ABCMdb

PMID: 12709788

Tan JH, Low PS, Tan YS, Tong MC, Saha N, Yang H, Heng CK
ABCA1 gene polymorphisms and their associations with coronary artery disease and plasma lipids in males from three ethnic populations in Singapore.
Hum Genet. 2003 Jul;113(2):106-17. Epub 2003 Apr 23., [PubMed]

Sentences

No. Mutations Sentence Comment

6 ABCA1 p.Val825Ile While genotype-phenotype associations were not reproduced across populations and loci, V825I and M883I were clearly associated with CAD status in Malays with no effects on HDL-C or apoA1. Login to comment 17 ABCA1 p.Val825Ile The ABCA1 SNPs studied were: -14C>T, located in the proximal promoter (Pullinger et al. 2000; Zwarts et al. 2002); 237indelG, an insertion/deletion of one G nucleotide in the 5'-untranslated region (UTR) (Pullinger et al. 2000; Zwarts et al. 2002); the missense SNPs, V825I in exon 17 (GTC→ATC) and M883I (ATG→ATA) in exon 18, both located upstream of the first nucleotide binding domain (Wang et al. 2000; Clee et al. 2001; Brousseau et al. 2001); and 8994A>G, a novel 3'UTR SNP discovered in the course of this study. Login to comment 20 ABCA1 p.Val825Ile The data from Malays showed a strong association of V825I and M883I with the CAD phenotype, especially when the two SNPs were considered simultaneously, and the association was not accompanied by changes in plasma HDL-C or apoA1 levels in the controls. Login to comment 24 ABCA1 p.Val825Ile The five SNPs and their alleles in this study were: -14C>T, 237indelG (2g, 3g alleles), V825I (GTC→ATC), M883I (ATG→ATA) (Pullinger et al. 2000; Wang et al. 2000; Clee et al. 2001; Brousseau et al. 2001; Zwarts et al. 2002), and 8994A>G, for which an association study is reported here for the first time. Login to comment 44 ABCA1 p.Ile883Met ABCA1 p.Val825Ile SNPs -14C>T, 237indelG, V825I and I883M were genotyped by restriction fragment length polymorphism (RFLP) assays. Login to comment 78 ABCA1 p.Val825Ile In Chinese and Malays, 108 Table 1 Genotyping methods Location SNP Forward primer, PCR size Genotyping reverse primer (bp)c Proximal promoter -14C>T 5'-CGGCTCCACGTGCTTTC-3', 177 BsmA1 5'-CCACTCACTCTCGTCCGCAATTAC-3' 2.5% agarose gel C: 177 bp T: 25, 144 bp Exon 2a 237indelG 5'-GCTGGATTAGCAGTCCTCATTG-3', 301, 302 Bsl1 5'UTR (2g/3g) 5'-CCCCAACTCAAAACCACAAAG-3' 10% polyacrylamide gel 2g: 148, 153 bp 3g: 93, 56, 153 bp Exon 17 V825I 5'-GGTAGCCCACCACTCCCCTAAAG-3', 525 DpnII 5'-ATCAGCTGCCTGTCCTTGGACTA-3' 2.5% agarose gel G: 62, 423, 40 bp A: 62, 241, 182, 40 bp Exon 18b M883I 5'-ATGATGCTGAGCTTGGCTCATAC-3', 171 BsmI 5'-AGGTCAACAGCACTTACTTTCTGG-3' 3% agarose gel A: 171 bp G: 150, 21 bp Exon 50 3'UTR 8994A>G 5'-ATGAGAGAACTATTGTTTGGG-3', 109 SSCP 5'-CTGAAGTCTTACACCTTTAGCG-3' 20% polyacrylamide + 5% glycerol native gel. Login to comment 82 ABCA1 p.Val825Ile There were strong ethnic contrasts in allele frequencies at V825I and M883I (Table 3). Login to comment 87 ABCA1 p.Val825Ile ABCA1 p.Val825Ile 237indelG and V825I Comparisons of allele and genotype distributions at 237indelG and V825I loci did not indicate any association with CAD status in all three ethnic groups. Login to comment 104 ABCA1 p.Val825Ile ABCA1 p.Val825Ile Genomic distances separating the five SNPs are: -14C>T and 237indelG, 24 kb; 237indelG and V825I, 78 kb; V825I and M883I, 1.3 kb; and M883I and 8994A>G, 42 kb. Login to comment 105 ABCA1 p.Val825Ile With the exception of the pair V825I and M883I, the magnitude of LD was generally low (r2<0.06), although statistical significance was noted in some situations. Login to comment 106 ABCA1 p.Val825Ile ABCA1 p.Val825Ile Strong and statistical 110 Table 3 Genotype and