7 (193) 43.1 &#b1; 8.0 (14) 35.3 &#b1; 6.4 (933) 34.7 &#b1; 6.4 (332) 34.5 &#b1; 6.5 (23) Nonsynonymous R219K 41.2 &#b1; 9.4 (364) 40.8 &#b1; 8.6 (480) 41.2 &#b1; 10 (152) 35.2 &#b1; 7.3 (574) 35.3 &#b1; 7.3 (688) 35.2 &#b1; 7.6 (204) V771M 40.9 &#b1; 9.2 (896) 42.8 &#b1; 9.3 (82) 38.7 &#b1; 10 (3) 35.1 &#b1; 7.2c (1330) 37.1 &#b1; 8.0c (144) 45.7 &#b1; 10.7 (3) V825I 40.6 &#b1; 9.4 (842) 38.9 &#b1; 8.5 (117) 42 (1) 35.8 &#b1; 8.7 (1005) 37.1 &#b1; 9.5 (140) (-) I883M 41.1 &#b1; 9.5 (643) 40.8 &#b1; 8.4 (372) 41.4 &#b1; 9.1 (69) 35.0 &#b1; 7.0 (922) 35.7 &#b1; 8.0 (457) 35.6 &#b1; 7.4 (69) E1172D 40.5 &#b1; 8.8 (907) 40.5 &#b1; 7.6 (93) 29 (1) 34.6 &#b1; 7.3 (1129) 35.4 &#b1; 7.6 (105) 30.7 &#b1; 8.7 (3) R1587K 41.1 &#b1; 9.4 (410) 40.8 &#b1; 9.6 (433) 41.0 &#b1; 10.1 (94) 35.9 &#b1; 8.1 (617) 35.1 &#b1; 7.6 (579) 35.3 &#b1; 8.6 (155) Numbers of subjects are shown in parenthesis. Login to comment
115 Informative associations between HDL-C levels and the R219K, V771M, and I883M polymorphisms will be discussed. Login to comment
148 Of these, only the V771M polymorphism appeared to be associated with altered HDL-C levels in males (Table 3). Login to comment
151 Analysis of covariance revealed that the V771M polymorphism was primarily associated with plasma HDL-C, not with triglycerides, in Turkish males (P < 0.05). Login to comment
153 The V771M polymorphism had no significant effect on HDL-C levels in females (Table 3). Login to comment
162 Genotypic (left) and allelic (right) frequencies of the ABCA1 V771M polymorphism in males with low (ࣘ30 mg/dl), moderate (30-40 mg/dl), or high (ࣙ40 mg/dl) levels of HDL-C. Login to comment
169 In contrast, the combinations of C-14T with R219K and of V771M with I883M were associated with altered HDL-C levels. Login to comment
176 To assess the combined effect of the V771M and I883M polymorphisms on HDL-C levels, subjects were stratified by the I883M genotype (II, IM, or MM) versus V771M. Login to comment
180 Separate haplotype blocks of ABCA1 In order to assess whether the length of the ABCA1 locus could be treated as a single haplotype block, haplotypes were constructed and significant LDs between polymorphisms were calculated using 10 common ABCA1 polymorphisms Table 4 Interactive effects of ABCA1 polymorphisms on mean plasma HDL-C levels (mg/dl &#b1; S.D.) R219K C-14T Females Males RR CC 41.4 &#b1; 8.5 (128) 34.7 &#b1; 6.7 (207) CT 41.6 &#b1; 9.8 (150) 35.7 &#b1; 7.6 (253) TT 41.3 &#b1; 8.9 (55) 36.3 &#b1; 7.8 (84) RK CC 41.8 &#b1; 8.3 (169) 34.8 &#b1; 7.4 (261) CT 39.9 &#b1; 8.3 (203) 35.5 &#b1; 6.8 (309) TT 39.5 &#b1; 9.0 (60) 36.8 &#b1; 8.5 (84) KK CC 39.8 &#b1; 11.2 (60) 34.0 &#b1; 6.2 (69) CT 41.1 &#b1; 9.0 (60) 35.7 &#b1; 8.4 (102) TT 44.7 &#b1; 9.8a (22) 37.1 &#b1; 7.8a (22) I883M V771M II VV 40.9 &#b1; 9.8 (499) 34.8 &#b1; 6.8 (797) VM 41.4 &#b1; 8.3 (74) 36.7 &#b1; 8.3b (112) IM VV 40.3 &#b1; 8.0 (313) 35.1 &#b1; 8.1 (427) VM 44.2 &#b1; 11.5b (17) 37.3 &#b1; 7.4b (26) MM VV 41.6 &#b1; 9.2 (60) 35.6 &#b1; 7.5 (67) Numbers of subjects are shown in parenthesis. Login to comment
189 Many of the rare single nucleotide polymorphisms, such as V771M, were not well represented on the 26 common haplotypes and therefore existed only on the remaining rare haplotypes. Login to comment
203 However, further analysis Table 5 Allele frequency and significant (P < 0.01) pair-wise linkage disequilibrium coefficients between the ABCA1 polymorphisms in a random Turkish population Position Allele % T-564C G-99C C-14T InsG 319 R219K V771M V825I I883M E1172D R1587K T-564C 52.3/47.7 - G-99C 75.8/24.2 0.36 - C-14T 62.3/37.7 -0.96 -0.98 - InsG 319 85.8/14.2 - - - - R219K 61.5/38.5 - - - - V771M 94.9/5.1 - - - 0.99 - V825I 93.8/6.2 -0.40 -0.69 - - -0.76 - - I883M 78.2/21.8 - -0.42 - - 0.20 -0.79 0.91 - E1172D 95.4/4.6 - - - - - 0.34 - - - R1587K 67.0/33.0 - - -0.23 - - 0.56 - - 0.87 - Table 6 Common haplotypes of promoter and coding regions of ABCA1 gene in a random Turkish population Promoter region haplotypes % T-564C G-99C C-14T InsG 319 1 31.7 0 0 1 0 2 20.1 1 1 0 0 3 19.9 1 0 0 0 4 12.7 0 0 0 0 5 4.6 0 0 1 1 6 4.2 1 1 0 1 7 3.2 1 0 0 1 8 2.5 0 0 0 1 Sum 98.9 Coding region haplotypes % R219K V771M V825I I883M E1172D R1587K 1 39.3 0 0 0 0 0 0 2 12.6 1 0 0 0 0 0 3 12.0 0 0 0 0 0 1 4 8.7 1 0 0 1 0 0 5 8.3 1 0 0 0 0 1 6 4.0 0 0 1 1 0 0 7 3.4 0 0 0 0 1 1 8 1.6 1 0 0 1 0 1 9 1.3 1 1 0 0 0 0 10 1.3 0 1 0 0 1 1 11 1.3 0 0 1 1 0 1 12 1.1 1 1 0 0 0 1 Sum 95.1 0: common allele; 1: rare allele. Login to comment
214 Haplotype structure and haplotype-phenotype association of polymorphisms in the coding region of ABCA1 When the haplotype structure of the coding region was constructed using six polymorphisms (R219K, V771M, V825I, I883M, E1172D, and R1587K; Table 6), 12 haplotypes with a frequency >1% accounted for 95.1% of all haplotypes. Login to comment
218 The rare allele frequency of the V771M polymorphism, which was associated with high HDL-C in males, was 5.1% (Table 2). Login to comment
220 Those remaining must be distributed among the rare (<1%) haplotypes, and this distribution may explain the lack of association for the V771M on haplotype analysis. Login to comment
229 (rare allele in LD with rare allele) was observed between pairs of V771M and InsG 319, V825I and I883M, and R1587K and E1172D. Login to comment
278 In the analysis of covariance, where the sources of variance on plasma HDL-C levels were examined, introduction of interaction variables (smoking or alcohol consumption) &#d7; (C-14T or V771M) to the model showed that neither parameter modulated (P > 0.05) the effect of polymorphisms on HDL-C levels in males or females or when data for both genders were pooled. Login to comment
294 The V771M polymorphism was associated with high HDL-C in females and consistent trends in males [17], whereas male subjects with the 771M allele had decreased focal atherosclerosis without alterations in plasma lipid levels [12]. Login to comment
303 A functional promoter polymorphism, C-14T, and a coding sequence polymorphism, V771M, in the ABCA1 gene appeared to affect HDL-C levels in Turks and these results could be replicated when our entire data set was randomly divided in two different subsets (Supplemental Table II). Login to comment

PMID: 16429166 [PubMed] Brunham LR et al: "Accurate prediction of the functional significance of single nucleotide polymorphisms and mutations in the ABCA1 gene."

