ABCMdb

PMID: 18706283

Iatan I, Alrasadi K, Ruel I, Alwaili K, Genest J
Effect of ABCA1 mutations on risk for myocardial infarction.
Curr Atheroscler Rep. 2008 Oct;10(5):413-26., [PubMed]

Sentences

No. Mutations Sentence Comment

74 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val771Met ABCA1 p.Glu1172Asp 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 87 ABCA1 p.Asn1800His One mutation (ABCA1 N1800H) was found in both Canadian and Dallas low-HDL-C groups. Login to comment 109 ABCA1 p.Arg219Lys As previously described [30,33,34], of the 16 polymorphisms located in the promoter and the 10 found in the coding region, it was concluded that only the R219K polymorphism was associated with MI, decreasing its risk (odds ratio of 0.80; 95% CI, 0.68-0.94; P = 0.007), whereas no haplotypes were involved in the susceptibility to CHD. Login to comment 112 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp 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 113 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Glu1172Asp The principal finding of the study indicated that common genetic variation in ABCA1 predicts risk of CHD in the general population, but that their association was independent of plasma HDL-C levels: SNPs predicting increased MI risk were associated with either increases (V771 and V825I) or decreases (R1587K) in HDL-C, or no effect on HDL-C (R219K, I883M, E1172D). Login to comment 115 ABCA1 p.Ile883Met ABCA1 p.Val771Met ABCA1 p.Glu1172Asp 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 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Val771Met ABCA1 p.Glu1172Asp Additive effects on CHD risk were also observed for the V771M/I883M and I883M/E1172D pairs. Login to comment 117 ABCA1 p.Ile883Met ABCA1 p.Glu1172Asp In fact, the I883M and E1172D SNPs were previously determined by Brousseau et al. [30] in a study of 2028 white men to have increased frequencies in cases compared with controls, in addition to detecting increased risk of future CHD events associated with the 1172D allele (Table 2). Login to comment 119 ABCA1 p.Gln597Arg ABCA1 p.Cys1477Arg ABCA1 p.Arg909* ABCA1 p.Met1091Thr ABCA1 p.Thr929Ile ABCA1 p.Arg2144* ABCA1 p.Pro2150Leu Genetic variation in ABCA1 and risk of myocardial infarction Study* / year Population screened HDL-C, mmol/L ABCA1 variants Conclusions Clee et al. [28] / 2000 Within 11 TD families: Del L693, R2144X † , Del E,D1893,94 † , R909X, M1091T † , P2150L † , ivs25+1G→C, Del C6825→2145X, CTC6952- 4TT→2203X, C1477R, Q597R, T929I ABCA1 heterozygous patients had a 40%-45% decrease in HDL-C and a greater than threefold increased risk of CHD versus unaffected individuals. Login to comment 121 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Glu1172Asp TD patients ( n = 5) 0.08 ± 0.05 ABCA1 heterozygous patients ( n = 77) 0.74 ± 0.24 Unaffected individuals ( n = 156) 1.31 ± 0.35 Brousseau et al. [30] / 2001 VA-HIT study, men with established CHD ( n = 1014) 0.83 ± 0.13 R219K, I883M, E1172D † Frequencies of the 3 ABCA1 variants were signifi cantly increased in VA-HIT. Login to comment 123 ABCA1 p.Glu1172Asp In VA-HIT, E1172D was associated with an increased risk of CHD. Login to comment 124 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Framingham Offspring Study, CHD-free control men ( n = 1014) 1.14 ± 0.31 Clee et al. [33] / 2001 REGRESS cohort, with established CHD ( n = 804) R219K genotype: R219K † The R219K SNP is associated with a decreased progression of CHD, decreased TG, and increased HDL-C RR: 0.92 ± 0.22 RK: 0.93 ± 0.23 KK: 0.92 ± 0.20 Lutucuta et al. [38] / 2001 Lipoprotein Coronary Atherosclerosis Study patients ( n = 372) C-477T genotype: C-477T † , A-419C, G-320C The C-477T variant was strongly associated with the severity of coronary atherosclerosis, with modest effect on HDL-C CC: 1.14 ± 0.29 CT: 1.10 ± 0.28 TT: 1.19 ± 0.32 *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 132 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys GG: 0.93 ± 0.23 GC: 0.92 ± 0.22 CC: 0.94 ± 0.29 C-17G genotype: CC: 0.92 ± 0.22 CG: 0.93 ± 0.23 GG: 0.88 ± 0.21 C69T genotype: CC: 0.91 ± 0.22 CT: 0.91 ± 0.19 TT: 0.95 ± 0.30 A-1095G genotype: AA: 0.93 ± 0.24 AG: 0.93 ± 0.22 GG: 0.83 ± 0.20 InsG319 genotype: No ins: 0.92 ± 0.23 G: 0.93 ± 0.23 GG: 0.89 ± 0.30 Cenarro et al. [34] / 2003 Spanish heterozygous FH patients with premature CHD ( n = 216) or without ( n = 158) R219K genotype: R219K † The frequency of the K219 allele was signifi cantly higher in the FH group without premature CHD than in FH patients with premature CHD RR: 1.27 ± 0.36 RK + KK: 1.32 ± 0.40 *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 135 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val825Ile Genetic variation in ABCA1 and risk of myocardial infarction Study* / year Population screened HDL-C, mmol/L ABCA1 variants Conclusions Evans and Beil [41] / 2003 Patients attending a lipid outpatient clinic ( n = 813) R219K genotype: R219K † The K219 allele was signifi cantly protective against CHD in patients with hyperlipidemia and elevated Lp(a), as well as decreasing TG levels RR: 1.32 ± 0.03 RK: 1.34 ± 0.03 KK: 1.27 ± 0.31 Harada et al. [29] / 2003 Japanese patients ( n = 410) I883M genotype: I883M, R219K The I883M polymorphism was signifi cantly associated with higher HDL-C in Japanese patients, but not with CHD II: 1.16 ± 0.30 IM: 1.26 ± 0.42 MM: 1.27 ± 0.37; P = 0.05 R219K genotype: RR: 1.26 ± 0.41 RK: 1.25 ± 0.40 KK: 1.24 ± 0.35 Tan et al. [42] / 2003 Cases: Chinese ( n = 512), Malay ( n = 110), and Indian ( n = 164) men with established CHD Chinese: CAD: 0.89 ± 0.28, Ctl: 1.19 ± 0.32; P < 0.0005 C-14T, 237indelG, V825I † , M883I † , A8994G The V825I and M883I polymorphisms are positive markers for the CHD phenotype in Malays, but with no effect on HDL-C Malays: CAD: 0.83 ± 0.27, Ctl: 1.15 ± 0.27; P < 0.0005 Controls: Chinese ( n = 271), Malay ( n = 179), and Indian ( n = 231) men Indians: CAD: 0.79 ± 0.24, Ctl: 1.00 ± 0.26; P < 0.0005 Tregouet et al. [31] / 2004 Subgroup of ECTIM cohort ( n = 452 cases and n = 465 controls) NA C-564T, R219K † , R1587K ABCA1 polymorphisms, but not haplotypes, are involved in variability of apoA-I and the susceptibility to CHD. Login to comment 137 ABCA1 p.Arg219Lys R219K was associated with MI (K219 allele associated with a decreased risk), but not with apoA-I. Login to comment 141 ABCA1 p.Arg219Lys Genetic variation in ABCA1 and risk of myocardial infarction Study* / year Population screened HDL-C, mmol/L ABCA1 variants Conclusions Shioji et al. [43] / 2004 Japanese Suita Study ( n = 1880) Suita group: 1.44 ± 0.02 G-273C The G-273C polymorphism was signifi cantly associated with HDL-C in the general Japanese population but not on the incidence of MI MI group ( n = 598 men) MI group: 1.09 ± 0.01; P < 0.0001 Bertolini et al. [39] / 2004 FH patients: All FH patients: males: 1.18 ± 0.02, females: 1.39 ± 0.02; P < 0.0001 R219K † The K219 allele was signifi cantly protective against CHD, and this effect was more pronounced in males than in females and in smokers versus nonsmokers (but there was no signifi cant effect on lipid concentrations). Login to comment 144 ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn CC: 1.29 ± 0.64 CT: 1.28 ± 0.32 TT: 1.26 ± 0.35 Frikke-Schmidt et al. [36] / 2005 Copenhagen City Heart Study: K776N Heterozygosity for the K776N ABCA1 mutation conferred a twofold to threefold increase risk of IHD, independent of plasma HDL-C. Login to comment 145 ABCA1 p.Lys776Asn The K776N polymorphism was a better predictor of IHD as compared with traditional cardiovascular risk factors. Login to comment 146 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Lys776Asn Noncarriers ( n = 9039) Women: 1.72 ± 0.01 Men: 1.38 ± 0.01 K776N carriers ( n = 37) Women: 1.82 ± 0.11 Men: 1.18 ± 0.09 P = 0.05 Martin et al. [37] / 2006 Cohort of males diagnosed with MI ( n = 170) NA C-477T † , R219K, I883M In long-term MI prognosis, the C-477T ABCA1 variant was associated with an unfavorable clinical evolution Controls: valvular patients with normal coronariography controls ( n = 100) *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 149 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Val771Met ABCA1 p.Val771Met 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 151 ABCA1 p.Ile883Met Ctl: 1.27 ± 0.31; P < 0.0001 Jensen et al. [48] / 2007 Subgroup of the Nurses` Health Study, with MI ( n = 249) or without ( n = 494) Median (range) C-565T † , G-191C † , C-17G, I883M, R1587K The C-565T and G-191C polymorphisms were inversely associated with the risk of CHD, independent of HDL-C. Login to comment 152 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Val771Met ABCA1 p.Glu1172Asp 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 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp 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 ABCA1 p.Ile883Met ABCA1 p.Val771Met ABCA1 p.Glu1172Asp The V771M, I883M, and E1172D polymorphisms signifi cantly predicted IHD risk, but their association was not related to HDL-C. Login to comment 161 ABCA1 p.Ile883Met ABCA1 p.Val771Met ABCA1 p.Glu1172Asp 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 165 ABCA1 p.Lys776Asn Indeed, it was documented that a completely conserved ABCA1 common mutation, K776N (frequency, 0.4%), was found to confer a twofold to threefold increase in risk of IHD in 37 heterozygous participants in the Copenhagen City Heart Study (Table 2). Login to comment 170 ABCA1 p.Arg219Lys Three ABCA1 SNPs were analyzed (-477C/T, R219K, and I883) in a cohort of 170 young male survivors of MI (mean age, 43 ± 5 years) in order to determine their influence in long-term prognosis. Login to comment 174 ABCA1 p.Arg219Lys Additionally, several recent studies have examined the role of the R219K SNP in lipoprotein metabolism and CHD. Login to comment