allele frequency distributions of ABCA1 SNPs (n number of individuals, n.s. not significant) SNP Chinese males Malay males Indian males CAD Controls CAD Controls CAD Controls -14C>T CC 203 (41.4%) 90 (40.5%) 44 (40%) 52 (41.3%) 45 (28.3%) 78 (37%) CT 242 (49.4%) 107 (48.2%) 60 (54.5%) 68 (54%) 87 (54.7%) 117 (55.5%) TT 45 (9.2%) 25 (11.3%) 6 (5.5%) 6 (4.8%) 27 (17%) 16 (7.6%) n 490 222 110 126 159 211 HWE exact P 0.027 n.s. 0.003 0.001 n.s. 0.001 Frequency C 0.661 0.646 0.673 0.683 0.557* 0.647* 237indelG 2g2g 367 (71.1%) 181 (73%) 70 (61.9%) 126 (71.6%) 92 (57.5%) 115 (49.8%) 2g3g 133 (25.8%) 57 (23%) 40 (35.4%) 44 (25%) 51 (31.9%) 93 (40.3%) 3g3g 16 (3.1%) 10 (4%) 3 (2.7%) 6 (3.4%) 17 (10.6%) 23 (10%) n 516 248 113 176 160 231 HWE exact P n.s. n.s. n.s. n.s. n.s. n.s. Frequency 2g 0.840 0.845 0.796 0.841 0.734 0.699 V825I (GTC>ATC) GG 92 (31.3%) 34 (31.5%) 37 (48.1%) 62 (50.4%) 71 (85.5%) 97 (89%) GA 142 (48.3%) 58 (53.7%) 31 (40.3%) 52 (42.3%) 10 (12%) 12 (11%) AA 60 (20.4%) 16 (14.8%) 9 (11.7%) 9 (7.3%) 2 (2.4%) 0 (0%) n 294 108 77 123 83 109 HWE exact P n.s. n.s. n.s. n.s. n.s. n.s. Frequency G 0.554 0.583 0.682 0.715 0.916 0.945 M883I (ATG>ATA) GG 168 (46.2%) 97 (38.8%) 26 (26%) 22 (13.2%) 6 (3.9%) 3 (1.3%) GA 169 (46.4%) 134 (53.6%) 45 (45%) 87 (52.1%) 20 (13.2%) 34 (15.2%) AA 27 (7.4%) 19 (7.6%) 29 (29%) 58 (34.7%) 126 (82.9%) 186 (83.4%) n 364 250 100 167 152 223 HWE exact P n.s. 0.002 n.s. n.s. n.s. n.s. Frequency G 0.694 0.656 0.485* 0.392* 0.105 0.090 8994A>G AA 342 (66.4%) 193 (71%) 84 (75%) 130 (72.6%) 117 (70.5%) 162 (69.5%) AG 152 (29.5%) 75 (27.6%) 22 (19.6%) 39 (21.8%) 45 (27.1%) 66 (28.3%) GG 21 (4.1%) 4 (1.5%) 6 (5.4%) 10 (5.6%) 4 (2.4%) 5 (2.1%) n 515 272 112 179 166 233 HWE exact P n.s. n.s. n.s. n.s. n.s. n.s. Frequency A 0.812* 0.847* 0.848 0.835 0.840 0.837 *P<0.05, allele frequencies that are statistically different between cases and controls by Fisher`s exact test (one-sided) significant LD was detected between V825I and M883I in both Chinese and Indian case-control samples, as well as in Malay cases, but not in Malay controls (data not shown). Login to comment 118 ABCA1 p.Val825Ile All configurations that omitted both V825I and M883I, or included the former but not the latter, gave insignificant test results, whereas those that included both produced consistently significant outcomes. Login to comment 119 ABCA1 p.Val825Ile ABCA1 p.Val825Ile Furthermore there may be a stronger association with M883I compared with V825I because some haplotype configurations involving M883I, but not V825I, were sufficient to detect a positive association. Login to comment 120 ABCA1 p.Val825Ile ABCA1 p.Val825Ile Hence, based on the results of the haplotype analysis, both V825I and M883I were necessary to be strongly associated with the CAD phenotype in the Malay population, and studying the effect of either SNP alone, in particular V825I, might weaken the association. Login to comment 121 ABCA1 p.Val825Ile The reason is that V825I and M883I were not in perfect LD. Login to comment 127 ABCA1 p.Val825Ile In Malay cases, for all the eight locus combinations that involved both V825I and M883I, all of them tested positive for disequilibria, whereas in the corresponding controls, every locus combination remained in HWE (Table 6). Login to comment 133 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Val825Ile ABCA1 p.Val825Ile Notably, the seven significant disequilibria (out of a possible eight) in the Chinese CAD group involved both V825I and I883M; however, two of these disequilibria were also found in the Chinese control group and therefore it was hard to deduce the