No. Sentence Comment

45 À3), R219K, V771M, I883M, D1289N, and P2150L, four had cholesterol efflux values that were not statistically different from wild-type ABCA1. Login to comment
46 This included two variants, D1289N and P2150L, that have been previously reported to be disease-causing mutations [4,8,9], as well as two cSNPs, R219K and V771M. Login to comment
48 This SNP has been reported to be associated with decreased HDL cholesterol and increased severity of atherosclerosis in Table 1. subPSEC Scores and Probability of Functional Impairment (Pdeleterious) for ABCA1 Mutations and SNPs Mutations SNPs Variant SubPSEC Pdeleterious Variant subPSEC Pdeleterious P85L À4.62 0.83 R219K À0.57 0.08 H160F À2.79 0.45 V399A À2.26 0.32 R230C À4.27 0.78 V771M À2.86 0.46 A255T À1.81 0.23 T774P À1.99 0.27 E284K À2.34 0.34 K776N À3.53 0.63 Y482C À4.21 0.77 V825I À1.06 0.13 R587W À6.04 0.95 I883M À1.38 0.17 W590S À5.19 0.9 E1172D À1.96 0.26 W590L À4.48 0.82 R1587K À0.58 0.08 Q597R À7.15 0.98 S1731C À4.21 0.77 T929I À4.29 0.78 N935H À8.54 1 N935S À7.53 0.99 A937V À6.6 0.97 A1046D À7.52 0.99 M1091T À3.56 0.64 D1099Y À6.09 0.96 D1289N À2.48 0.37 L1379F À3.81 0.69 C1477R À5.44 0.92 S1506L À5.17 0.9 N1611D À5.69 0.94 R1680W À6.02 0.95 V1704D À3.21 0.55 N1800H À4.23 0.77 R1901S À5.06 0.89 F2009S À2.73 0.43 R2081W À8.08 0.99 P2150L À2.88 0.47 Q2196H À2.74 0.43 DOI: 10.1371/journal.pgen.0010083.t001 PLoS Genetics | www.plosgenetics.org December 2005 | Volume 1 | Issue 6 | e83 0740 Accurate Prediction of ABCA1 Variants Synopsis A major goal of human genetics research is to understand how genetic variation leads to differences in the function of genes. Login to comment
75 Cholesterol Efflux Values for 293 Cells Transfected with ABCA1 Variants and subPSEC and PolyPhen Predictions of the Functional Impact of these Variants Variant Variant Type subPSEC Cholesterol Efflux PolyPhen R2081W Mutation À8.08 21.1 6 21%* Probably damaging N935S Mutation À7.53 29.3 6 13%* Benign A1046D Mutation À7.52 16.8 6 7%* Possibly damaging Q597R Mutation À7.15 17.7 6 14%* Probably damaging R587W Mutation À6.04 31.7 6 33%* Probably damaging C1477R Mutation À5.44 20.5 6 10%* Probably damaging W590S Mutation À5.19 47.1 6 13%* Probably damaging S1506L Mutation À5.17 17.8 6 15%* Probably damaging T929I Mutation À4.29 69.9 6 11%* Possibly damaging N1800H Mutation À4.23 31.3 6 16%* Possibly damaging S1731C SNP À4.21 12.3 6 10%* Possibly damaging M1091T Mutation À3.56 6.9 6 20%* Probably damaging P2150L Mutation À2.88 88.4 6 21% Probably damaging V771M SNP À2.86 145.4 6 33% Benign D1289N Mutation À2.48 137.7 6 86% Benign I883M SNP À1.38 69.1 6 16%* Benign R219K SNP À0.57 103.7 6 21.05 Benign Wild-type - 0.0 100% - *p , 0.01 compared to wild-type ABCA1. Login to comment

PMID: 16226177 [PubMed] Frikke-Schmidt R et al: "Mutation in ABCA1 predicted risk of ischemic heart disease in the Copenhagen City Heart Study Population."

No. Sentence Comment

86 A rare single nucleotide polymorphism (SNP) (V771M, allele frequency 0.03) and a muta- Figure 1. Login to comment
95 Although we have recently shown that V771M is associated with increased HDL-C levels (9), effects on risk of IHD have not been documented for either of these variants (14,28). Login to comment
107 However, at the individual level, K776N appears to have a marked impact on risk. Login to comment
109 However, several arguments favor a true observation: 1) the involved amino acid residue is completely conserved between species and relatively conserved between 12 ABCAs with very different transport functions; 2) the amino acid substitution changes the charge of the side-chain, potentially leading to structural alterations of the protein, and consequently to altered protein interactions or transport properties; 3) in the CFTR (or ABCC7), a disease-causing mutation (R347P) has been identified at a site that corresponds to residue 764 in ABCA1 (15), and thus in close vicinity to K776N; 4) the present study is of a large cohort, and therefore includes only incident cases, avoiding the normal pitfalls of case reports and case-control studies (30); 5) we observed a similar trend on risk of IHD in a separate case-control study; 6) we have previously determined effects on lipids and lipoproteins of all non-synonymous SNPs identified in ABCA1 (R219K, V771M, V825I, I883M, E1172D, R1587K). Login to comment
84 A rare single nucleotide polymorphism (SNP) (V771M, allele frequency 0.03) and a muta- Figure 1. Login to comment
93 Although we have recently shown that V771M is associated with increased HDL-C levels (9), effects on risk of IHD have not been documented for either of these variants (14,28). Login to comment

PMID: 16183915 [PubMed] Oram JF et al: "ATP-binding cassette transporter A1: a cell cholesterol exporter that protects against cardiovascular disease."

No. Sentence Comment

431 The most studied of these SNPs is the R219K variant, with the K allele being associated with higher levels of HDL (255). Login to comment
432 V771M and V825I SNPs have also been reported to be associated with increased HDL levels, whereas R1587K is associated with low levels of HDL (78, 255). Login to comment

PMID: 15262183 [PubMed] Probst MC et al: "Screening for functional sequence variations and mutations in ABCA1."

No. Sentence Comment

9 In one individual with extremely high HDL levels, the V771M polymorphism was found in a homozygous state. Login to comment
59 19 years 30 years 53 years Chol TG LDL HDL Lp(a) 116 59 82 30 <5.9 Apo E3/E4 GOT 23U/L, GPT 20 U/L, bilirubine (tot.) 1.16 Chol TG LDL HDL Lp(a) 153 94 112 27 22.7 Apo E3/E3 Chol TG LDL HDL Lp(a) 131 50 88 40 10.9 ApoE2/E3 60 years Chol TG LDL HDL Lp(a) 161 107 91 60 <5.9 ApoE3/E4 (TC ∆ ) Exon 23 G6PD deficiency R1068C I-1 I-1 I-2 I-2 dec. 67 years II-1 II-1 II-2 II-2 40 years 31 years 70 years Chol TG LDL HDL ApoAI 309 59 228 70 170 Chol TG LDL HDL ApoAI 283 145 175 54 156 Chol TG LDL HDL ApoAI 304 48 168 125 244 n.d. 60 years 32 years 23 years Chol TG LDL HDL ApoAI 237 100 121 48 110 Chol TG LDL HDL ApoAI 316 24 2 5 Chol TG LDL HDL ApoAI 158 74 109 33 86 68 years Chol TG LDL HDL ApoAI 121 191 33 87 96 49 I-1 I-2 II-1 II-2 V771M (patient A) (patient D) (patient E) A D E Fig. 1. Login to comment
123 These Table 1 Primers and probes for TaqMan analysis of novel polymorphisms in the coding region of ABCA1 W590L (G2082C) TM-W590L-f 5 -AGC TGA CCC CTT TGA GGA CAT-3 TM-W590L-r 5 -CTC CAC CAC ATC CTG CAA GTA G-3 TM-W590-vic 5 -VIC-CCC CCC ¯ AGA CGT A-MGB-NFQ-3 TM-L590-fam 5 -FAM-CCC CCG ¯ AGA CGT A-MGB-NFQ-3 V771M (G2624A) TM-V771M-f 5 -GGC ATC ATC TAC TTC ACG CTG TA-3 TM-V771M-r 5 -CAG AGG TAC TCA CAG CGA AGA TCT T-3 TM-V771-vic 5 -FAM-TGT GAA GCC CAC ¯ GTA G-MGB-NFQ-3 TM-M771-fam 5 -VIC-TGA AGC CCA T ¯ GT AGT C-MGB-NFQ-3 W840R (T2831A) TM-W840R-f 5 -GCT GTT TGA CAC CTT CCT CTA TGG-3 TM-W840R-r 5 -TGT ACC TGG AAA GAC AGC CTC AA-3 TM-W840-vic 5 -VIC-TGT ACC A ¯ GG TCA TCA C-MGB-NFQ-3 TM-R840-fam 5 -FAM-TGT ACC T ¯ GG TCA TCA C-MGB-NFQ-3 P2150L (C6762T) TM-P2150L-f 5 -TTC AGG TTT GGA GAT GGT TAT ACA ATA G-3 TM-P2150L-r 5 -GAA ATG CAA GTC CAA AGA AAT CCT-3 TM-P2150-vic 5 -VIC-CAA CCC ¯ GGA CCT GA-MGB-NFQ-3 TM-L2150-fam 5 -FAM-CAA CCT ¯ GGA CCT GAA-MGB-NFQ-3 F2163S (T6801C) TM-F2163S-f 5 -AAG CCT GTC CAG GAT TTC TTT G-3 TM-F2163S-r 5 -CAT GTT CCG GTG TTT CTC TTT TAG-3 TM-F2163-vic 5 -VIC-CCA GGA A ¯ AT GCA AGT C-MGB-NFQ-3 TM-S2163-fam 5 -FAM-CAG GAG ¯ ATG CAA GTC-MGB-NFQ-3 V2244I (G7043A) TM-V2244I-f 5 -ATG ATG ACC ACT TAA AAG ACC TCT CA-3 TM-V2244I-r 5 -GCT TTC TTT CAC TTT CTC ATC CTG TAG-3 TM-V2244-vic 5 -VIC-TGG ACG ¯ TTG CAG TTC-MGB-NFQ-3 TM-I2244-fam 5 -FAM-AGT AGT GGA CA ¯ T TGC-MGB-NFQ-3 Positions of sequence variations refer to accession number NM005502. Login to comment
181 Table 4 Frequencies of VNTR-SRY in various study groups and mean HDL levels (males only) DONORS High-HDL Low-HDL Total Individuals 50 33 44 221 HDL-C 57 ± 12 93 ± 16 35 ± 7 59 ± 25 Homozygotes wt (%) 2.0 12.1 6.8 6.3 (GTTT) (%) 8.0 3.0 2.3 4.7 (GTTTTGTTT) (%) 18.0 21.2 29.5 22.8 Heterozygotes wt/ (GTTT) (%) 12.0 15.2 11.4 12.6 wt/ (GTTTTGTTT) (%) 24.0 15.2 15.9 18.9 (GTTT)/ (GTTTTGTTT) (%) 34.0 33.3 34.1 33.9 Allele frequencies wt (%) 20.0 27.3 20.5 22.0 (GTTT) (%) 32.0 27.3 25.0 28.3 (GTTTTGTTT) (%) 47.0 45.5 54.5 49.2 P(χ2) - 0.541 0.516 In patient A (individual II-1 in pedigree A, Fig. 1) we identified a G102555A (V771M) polymorphism in a homozygous state. Login to comment
183 The V771M polymorphism was analyzed in the DONORS cohort. Login to comment
192 In addition, patient D was heterozygous for a novel sequence variation in exon 22, Table 5 Sequence variations found in ABCA1 and phenotypes of patients Exon Amino acid Nucleotide Position in DNA (AF275948) Position in mRNA (NM005502) Found in patient with 14 W590L TG ¯ G → TC ¯ G 98481 2082 HDL deficiency (C) 16 V771M G ¯ TG → A ¯ TG 102555 2624 Increased HDL (A) 17 W840R T ¯ GG → A ¯ GG 103822 2831 HDL deficiency (B) 22 R1068C C ¯ GC → T ¯ GC 109904 3515 HDL deficiency (D) 49 F2163S TT ¯ T → TC ¯ T 143483 6801 Low HDL and G6PD deficiency (E) 50 V2244I G ¯ TT → A ¯ TT 144665 7043 A C ABC B S A N ABC B S 44 23 703 681 718 740 769 747 774-794 822 842 1368 1346 1655 1677 1724 1702 1737 1759 1790 1768 1848 1870 642 660 W590L R1068C F2163S P2150L V2244I V771M W840R Fig. 4. Login to comment
237 In lipoprotein metabolism (cholesterol efflux) it is known that methionine oxidation in apo A-I is a key regulatory event in LCAT activation [9], thus the amino acid exchange valine to methionine at codon 771 may affect functionality [10-12]. Login to comment
238 Moreover, V771M is located very close to a putative transmembrane region (Fig. 4) and it is known that mutations in the SUR1 gene that are localized near the transmembrane region impair the interaction of this ABC transporter with Kir6.2 channel [13]. Login to comment
253 Two mutations have been found in a phenotype related to CVD, located in an important domain of ABCA1 (carboxy-terminus) and a rare homozygous polymorphism (V771M) was identified in a proband with extremely high HDL. Login to comment

PMID: 15024730 [PubMed] Katzov H et al: "Genetic variants of ABCA1 modify Alzheimer disease risk and quantitative traits related to beta-amyloid metabolism."

No. Sentence Comment

74 Details of ABCA1 SNPs, and Oligos for PCR and DASHn Variant dbSNP rsID Base change Forward primer sequence (50 ^30 ) Reverse primer sequence (30 ^50 ) Probe sequence (50 ^30 ) p.R219K rs2230806 c.658G4A g.10300705G4A b-TTTCTGAGCTTTGTGGCCTACC GCTCTGCTGCAGCCAGTTTCTC GTTTCTCCCTTGGTAGG p.V771M rs2066718 c.2314G4A g.102969093G4A b-TGTGTGTGGCATGGCAGGACTA GCGAAGATCTTGAGTGTGAAGC GAAGCCCACGTAGTCCT p.V825I rs4149312 c.2476G4A g.102967871G4A b-ATGGCTTCAATCTCACCACTTG GGTGTCAAACAGCATCATGGAG CATGGAGACCCAAGTGG p.I883M rs4149313 c.2650A4G g.102966591A4G b-GAGGTCAACAGCACTTACTTTCT AGAAGAGCCACCCTTGTTCCAA AAGAGAATGTCAGAAAG p.R1587K rs2230808 c.4762G4A g.102942642G4A b-ATTTATGACAGGACTGGACACC AGCGGTTTACCTTGACATTATT CATTATTTCTGGTGTCC n Genotyping of SNPs was performed using dynamic allele speci'c hybridization (DASH) [Prince et al., 2001]. Login to comment
88 While no supporting evidence of association with marker rs2230806 was detected, significant associations were observed for markers rs2230808 (c.4762G4A, p.R1587K) (P=0.016 for genotypes, P=0.013 for alleles) and marker rs2066718 (c.2314G4A, p.V771M) (P=0.029 for genotypes, P=0.031 for alleles) (Table 3). Login to comment
93 Single MarkerAssociations forABCA1and Alzheimer Diseasew p.R219K (rs2230806) G/G G/A A/A P value Set A AD 238 (.62) 125 (.33) 21 (.05) 0.014n Controls 102 (.58) 51 (.29) 22 (.13) Set B AD 58 (.48) 53 (.44) 9 (.08) 0.76 Controls 76 (.53) 59 (.41) 9 (.06) Set C AD 82 (.57) 53 (.37) 8 (.06) 0.66 Controls 183 (.56) 117 (.36) 26 (.08) Set D AD 183 (.56) 122 (.37) 22 (.07) 0.93 Controls 60 (.57) 40 (.38) 6 (.06) p.I883M (rs4149313) C/C C/T T/T Set A AD 2 (.01) 81 (.21) 301 (.78) 0.39 Controls 0 (.00) 31 (.18) 145 (.82) Set B AD 0 (.00) 29 (.24) 91 (.76) 0.27 Controls 3 (.02) 32 (.21) 115 (.77) Set C AD 2 (.01) 27 (.19) 116 (.80) 0.84 Controls 3 (.01) 53 (.17) 256 (.82) Set D AD 3 (.01) 68 (.21) 253 (.78) 0.61 Controls 2 (.02) 19 (.19) 83 (.80) p.R1587K (rs2230808) G/G G/A A/A Set A AD 253 (.66) 114 (.30) 15 (.04) 0.13 Controls 101 (.57) 66 (.38) 9 (.05) Set B AD 56 (.46) 58 (.48) 7 (.06) 0.016n Controls 96 (.64) 48 (.32) 7 (.05) Set C AD 80 (.55) 56 (.39) 9 (.06) 0.70 Controls 189 (.58) 121 (.37) 15 (.05) Det D AD 185 (.57) 118 (.36) 24 (.07) 0.18 Controls 68 (.64) 28 (.26) 10 (.09) p.V771M (rs2066718) G/G G/A A/A Set A AD 365 (.95) 20 (.05) 0 (.00) 0.28 Controls 167 (.95) 7 (.04) 1 (.01) Set B AD 109 (.98) 2 (.02) 0 (.00) 0.029n Controls 126 (.92) 11 (.08) 0 (.00) p.V825I (rs4149312) G/G G/A A/A Set A AD 341 (.93) 20 (.05) 4 (.01) 0.17 Controls 164 (.92) 15 (.08) 0 (.00) w Genotype frequencies for all studied SNPs in ABCA1 are presented. Login to comment

PMID: 14767869 [PubMed] Yamakawa-Kobayashi K et al: "Associations between serum high-density lipoprotein cholesterol or apolipoprotein AI levels and common genetic variants of the ABCA1 gene in Japanese school-aged children."