effects of V825I and I883M on the CAD status in Chinese. Login to comment 146 ABCA1 p.Val825Ile ABCA1 p.Val825Ile V825I Significant trends in lipids between V825I genotypes were not observed in any population. Login to comment 151 ABCA1 p.Val825Ile Codes for loci: 1 -14C>T, 2 237indelG, 3 V825I, 4 M883I, 5 8994A>G. Login to comment 160 ABCA1 p.Val825Ile The case-control analysis in the Malay population revealed that V825I and M883I are potential markers for the CAD phenotype, but this positive association was not accompanied by changes in plasma HDL-C or apoA1 concentrations in Malay controls. Login to comment 167 ABCA1 p.Val825Ile In our study, several lines of evidence implicate V825I and M883I in CAD susceptibility for the Malay population. Login to comment 169 ABCA1 p.Val825Ile ABCA1 p.Val825Ile However, the case-control analysis for V825I did not detect a significant difference, a result that could partly be explained by the smaller number of individuals genotyped for V825I, in which case there would be a higher chance of making a false negative inference or type II error. Login to comment 170 ABCA1 p.Val825Ile Also, the LD between V825I and M883I might have partially dissipated. Login to comment 171 ABCA1 p.Val825Ile ABCA1 p.Val825Ile While single-locus frequency comparison was ambiguous in assigning an effect to V825I, analyses using multiple SNPs clearly indicate that both V825I and M883I were associated with CAD status in Malays. Login to comment 173 ABCA1 p.Val825Ile Specifically, V825I and M883I were in strong LD in Malay cases but not in Malay controls. Login to comment 178 ABCA1 p.Val825Ile The association of both V825I and M883I in CAD susceptibility in Malays was revealed definitively in haplotype frequency and multi-locus disequilibria tests. Login to comment 180 ABCA1 p.Val825Ile ABCA1 p.Val825Ile Based on these observations, it seems that 8994A>G is inconsequential to the CAD phenotype, while the effects of -14C>T and 237indelG are inconclusive; but there is an obvious association of V825I and M883I with CAD status. Moreover, multi-locus HWE tests showed that any combinations that involved both V825I and M883I were always in disequilibria in Malay cases but not in the corresponding controls, thus reinforcing the haplotype association result. Login to comment 181 ABCA1 p.Val825Ile Since V825I and M883I code for missense SNPs and are sited near the critical nucleotide-binding domain of the ABCA1 protein, these allelic variants may potentially modulate the biological function of the transporter. Login to comment 186 ABCA1 p.Val825Ile In any case, it may be premature at this stage to do a functional analysis of V825I and M883I. Login to comment 189 ABCA1 p.Val825Ile Although the data in Malay case-control samples indicated a combined association of V825I and M883I with the CAD phenotype, genotypes of either SNP did not show changes in HDL-C or apoA1 in the controls. Login to comment 192 ABCA1 p.Val825Ile Genotypes of V825I showed no association with any lipids in the Malay controls. Login to comment 197 ABCA1 p.Val825Ile Existing literature on the associations of V825I and M883I with CAD agree with our findings in the Malay case-control study. Login to comment 199 ABCA1 p.Val825Ile Among male CAD participants in a Dutch cohort prospective study, obvious differences in CAD event rate were also detected for V825I or M883I, again without any change in HDL-C (Clee et al. 2001). Login to comment 221 ABCA1 p.Val825Ile In summary, our data showed a strong association of V825I and M883I with CAD susceptibility that was specific to the Malay population. Login to comment