No. Sentence Comment

2 In the present study, we analyzed the relationships between 5 single nucleotide polymorphisms (SNPs) and 2 insertion/deletion polymorphisms in the 5؅ flanking region and 5 missense polymorphisms of the ABCA1 gene and serum lipid levels in healthy school-aged children. We detected significant associations between the K219R and V771M polymorphisms, and HDL-C or apoAI levels. Login to comment
39 Missense Polymorphisms in the Coding Region To date, in the coding region of the ABCA1 gene, 9 SNPs inducing amino acid changes have been reported in the dbSNP database; we have ascertained that at least 5 of these missense mutations (K219R, V771M, V825I, M883I, and R1587K) are polymorphic in Japanese populations. Login to comment
40 Tight linkage disequilib- liums were observed between the V771M polymorphism and the M883I polymorphism, and the V825I polymorphism and the M883I polymorphism (data not shown). Login to comment
46 PCR Primers, Annealing Temperatures, Sizes of Amplified Fragments, and Restriction Enzymes Used for Genotyping of Each Polymorphism Forward Primer Reverse Primer Annealing Temp (°C) Size of Amplified Fragment (bp) Restriction Enzyme 5Ј-flanking region -937 to -936delAT F: CCTCTTCTACGGGTCTGTCCTG R: CAGCCTCCCTGTGATAAAAACA 64 321, 323 NlaIII -707G3A F: TGGAGGTCTGGAGTGGCTACAT R: CACAGAACAATATGGACCAGGCC 60 156 StuI -675 to -674ins GTTTGTTTT or insGTTTT F: CTGGTCCATATTGTTCTGTGTT R: CATAAATTGAGAGGAAGGAGGC 58 76, 81, 85 - -477C3T F: CGCCTATCAAAAATCAAAGTCC R: TCCGCGGTCTGCGTCCCCTTCC 60 371 AciI -320G3C F: AAAAAATTGCGGAAAGTA R: GCCGCAGACTCTCTAGTCCA 56 86 RsaI -191G3C F: CAAATTCCACTGGTGCCCTTGG R: TGTCTTAGGGTCCGCGGTCTGGGT 60 140 AvaII -17G3C F: ACCCCCACCCCACCCACCTCCC R: GTGCTCTCCCTCCTCCCCGCCGC 62 158 BstUI Coding region K219R F: TGACAAGTCTGTGCAATGGA R: GGCTTAAACTCAGCCACACC 58 379 StyI V771M F: AGTGCTTGGGATTGTTGAGG R: CACTGAAGAAAGGCCAGAGG 58 300 BsaAI V8251 F: CTGCTGTCTCCTGTGGCTTT R: GCTGCCTGTCCTTGGACTAT 58 349 Bsm AI M883I F: ACCCTGGTTCCAACCAGAAGAGGAT R: TTTAGAAAGGCAGGAGACATCG 58 125 EcoRV R1587K F: AGATTTATGACAGGACTGGACATCA R: CTGCCAACTTTACCATGAGTTG 55 129 Hpy188I NOTE. Mismatch nucleotides in primers are underlined. Login to comment
50 Significant associations between the K219R polymorphism and serum HDL-C or apoAI levels, and between the V771M polymorphism and apoAI levels, were observed in multiple linear regression analysis with sex, age, and BMI as covariates. Login to comment
54 *Statistical tests for TG levels were calculated on log-transformed values. Table 4. Relations Between Genotypes of Missense Polymorphisms and the Serum Levels of HDL-C, TG, and apoAI Genotype n HDL-C (mg/dL) P TG (mg/dL)* P apoAI (mg/dL) P K219R KK 97 56.9 Ϯ 11.3 .016 74.3 Ϯ 36.6 .43 136.0 Ϯ 18.8 .012 KR 160 52.2 Ϯ 10.3 77.2 Ϯ 32.3 128.7 Ϯ 17.3 RR 70 54.3 Ϯ 9.7 71.8 Ϯ 31.9 131.2 Ϯ 15.7 V771M VV 265 53.4 Ϯ 10.5 .13 74.4 Ϯ 32.3 .76 130.1 Ϯ 17.5 .035 VM 59 56.8 Ϯ 10.5 79.3 Ϯ 39.2 137.5 Ϯ 17.3 MM 3 57.7 Ϯ 18.2 71.0 Ϯ 14.0 133.3 Ϯ 23.5 V825I VV 134 53.2 Ϯ 10.9 .53 76.3 Ϯ 35.3 .77 130.7 Ϯ 18.3 .54 VI 156 54.9 Ϯ 10.3 74.8 Ϯ 31.6 132.5 Ϯ 17.2 II 37 53.8 Ϯ 11.2 73.1 Ϯ 35.4 129.5 Ϯ 17.4 M8831 MM 120 53.9 Ϯ 11.4 .73 75.3 Ϯ 35.1 .24 131.2 Ϯ 18.0 .90 MI 162 53.8 Ϯ 10.2 76.5 Ϯ 32.3 131.1 Ϯ 18.1 II 45 55.3 Ϯ 10.6 70.6 Ϯ 33.7 133.0 Ϯ 15.7 R1587K RR 114 54.5 Ϯ 10.7 .52 75.2 Ϯ 34.8 .063 131.7 Ϯ 16.9 .49 RK 154 54.0 Ϯ 10.3 78.1 Ϯ 34.3 131.9 Ϯ 17.5 KK 59 53.4 Ϯ 11.7 67.7 Ϯ 27.7 129.5 Ϯ 19.7 NOTE. Values are shown as mean Ϯ SD. P values were calculated by multiple linear regression analyses incorporating sex, age, and BMI as covariates. Login to comment
64 We analyzed the relationships between five SNPs and 2 insertion/deletion polymorphisms in the 5Ј flanking region and 5 missense polymorphisms of the ABCA1 gene and serum lipid levels in healthy school-aged Japanese children. We detected significant associations between the K219R and V771M polymorphisms, and HDL-C or apoAI levels. Login to comment
51 Significant associations between the K219R polymorphism and serum HDL-C or apoAI levels, and between the V771M polymorphism and apoAI levels, were observed in multiple linear regression analysis with sex, age, and BMI as covariates. Login to comment
55 *Statistical tests for TG levels were calculated on log-transformed values. Table 4. Relations Between Genotypes of Missense Polymorphisms and the Serum Levels of HDL-C, TG, and apoAI Genotype n HDL-C (mg/dL) P TG (mg/dL)* P apoAI (mg/dL) P K219R KK 97 56.9 afe; 11.3 .016 74.3 afe; 36.6 .43 136.0 afe; 18.8 .012 KR 160 52.2 afe; 10.3 77.2 afe; 32.3 128.7 afe; 17.3 RR 70 54.3 afe; 9.7 71.8 afe; 31.9 131.2 afe; 15.7 V771M VV 265 53.4 afe; 10.5 .13 74.4 afe; 32.3 .76 130.1 afe; 17.5 .035 VM 59 56.8 afe; 10.5 79.3 afe; 39.2 137.5 afe; 17.3 MM 3 57.7 afe; 18.2 71.0 afe; 14.0 133.3 afe; 23.5 V825I VV 134 53.2 afe; 10.9 .53 76.3 afe; 35.3 .77 130.7 afe; 18.3 .54 VI 156 54.9 afe; 10.3 74.8 afe; 31.6 132.5 afe; 17.2 II 37 53.8 afe; 11.2 73.1 afe; 35.4 129.5 afe; 17.4 M8831 MM 120 53.9 afe; 11.4 .73 75.3 afe; 35.1 .24 131.2 afe; 18.0 .90 MI 162 53.8 afe; 10.2 76.5 afe; 32.3 131.1 afe; 18.1 II 45 55.3 afe; 10.6 70.6 afe; 33.7 133.0 afe; 15.7 R1587K RR 114 54.5 afe; 10.7 .52 75.2 afe; 34.8 .063 131.7 afe; 16.9 .49 RK 154 54.0 afe; 10.3 78.1 afe; 34.3 131.9 afe; 17.5 KK 59 53.4 afe; 11.7 67.7 afe; 27.7 129.5 afe; 19.7 NOTE. Values are shown as mean afe; SD. P values were calculated by multiple linear regression analyses incorporating sex, age, and BMI as covariates. Login to comment
65 We analyzed the relationships between five SNPs and 2 insertion/deletion polymorphisms in the 5b18; flanking region and 5 missense polymorphisms of the ABCA1 gene and serum lipid levels in healthy school-aged Japanese children. We detected significant associations between the K219R and V771M polymorphisms, and HDL-C or apoAI levels. Login to comment

PMID: 12763760 [PubMed] Singaraja RR et al: "Efflux and atherosclerosis: the clinical and biochemical impact of variations in the ABCA1 gene."

No. Sentence Comment

136 Single Nucleotide Polymorphisms in the ABCA1 Gene Nucleotide Amino Acid Exon -1095A/G Promoter ⅐ ⅐ ⅐ -477C/T Promoter ⅐ ⅐ ⅐ -419A/C Promoter ⅐ ⅐ ⅐ -320G/C Promoter ⅐ ⅐ ⅐ -191G/C Promoter ⅐ ⅐ ⅐ C69T 5ЈUTR 1 C117G 5ЈUTR 1 InsG319 5ЈUTR 2 G378C 5ЈUTR 2 G1051A R219K 7 T1591C V399A 11 G2706A V771M 16 A2715C T774P 16 G2723C K776N 16 G2826A V825I 17 A3044G I883M 18 G3911C E1172D 24 G5255A R1587K 35 C5587G S1731C 38 markers, namely, increased arterial wall thickness and ABCA1-mediated cholesterol efflux, was performed.73 The study group consisted of 30 individuals heterozygous for 4 different missense mutations in the ABCA1 gene, C1477R, M1091T, P2150L, and T929I. Login to comment
147 The R219K, V771M, and I883M variants have been recognized as putative antiatherogenic polymorphisms, associated with increased HDL-C and decreased triglyceride levels (K219 and M883) and increased HDL-C and ApoA-I (M771).41,75,82 The E1172D, R1587K cSNPs have been reported to be associated with decreased HDL-C.75 Five promoter SNPs are associated with increased severity of atherosclerosis, including the -191C/-320C/-477T hap- lotype76,78 as well as the G-191C and A-1096G SNPs. Login to comment
148 In TABLE 4. Conservation of Amino Acids Polymorphic in Humans cSNP H. sapiens M. musculus G. gallus D. melanogaster C. elegans R219K R R K ⅐ ⅐ ⅐ L V399A V V V A I V771M V V V L Y T774P T S S S G K776N K K K K R V825I V V A M L I883M I V P R A E1172D E E E ⅐ ⅐ ⅐ ⅐ ⅐ ⅐ R1587K R K K E V S1731C S S S T H Five of 10 (50%) amino acids at which cSNPs occur are conserved with G. gallus, indicating a relatively less crucial functional role of these residues compared with those at which mutations occur (Figure 2). Login to comment
160 Clee et al75 reported significant LD between the R219K and the V771M, K776N, I883M, and R1587K cSNPs but found that after carriers of these variants were excluded, R219K remained significantly associated with degree of atherosclerosis and triglyceride levels. Login to comment
162 Functional Effects of cSNPs and Regulatory SNPs in the ABCA1 Gene Nucleotide Amino Acid/Position Lipids CAD/Atherosclerosis Antiatherogenic SNPs C-17G Promoter No change 2 InsG319 5ЈUTR No change 2 G1051A R219K 2 TG, 1 HDL, 1 ApoA-1, 1 ApoB, 1 LDL 2 A3044G I883M 2 TG, 1 HDL 1 Proatherogenic SNPs -191C/-320C/-477T haplotype Promoter No change 1 G-191C Promoter No change 1 A-1095G Promoter No change 1 C117G 5ЈUTR 1 TG No change G2706A V771M No change 1 G2868A V825I No change 1 G3911C E1172D 2 HDL, 2 ApoB 1 G5155A R1587K 2 HDL No change Associations with lipid levels and CAD are shown by arrows to represent the direction of association. Login to comment
171 The noncoding SNPs G-191C, C-69T, C-17G, and InsG319 and the cSNPs R219K, V771M, and V825I have all been found to be associated with differences in severity of atherosclerosis but not with changes in HDL-C levels in at least 1 study. Login to comment
128 Single Nucleotide Polymorphisms in the ABCA1 Gene Nucleotide Amino Acid Exon afa;1095A/G Promoter ዼ ዼ ዼ afa;477C/T Promoter ዼ ዼ ዼ afa;419A/C Promoter ዼ ዼ ዼ afa;320G/C Promoter ዼ ዼ ዼ afa;191G/C Promoter ዼ ዼ ዼ C69T 5b18;UTR 1 C117G 5b18;UTR 1 InsG319 5b18;UTR 2 G378C 5b18;UTR 2 G1051A R219K 7 T1591C V399A 11 G2706A V771M 16 A2715C T774P 16 G2723C K776N 16 G2826A V825I 17 A3044G I883M 18 G3911C E1172D 24 G5255A R1587K 35 C5587G S1731C 38 Singaraja et al Clinical and Biochemical Impact of ABCA1 Variants markers, namely, increased arterial wall thickness and ABCA1-mediated cholesterol efflux, was performed.73 The study group consisted of 30 individuals heterozygous for 4 different missense mutations in the ABCA1 gene, C1477R, M1091T, P2150L, and T929I. Login to comment
139 The R219K, V771M, and I883M variants have been recognized as putative antiatherogenic polymorphisms, associated with increased HDL-C and decreased triglyceride levels (K219 and M883) and increased HDL-C and ApoA-I (M771).41,75,82 The E1172D, R1587K cSNPs have been reported to be associated with decreased HDL-C.75 Five promoter SNPs are associated with increased severity of atherosclerosis, including the afa;191C/afa;320C/afa;477T hap- lotype76,78 as well as the G-191C and A-1096G SNPs. Login to comment
140 In TABLE 4. Conservation of Amino Acids Polymorphic in Humans cSNP H. sapiens M. musculus G. gallus D. melanogaster C. elegans R219K R R K ዼ ዼ ዼ L V399A V V V A I V771M V V V L Y T774P T S S S G K776N K K K K R V825I V V A M L I883M I V P R A E1172D E E E ዼ ዼ ዼ ዼ ዼ ዼ R1587K R K K E V S1731C S S S T H Five of 10 (50%) amino acids at which cSNPs occur are conserved with G. gallus, indicating a relatively less crucial functional role of these residues compared with those at which mutations occur (Figure 2). Login to comment
152 Clee et al75 reported significant LD between the R219K and the V771M, K776N, I883M, and R1587K cSNPs but found that after carriers of these variants were excluded, R219K remained significantly associated with degree of atherosclerosis and triglyceride levels. Login to comment
154 Functional Effects of cSNPs and Regulatory SNPs in the ABCA1 Gene Nucleotide Amino Acid/Position Lipids CAD/Atherosclerosis Antiatherogenic SNPs C-17G Promoter No change 2 InsG319 5b18;UTR No change 2 G1051A R219K 2 TG, 1 HDL, 1 ApoA-1, 1 ApoB, 1 LDL 2 A3044G I883M 2 TG, 1 HDL 1 Proatherogenic SNPs afa;191C/afa;320C/afa;477T haplotype Promoter No change 1 G-191C Promoter No change 1 A-1095G Promoter No change 1 C117G 5b18;UTR 1 TG No change G2706A V771M No change 1 G2868A V825I No change 1 G3911C E1172D 2 HDL, 2 ApoB 1 G5155A R1587K 2 HDL No change Associations with lipid levels and CAD are shown by arrows to represent the direction of association. Login to comment
163 The noncoding SNPs G-191C, C-69T, C-17G, and InsG319 and the cSNPs R219K, V771M, and V825I have all been found to be associated with differences in severity of atherosclerosis but not with changes in HDL-C levels in at least 1 study. Login to comment

PMID: 12840658 [PubMed] Miller M et al: "Genetics of HDL regulation in humans."

No. Sentence Comment

66 TD 1591 T/C 11 V399A extracellular [68] TD 1979 (110bpAlu Ins) 12 truncated truncation [60] TD/FHA 2154 C/T 14 R587W extracellular [67,69] TD 2164 G/C 14 W590S extracellular [61] TD 2185 A/G 14 Q597R extracellular [59,67] TD 2219 G/del 14 truncated, 635X truncated [60,61] FHA 2472-2474 3bp del 15 Del L693 TM domain #3 [59] phosphorylation 2706 G/A 16 V771M extracellular [68] 2715 A/C 16 T774P extracellular [68] 2723 G/C 16 K776N extracellular [68] 2868 G/A 17 V825I TM domain #6 [67,68] TD/FHA 3044 A/G 18 I883M cytoplasmic [68] phosphorylat site FHA 3120 C/T 19 R909X truncation [63,71] TD 3181 C/T 19 T929I cytoplasmic [62] TD 3199 A/G 19 N935S Walker A [61] TD 3205 C/T 19 A937V Walker A [61] TD 3532 C/A 22 A1046D cytoplasmic, Walker A/B [70] FHA 3667 T/C 23 M1091T cytoplasmic [63] 3690 G/T 23 D1099Y cytoplasmic [9] TD 3738 2bp del 23 1145X truncation [66] FHA 3911 G/C 24 E1172D linker/cytoplasmic [68] FHA 4242 4bp del 27 1297X truncated [64] TD 4260 G/A 27 D1289N linker cytoplasm [64,65] TD 4824 T/C 31 C1477R extracellular [59] TD 4912 C/T 32 S1506L extracellular loop #2 [71] TD 5025 ins A 34 A1544S?1552X truncation [70] 5059 T/C 34 I1555T extracellular loop #2 [67] 5155 G/A 35 R1587K extracellular loop #2 [68] FHA 5226 A/G 36 N1611D extracellular loop #2 [75..] 5338 T/C 36 L1648P extracellular loop #2 [67] TD 5443 C/T 37 R1680W cytoplasmic [74.] Login to comment

PMID: 12700893 [PubMed] Evans D et al: "The association of the R219K polymorphism in the ATP-binding cassette transporter 1 ( ABCA1) gene with coronary heart disease and hyperlipidaemia."

No. Sentence Comment

87 Clee et al. [15] found that the R219K polymorphism was in linkage disequilibrium with two less frequent variants, V771M and K776N; however, excluding patients who were also carriers of these polymorphisms did not alter the results they obtained for the R219K polymorphism. Login to comment

PMID: 11238261 [PubMed] Clee SM et al: "Common genetic variation in ABCA1 is associated with altered lipoprotein levels and a modified risk for coronary artery disease."

No. Sentence Comment

44 To screen the V399A, V771M, T774P, I883M, and E1172D cSNPs, TaqMan-based assays12 were developed. Login to comment
48 Methods for Restriction Fragment Length Polymorphism Screening of ABCA1 cSNPs Variant pmol of Each Oligo Forward Oligo (5Ј33Ј)* Reverse Oligo (5Ј33Ј)* Annealing Temperature, °C Enzyme Product, bp Wild-type Allele Variant Allele % Agarose Gel for Resolution G1051A 20 GTATTTTTGCAAGGCTACCAGTTACATTTGACAA 60 EcoN I 177 1.5 (R219K) GATTGGCTTCAGGATGTCCATGTTGGAA 107, 70 T1591C 27.5 GCTGCTGTGATGGGGTATCT 57 Hph I 117, 103, 48, 33 1.5 (V399A) ACCTCACTCACACCTGGGAA 220, 48, 33 G2706A 27.5 CAAGTGAGTGCTTGGGATTG 57 BsaA I 98, 252 2 (V771M) TGCTTTTATTCAGGGACTCCA 350 A2715C 27.5 GTGATCCCAGCGTGGTGTTTGTCTT 55 Hph I 56, 69, 95 2 (T774P) GAAAGGCCAGAGGTACTCACAGCGAAGATCTTGAGGG 56, 161 G2723C 12 TCGTTTTATTCAGGGACTCCA 55 Bgl II 269, 80 2 (K776N) CAAGTGAGTGCTTGGGATTG 349 G2868A 27.5 CCCATGCACTGCAGAGATTC 57 Bsa I 149, 237 2 (V825I) GCAAATTCAAATTTCTCCAGG 386 A3044G 27.5 GAGAAGAGCCACCCTGGTTCCAACCAGAAGAGGAT 55 EcoR V 94, 35 2.5 (I883M) AAGGCAGGAGACATCGCTT 129 G3911C 27.5 GAGCAGTTCTGATGCTGGCCTGGGCAGCGACCACGA 55 BssS I 104, 37 2 (E1172D) TCTGCACCTCTCCTCCTCTG 141 G5155A 27.5 CAGCTTGGGAAGATTTATGACAGGACTGGACACGA 55 BssS I 114, 31 2 (R1587K) ATGCCCCTGCCAACTTAC 145 C5587G 20 GTGCAATTACGTTGTCCCTGCCACACT 60 Mnl I 82, 35 3 (S1731C) CCATACAGCAAAAGTAGAAGGGCTAGCACA 117 *Bold indicates mismatch in oligo to create restriction site. Login to comment
85 Frequencies of ABCA1 cSNPs Nucleotide Change Amino Acid Change Exon REGRESS Carrier Frequency Allele Frequency n* Nonsynonymous G1051A R219K 7 46.3 0.254 1588 T1591C V399A 11 1.6 0.008 1098 G2706A V771M 16 5.8 0.029 1270 A2715C T774P 16 0.6 0.003 1250 G2723C K776N 16 0.5 0.003 1106 G2868A V825I 17 15.7 0.081 1364 A3044G I883M 18 23.8 0.136 840 G3911C E1172D 24 5.3 0.026 1288 G5155A R1587K 35 44.3 0.259 1566 C5587G† S1731C 38 0 0 558 Synonymous From sequencing G869A None 6 62.5 0.38 32 C1331T None 9 31.3 0.19 32 G1343A None 9 25 0.133 32 T3554G None 22 12.5 0.059 32 G4676A None 30 6.3 0.06 32 C6842T None 49 6.3 0.033 32 *Number of alleles screened. Login to comment
134 Carriers of the V771M (nϭ37 VM) had decreased focal atherosclerosis (MOD) compared with noncarriers (Table 6) and a trend toward less diffuse atherosclerosis (increased MSD). Login to comment
135 Carriers of V771M had no difference in lipid levels compared with noncarriers. Login to comment
136 However, all but 2 carriers of V771M were also carriers of R219K. Login to comment
140 The presence of this variant in individuals heterozygous for the R2144X ABCA1 mutation was associated with further significantly decreased HDL-C compared with R2144X carriers without this polymorphism (0.16Ϯ0.04 mmol/L, nϭ2, versus 0.64Ϯ0.14 mmol/L, nϭ10; Pϭ0.0009). Login to comment
144 Two rare cSNPs (V771M and K776N) are most commonly found in individuals carrying the R219K K allele. Login to comment
145 If all V771M and K776N carriers are excluded, the results are unaltered, with increased MOD (1.80Ϯ0.35 versus 1.73Ϯ0.35 mm, Pϭ0.006) and MSD (2.76Ϯ0.36 versus 2.70Ϯ0.37 mm, Pϭ0.02) and lower mean TG levels (1.71Ϯ0.75 versus 1.84Ϯ0.77 mmol/L, Pϭ0.02) in carriers of R219K (nϭ329) compared with noncarriers (nϭ422). Login to comment
156 No significant differences in lipid levels or CAD were observed for E1172D carriers compared with R1587K heterozygotes without E1172D. Login to comment
161 ABCA cSNPs in REGRESS MOD, mm MSD, mm HDL-C, mmol/L TG, mmol/L Carrier Noncarrier P Carrier Noncarrier P Carrier Noncarrier P Carrier Noncarrier P V825I 1.74Ϯ0.37 (107) 1.77Ϯ0.35 (575) 0.39 2.70Ϯ0.38 2.75Ϯ0.38 0.21 0.91Ϯ0.23 0.93Ϯ0.22 0.42 1.86Ϯ0.84 1.80Ϯ0.76 0.49 I883M 1.74Ϯ0.38 (100) 1.75Ϯ0.36 (320) 0.71 2.69Ϯ0.38 2.73Ϯ0.36 0.41 0.91Ϯ0.22 0.91Ϯ0.21 0.97 1.75Ϯ0.77 1.82Ϯ0.75 0.42 R1587K 1.77Ϯ0.34 (346) 1.76Ϯ0.37 (433) 0.75 2.73Ϯ0.39 2.74Ϯ0.36 0.64 0.90Ϯ0.22 0.94Ϯ0.23 0.03 1.79Ϯ0.76 1.81Ϯ0.78 0.77 V399A 1.92Ϯ0.32 (9) 1.73Ϯ0.35 (540) 0.13 2.73Ϯ0.40 2.71Ϯ0.37 0.89 1.03Ϯ0.28 0.92Ϯ0.23 0.15 1.71Ϯ0.63 1.82Ϯ0.78 0.68 V771M 1.89Ϯ0.38 (37) 1.76Ϯ0.35 (598) 0.045 2.83Ϯ0.49 2.73Ϯ0.37 0.13 0.91Ϯ0.20 0.92Ϯ0.22 0.58 1.98Ϯ0.79 1.78Ϯ0.76 0.11 T774P 1.63Ϯ0.31 (4) 1.76Ϯ0.36 (621) 0.47 2.85Ϯ0.34 2.73Ϯ0.37 0.52 0.85Ϯ0.07 0.93Ϯ0.22 0.50 1.90Ϯ1.04 1.82Ϯ0.77 0.84 K776N 1.92Ϯ0.33 (3) 1.78Ϯ0.34 (546) 0.48 2.95Ϯ0.48 2.76Ϯ0.37 0.36 0.94Ϯ0.28 0.93Ϯ0.22 0.93 2.25Ϯ0.94 1.76Ϯ0.76 0.26 E117SD 1.80Ϯ0.39 (34) 1.77Ϯ0.36 (610) 0.67 2.78Ϯ0.35 2.74Ϯ0.37 0.42 0.93Ϯ0.23 0.94Ϯ0.23 0.89 1.80Ϯ0.90 1.77Ϯ0.76 0.80 Values are meanϮSD (n). Login to comment
166 The phenotypic effects of the remaining cSNPs are less striking than those of R219K. Login to comment
171 The lack of obvious differences in HDL-C in carriers of different cSNPs (R219K, V771M, and I883M), together with clear differences in CAD, suggests that stimulating the RCT pathway can increase the net flux of cholesterol toward the liver without altering steady-state plasma HDL-C levels. Login to comment
186 Furthermore, we show that I883M is a common variant that is possibly associated with an increased risk of CAD in the homozygous state, although no differences in HDL-C were evident. Login to comment
191 Similarly, the region containing the V771M, T774P, and K776N variants is unlikely to be critical to ABCA1 function, because a high degree of polymorphism is tolerated without functional effects. Login to comment
39 To screen the V399A, V771M, T774P, I883M, and E1172D cSNPs, TaqMan-based assays12 were developed. Login to comment
43 Methods for Restriction Fragment Length Polymorphism Screening of ABCA1 cSNPs Variant pmol of Each Oligo Forward Oligo (5b18;33b18;)* Reverse Oligo (5b18;33b18;)* Annealing Temperature, &#b0;C Enzyme Product, bp Wild-type Allele Variant Allele % Agarose Gel for Resolution G1051A 20 GTATTTTTGCAAGGCTACCAGTTACATTTGACAA 60 EcoN I 177 1.5 (R219K) GATTGGCTTCAGGATGTCCATGTTGGAA 107, 70 T1591C 27.5 GCTGCTGTGATGGGGTATCT 57 Hph I 117, 103, 48, 33 1.5 (V399A) ACCTCACTCACACCTGGGAA 220, 48, 33 G2706A 27.5 CAAGTGAGTGCTTGGGATTG 57 BsaA I 98, 252 2 (V771M) TGCTTTTATTCAGGGACTCCA 350 A2715C 27.5 GTGATCCCAGCGTGGTGTTTGTCTT 55 Hph I 56, 69, 95 2 (T774P) GAAAGGCCAGAGGTACTCACAGCGAAGATCTTGAGGG 56, 161 G2723C 12 TCGTTTTATTCAGGGACTCCA 55 Bgl II 269, 80 2 (K776N) CAAGTGAGTGCTTGGGATTG 349 G2868A 27.5 CCCATGCACTGCAGAGATTC 57 Bsa I 149, 237 2 (V825I) GCAAATTCAAATTTCTCCAGG 386 A3044G 27.5 GAGAAGAGCCACCCTGGTTCCAACCAGAAGAGGAT 55 EcoR V 94, 35 2.5 (I883M) AAGGCAGGAGACATCGCTT 129 G3911C 27.5 GAGCAGTTCTGATGCTGGCCTGGGCAGCGACCACGA 55 BssS I 104, 37 2 (E1172D) TCTGCACCTCTCCTCCTCTG 141 G5155A 27.5 CAGCTTGGGAAGATTTATGACAGGACTGGACACGA 55 BssS I 114, 31 2 (R1587K) ATGCCCCTGCCAACTTAC 145 C5587G 20 GTGCAATTACGTTGTCCCTGCCACACT 60 Mnl I 82, 35 3 (S1731C) CCATACAGCAAAAGTAGAAGGGCTAGCACA 117 *Bold indicates mismatch in oligo to create restriction site. Login to comment
80 Frequencies of ABCA1 cSNPs Nucleotide Change Amino Acid Change Exon REGRESS Carrier Frequency Allele Frequency n* Nonsynonymous G1051A R219K 7 46.3 0.254 1588 T1591C V399A 11 1.6 0.008 1098 G2706A V771M 16 5.8 0.029 1270 A2715C T774P 16 0.6 0.003 1250 G2723C K776N 16 0.5 0.003 1106 G2868A V825I 17 15.7 0.081 1364 A3044G I883M 18 23.8 0.136 840 G3911C E1172D 24 5.3 0.026 1288 G5155A R1587K 35 44.3 0.259 1566 C5587Gߤ S1731C 38 0 0 558 Synonymous From sequencing G869A None 6 62.5 0.38 32 C1331T None 9 31.3 0.19 32 G1343A None 9 25 0.133 32 T3554G None 22 12.5 0.059 32 G4676A None 30 6.3 0.06 32 C6842T None 49 6.3 0.033 32 *Number of alleles screened. Login to comment
129 Carriers of the V771M (nafd;37 VM) had decreased focal atherosclerosis (MOD) compared with noncarriers (Table 6) and a trend toward less diffuse atherosclerosis (increased MSD). Login to comment
130 Carriers of V771M had no difference in lipid levels compared with noncarriers. Login to comment
131 However, all but 2 carriers of V771M were also carriers of R219K. Login to comment
139 Two rare cSNPs (V771M and K776N) are most commonly found in individuals carrying the R219K K allele. Login to comment

PMID: 19341173 [PubMed] Ksiazek J et al: "Is dyslipidemia sustained during remission of nephrotic syndrome genetically determined? Evaluation of genetic polymorphisms of proteins involved in lipoprotein metabolism in children and adolescents with nephrotic syndrome."

No. Sentence Comment

8 We evalauated associations between lipid profile and genetic polymorphisms, V771M, V825I, and R1587K of the gene encoding the cassette ABCA1 (adenosine triphosphate binding cassette transporter A1) protein synthesis, a b5;3 polymorphism of the gene encoding the type b5; of apolipoprotein E (apoE) synthesis and that of the gene encoding the cholesterol ester transfer protein (CETP) synthesis. Login to comment
10 V771M polymorphism was found only in 2 (4%) patients and one subject had abnormal lipid profile. Login to comment
36 Some investigators have suggestߛ ed higher incidence of specific genotypes in paߛ tients with nephritic syndrome and endߛstage Table 1ߓ Characteristics of patients Patients Total Males Females Steroidߛresistant Number (n) % ߗ 50 100 35 70 15 30 12 24 Mean age (years) SD ߗ 10.45 ߗߗ 3.04 10.5 ߗ 3.13 10.35 ߗ 2.82 Duration of treatment (years) SD ߗߗ 7.09 ߗߗ 2.88 ߗ 6.88 ߗ 3.14 ߗ 7.55 ߗ 2.19 Histological diagnosis MCNS ߗ 21 14 ߗ 7 ߗ 1 MPGN ߗ 26 19 ߗ 7 ߗ 9 FSGS ߗߗ 3 ߗ 1 ߗ 2 ߗ 2 Abbreviations: FSGS - focal segmental glomerulosclerosis, MCNS - minimal change nephrotic syndrome, MPGN - mesangial proliferative glomerulonephritis, SD - standard deviation of the ABCA1 gene (V771M, V825I and R1587K), a polymorphism of the CETP gene and polymorߛ phisms of the apoE gene. Login to comment
39 Three single nuߛ cleotide variants of guanine (G) > adenine (A) transition of the ABCA1 gene such as V771M, V825I i R1587K that determine the HDLߛC plasma level were genotyped by the selfߛdevelߛ oped method, using the restriction enzyme Tail for determining polymorphism V771M, the reߛ striction enzyme MboI for polymorphism V825I and the restriction enzyme Bgl II for R1587K polymorphism. Login to comment
56 The results were assessed in comparison with normal reference values coming from the evaluߛ ation of the healthy Warszawa population aged between 6 and 20, published previously by inߛ vestigators from the Children`s Memorial Health Institute.14 In all subjects the following genetic polyߛ morphisms were evaluated: - three nonߛsynonߛ ymous single nucleotide polymorphisms variants Table 2ߓ Median values of lipid profile parameters in patients with dyslipidemia (nߙ=ߙ37) and normolipidemia (nߙ=ߙ13) during remission of nephrotic syndrome Parameter mg/dl nߙ=ߙ13 nߙ=ߙ37 pa TC (mg/dl) 175.8 232 <0.0001 HDLߛC (mg/dl) ߗ 55 ߗ 49 NS LDLߛC (mg/dl) 100.66 163.29 <0.0001 VLDLߛC (mg/dl) ߗ 14.2308 ߗ 21.6 0.0015 TG (mg/dl) ߗ 77.2222 156.25 0.00007 ApoB (g/dl) ߗߗ 0.8067 ߗߗ 1.22 0.000004 ApoA1 (g/dl) ߗߗ 1.52 ߗߗ 1.51 NS OxyߛLDL (mU/ml) 278.28 504.9 0.0022 GPX (u/gHb) ߗ 32.30 ߗ 30.71 0.0016 Lp(a) (mg/dl) ߗ 10.20 ߗ 15.62 0.0184 Albumin (g/l) ߗ 40.73 ߗ 37.52 0.0014 aߓ MannߛWhitney`s test Abbreviations: apoA1 - apolipoprotein A1, apoB - apolipoprotein B, GPX - glutathione peroxidase, HDLߛC - highߛdensity lipoprotein cholesterol, LDLߛC - lowߛdensity lipoprotein cholesterol, Lp (a) - lipoprotein (a), NS - not significant, oxyߛLDLߛC - oxidized LDLߛcholesterol, TC - total cholesterol, TG - triglycerides, VLDLߛC - very lowߛdensity lipoprotein cholesterol Table 3ߓ Number of patients with ABCA1 genetic polymorphisms Patients Polymorphic variants V771M V825I R1587K V825 Iߙ+ߙR1587K GA GA AA GA AA GAߛGA GAߛAA s - d. ns nߙ=ߙ38 2 ߗ 9 1 11 2 5 1 s - r. ns nߙ=ߙ12 - ߗ 3 - ߗ 6 2 2 1 Overall nߙ=ߙ50 2 (4%) 13 (26%) 21 (42%) 9 (18%) Abbreviations: AA, GA, GG - variants of polymorphism of ABCA1 gene, sߛd ns - steroidߛdependent nephrotic syndrome, sߛr ns - steroidߛresistant nephrotic syndrome, in TABLE 3. Login to comment
57 The V771M of ABCA1 gene polymorߛ phism of GA variant was confirmed in 2 (4%) paߛ tients. Login to comment
81 The number and distribution of specific gene polymorphisms of ABCA1 are presented Table 4ߓ Distribution of significant (compared to reference data) lipid abnormalities in subgroups of patients divided with regard to ABCA1 genetic polymorphisms Polymorphism Disturbances V771M nߙ=ߙ2 (4%) V825I nߙ=ߙ13 (26%) R1587K nߙ=ߙ21 (42%) V8251ߙ+ߙR1587K nߙ=ߙ9 (18%) GA nߙ=ߙ2 AA GA nߙ=ߙ12 AA nߙ=ߙ1 GA nߙ=ߙ17 AA nߙ=ߙ4 GAߛGA nߙ=ߙ7 GAߛAA nߙ=ߙ2 ࢏ TC - - 1 - 2 - 1 - ࢏ TCߙ+ߙ࢏ TG 1 - 2 - 3 1 2 2 ࢏TCߙ+ߙ࢏ TGߙ+ߙ࢑ HDLߛC - - 2 - 4 1 1 - ࢏TCߙ+ߙ࢑ HDLߛC - - 1 - - 1 - - ࢏ TGߙ+ߙ࢑ HDLߛC - - 1 - 1 1 - ߙ+ߙ࢑ HDLߛC - - 2 1 2 1 1 - Overall 1 50% - 10 76.9% 16 76.2% 7 77.8% No disturbances 1 50% - 3 23.1% 5 33.8% 2 22.2% Abbreviations: AA, GA, GG - variants of polymorphism of ABCA1 gene, HDLߛC - fraction HDL of cholesterol, TC - total cholesterol, ߓ TG - triglycerides, V771M, V825I, R587K - nonߛsynonymous single nucleotide polymorphisms of ABCA1 cassette gene Table 5ߓ Distribution of significant (compared to reference data) lipid abnormalities in subgroups of patients divided with regard to CETP gene polymorphisms Polymorphism Disturbances GA variant nߙ=ߙ25 (50%) AA variant nߙ=ߙ6 (12%) ࢏ TCߙ+ߙTG 3 2 ࢏TCߙ+ߙTGߙ+ߙ࢑ HDLߛC 3 2 ࢏ TGߙ+ߙ࢑ HDLߛC 1 - ࢏ TCߙ+ߙ࢑ HDLߛC 1 - ࢏ TC 4 1 - ࢑ HDLߛC 4 1 Overall 22/31 71% No lipid disturbances 9/31 29% Abbreviations: AA, GA, GG - variants of polymorphism of the gene, HDLߛC - fraction HDL of cholesterol, TC - total cholesterol, TG - triglycerides was a nonߛsignificant trend (pߙ=ߙ0.067) in terms of association between the triglyceride level and R1587K genotype. Login to comment
100 There Table 6ߓ Distribution of significant (compared to reference data) lipid abnormalities in subgroups of patients divided with regard to apoE gene polymorphisms Lipid disturbances ApoE subtype b5;3b5;3 nߙ=ߙ35 (70%) b5;3b5;4 nߙ=ߙ6 b5;2b5;3 nߙ=ߙ5 b5;2b5;4 nߙ=ߙ1 b5;4b5;4 nߙ=ߙ2 b5;2b5;2 nߙ=ߙ1 ࢏TCߙ+ߙ࢏TGߙ+ߙ࢑ HDLߛC ߗ 4 2 2 1 - - ࢏TGߙ+ߙ࢑HDLߛC ߗ 1 - - - 1 - ࢑ HDLߛC ߗ 5 1 1 - - 1 ࢏TC ߗ 7 1 - - - - ࢏TCߙ+ߙ࢏TG ߗ 7 1 - - - - ࢏TCߙ+ߙ࢑ HDLߛC ߗ 2 - - - - - Overall 26 (74.3%) 5 3 1 1 1 No disturbances ߗ 9 (25.7%) 1 2 - 1 - Abbreviations: apoE - apolipoprotein E, HDLߛC - fraction HDL of cholesterol, TC - total cholesterol, TG - triglycerides Table 7ߓ Distribution of lipid disturbances prevalence in children with and without specific genetic polymorphisms(summary) Polymorphism Number of patients (n) with polymorphisms and lipid abnormalities with no polymorphisms and lipid abnormalities V771M nߙ=ߙ2/50 1/2 (50%) 36/48 (76.6%) V825I nߙ=ߙ13/50 10/13 (76.9%) 27/37 (73%) R1587K nߙ=ߙ21/50 16/21 (76.2%) 21/29 (72.4%) CETP nߙ=ߙ31/50 22/31 (71%) 15/19 (78.9%) apo b5;3b5;3 nߙ=ߙ35/50 26/35 (74.35) - Other types apoE nߙ=ߙ15/50 12/15 (73.3%) - Abbreviations: apoE- polymorphism of apoE gene, CETP - polymorphism of CETP gene, 14ߓ Litwin M, a;ladowska J, Antoniewicz J, et al.: Metabolic abnormalities, insulin resistance and metabolic syndrome in children with primary hyperߛ tension. Login to comment

PMID: 23136402 [PubMed] Bochem AE et al: "ABCA1 mutation carriers with low high-density lipoprotein cholesterol are characterized by a larger atherosclerotic burden."

No. Sentence Comment

81 Efflux measured in fibroblasts from a heterozygous p.Cys1477Arg carrier was used as a positive control since the efflux capacity has consistently been shown to be impaired.19,27 One patient compound heterozygous for mutation p.Arg579Gln and p.Val771Met was included. Login to comment
82 In the view of contradictory statements on functionality of mutation p.Val771Met,31 we assumed that the major part of the efflux impairment of the p.Arg579Gln and p.Val771Met combination is attributable to p.Arg579Gln. Login to comment

PMID: 23555974 [PubMed] Song C et al: "Genetic variants from lipid-related pathways and risk for incident myocardial infarction."

No. Sentence Comment

225 Andrikovics H, Pongracz E, Kalina E, Szilvasi A, Aslanidis C, et al. (2006) Decreased frequencies of ABCA1 polymorphisms R219K and V771M in Hungarian patients with cerebrovascular and cardiovascular diseases. Login to comment

PMID: 24376512 [PubMed] Nakamura A et al: "Gene-gene combination effect and interactions among ABCA1, APOA1, SR-B1, and CETP polymorphisms for serum high-density lipoprotein-cholesterol in the Japanese population."

No. Sentence Comment

52 doi:10.1371/journal.pone.0082046.g001 polymorphisms (SNPs) that have been reported to be associated with HDL-C levels in previous studies [11-17]: ABCA1-565C.T (rs2422493), R1587K (rs2230808), -273G.C (rs1800976), V771M (rs2066718), -17C.G (rs2740483), and V825I (rs2066715); APOA1 A61T (rs12718465); LCAT (rs4986970); CETP Taq1B (rs708272), G/T (rs3764261), I405V (rs5882), and -629C.A (rs1800775); SR-B1 A.G (rs3782287), A350A (rs5888), and V135I (rs5891). Login to comment
146 Gene rs Number Alias Allele MAF ABCA1 rs2422493 2565C.T C.T 0.408 rs2230808 R1587K G.A 0.399 rs1800976 2273G.C G.C 0.409 rs2066718 V771M G.A 0.075 rs2740483 217C.G C.G 0.295 rs2066715 V825I G.A 0.361 APOA1 rs12718465 A61T C.T 0.068 CETP rs708272 Taq1B C.T 0.398 rs3764261 G/T G.T 0.272 rs5882 Ile405Val A.G 0.495 rs1800775 2629C.A A.C 0.445 SR-B1 rs3782287 A.G G.A 0.244 rs5888 A350A C.T 0.220 MAF, minor allele frequency. Login to comment

PMID: 24385509 [PubMed] Westerterp M et al: "ATP-binding cassette transporters, atherosclerosis, and inflammation."

No. Sentence Comment

59 In a Mendelian randomization approach in a prospective cohort comprising ࣈ9000 individuals, heterozygosity for the ABCA1 mutation K776N led to a 2-to-3 times higher risk of ischemic heart disease.105 Furthermore, 5 single-nucleotide polymorphisms (SNPs) inABCA1 (V771M,V825I, I883M, E1172D, R1587K) were shown to predict risk of ischemic heart disease in a cohort of 9259 individuals.106 However, the same group reported more recently that heterozygosity for 4 loss-of-function mutations (P1065S, G1216V, N1800H, R2144X) was not associated with a higher risk of ischemic heart disease in 3 prospective cohorts comprising 56ߙ886 individuals.107 It must be noted, however, that only small decreases in HDL, of ࣈ28% as opposed to ࣈ50% in previously reported ABCA1 heterozygotes, were observed.94,101-103,107 Also, the residual cholesterol efflux was substantial (74%-79% for P1065S and G1216V and 48%-49% for N1800H and R2144X for homozygous mutations compared with controls),107 whereas in patients with TD there was only 20% to 30% residual cholesterol efflux.108 In addition, LDL levels were reduced by ࣈ25%, probably offsetting the effects of reduced HDL on CVD.107 Thus, the conflicting results in these studies could be related to inclusion of relatively mild ABCA1 mutations as well as offsetting effects of reduced LDL cholesterol levels.109 In a meta-analysis of genome-wide association studies, SNPs near the ABCA1 gene have been associated with HDL and total cholesterol levels,110,111 but not with cardiovascular risk.112 Although these studies have the benefit of huge statistical power, some caution is merited in the interpretation of findings. Login to comment

PMID: 24466114 [PubMed] Yin YW et al: "Influence of ATP-binding cassette transporter 1 R219K and M883I polymorphisms on development of atherosclerosis: a meta-analysis of 58 studies."

No. Sentence Comment

28 Recently, a number of molecular epidemiological studies have been done to evaluate the associations between the ABCA1 gene polymorphisms (such as R219K, M883I, C69T, V825I, R1587K, V771M and 2565C/T) and the risk of atherosclerotic diseases [248]. Login to comment

PMID: 25286446 [PubMed] Kelishadi R et al: "Genetic association with low concentrations of high density lipoprotein-cholesterol in a pediatric population of the Middle East and North Africa: the CASPIAN-III study."

No. Sentence Comment

99 Gene name, polymorphism name and identification number (genotypes and frequencies), minor allele frequency HDL-C < 5th percentile (n &#bc; 250) HDL-C 5e95th percentile (n &#bc; 250) HDL-C > 95th percentile (n &#bc; 250) LPL D9N rs1801177 (AA/AG/GG) 226/24/0 231/19/0 250/0/0 MAF 0.048 0.038 0 LPL HindIII rs320 (GG/GT/TT) 145/102/3 117/120/13 4/121/125 MAF 0.216 0.292 0.742 LPL S447X rs328 (CC/CG/GG) 228/22/0 203/46/1 163/73/14 MAF 0.044 0.096 0.202 ABCAI V771M rs2066718 (GG/GA/AA) 249/1/0 237/13/0 234/16/0 MAF 0.002 0.026 0.032 ABCAI R1587K rs2230808 (AA/AG/GG) 106/106/38 141/93/16 194/56/0 MAF 0.364 0.250 0.112 CETP TaqIB rs708272 (CC/CT/TT) 181/67/2 63/147/40 34/162/54 MAF 0.142 0.454 0.540 CETP A373P rs5880 (CC/CG/GG) 188/58/4 217/33/0 247/3/0 MAF 0.132 0.066 0.006 APOC3 SstI rs5128 (CC/CG/GG) 208/40/2 209/39/2 211/39/0 MAF 0.088 0.086 0.078 APOA1 MspI rs2893157 (GG/GA/AA) 189/59/0 182/63/5 169/73/8 MAF 0.119 0.146 0.178 APOA5 C-1131T rs662799 (CC/CT/TT) 242/3/5 245/2/3 250/0/0 MAF 0.026 0.016 0 MAF, minor allele frequency; HDL-C, high density lipoprotein cholesterol; LPL, gene encoding lipoprotein lipase; ABCA1, gene encoding ATP binding cassette transporter A1; CETP, gene encoding cholesteryl ester transfer protein; APOC3 gene encoding apo C-III; APOA1, gene encoding apolipoprotein (apo) A-I; APOA5, gene encoding apo A-V. Login to comment
122 Another study found that the V771M SNP was associated with higher HDL levels in Turkmen [47]. Login to comment
125 A study among Japanese healthy children, documented significant associations of the ABCA1 K219R and V771M polymorphisms with HDL-C concentrations, and suggested that these alleles have antiatherogenic effects [49]. Login to comment
132 SNP (rs number) Unadjusted Adjusteda Or 95% CI for OR P-value Or 95% CI for OR P-value APOA1 Msp1 1.87 (1.55, 2.21) <0.0001 1.01 (0.67, 1.49) 0.98 ABCA1 r1587K 3.16 (2.54, 3.93) <0.0001 2.43 (1.68, 3.50) <0.0001 ABCA1 V771M 1.89 (1.62, 2.21) <0.0001 0.47 (0.19, 1.52) 0.09 CETP Taq1 0.54 (0.42, 0.67) <0.0001 0.08 (0.05, 0.13) <0.0001 CETP A373P 2.46 (2.08, 2.92) <0.0001 5.79 (3.40, 9.84) <0.0001 APOC3 Sst1 2.02 (1.71, 2.38) <0.0001 1.08 (0.68, 1.72) 0.73 HDL-C, high density lipoprotein cholesterol; SNP, single nucleotide polymorphism; OR, Odds ratio. Login to comment
135 HDL-C < 5th percentile HDL-C 5e95th percentile LPL D9N rs1801177 HDL-C 5e95th percentile NS (0.44) HDL-C>95th percentile <0.0001 <0.0001 LPL HindIII rs320 HDL-C 5e95th percentile 0.0058 HDL-C > 95th percentile <0.0001 <0.0001 LPL S447X rs328 HDL-C 5e95th percentile 0.0013 HDL-C > 95th percentile <0.0001 <0.0001 ABCAI V771M rs2066718 HDL-C 5e95th percentile 0.0012 HDL-C > 95th percentile 0.0002 NS (0.57) ABCAI R1587K rs2230808 HDL-C 5e95th percentile <0.0001 HDL-C > 95th percentile <0.0001 <0.0001 CETP TaqIB rs708272 HDL-C 5e95th percentile <0.0001 HDL-C > 95th percentile <0.0001 0.0065 CETP A373P rs5880 HDL-C 5e95th percentile 0.0005 HDL-C > 95th percentile <0.0001 <0.0001 APOC3 SstI rs5128 HDL-C 5e95th percentile NS (0.91) HDL-C > 95th percentile NS (0.57) NS (0.64) APOA1 MspI rs2893157 HDL-C 5e95th percentile NS (0.36) HDL-C > 95th percentile 0.022 NS (0.17) APOA5 C-1131T rs662799 HDL-C 5e95th percentile NS (0.27) HDL-C > 95th percentile 0.0003 0.0045 HDL-C, high density lipoprotein cholesterol; LPL, gene encoding lipoprotein lipase; ABCA1, gene encoding ATP binding cassette transporter A1; CETP, gene encoding cholesteryl ester transfer protein; APOC3 gene encoding apo C-III; APOA1, gene encoding apolipoprotein (apo) A-I; APOA5, gene encoding apo A-V; NS, not significant. Login to comment

PMID: 25527331 [PubMed] Yin YW et al: "ATP-binding cassette transporter 1 C69T and V825I polymorphisms in the development of atherosclerosis: a meta-analysis of 18,320 subjects."

No. Sentence Comment

122 So far, at least seven single-nucleotide polymorphisms at the ABCA1 gene promoter have been studied to investigate the associations between these variants and the susceptibility of atherosclerotic diseases, such as R219K, M883I, C69T, V825I, R1587K, V771M and -565C/T. Login to comment

PMID: 26243156 [PubMed] Fawzy MS et al: "Functional and Structural Impact of ATP-Binding Cassette Transporter A1 R219K and I883M Gene Polymorphisms in Obese Children and Adolescents."

No. Sentence Comment

220 Moreover, in the ABCA1 gene, a strong linkage disequilibrium exists between R219K/V771M and M825I/I883M (D0 [ 0.9) [21]. Login to comment
221 The two SNPs (V771M and M825I) were previously found to be associated with increased plasma HDL-c and cholesterol concentration, respectively, thus speculating the probability that R219K and I883M may not be the true associated variants, but could instead reflect the functional impact of other nearby linked gene polymorphisms. Login to comment