Association Between ABCA1 Gene Polymorphisms And Coronary Heart Disease

Coronary heart disease (CHD) is a common type of cardiovascular disease which is generally induced by genetic and environmental factors. CHD is one of the leading causes of death at present, and it was estimated that the number of death caused by CHD will account for 13.1% of all deaths worldwide in 2030. The incidence of CHD was increasing and the age of onset became younger over the past several decades, and CHD was considered to be a public health problem all over the world. ABCA1 is a large trans-membrane protein that participates in the initial step of reverse cholesterol transportation (RCT) and HDL particle formation by regulating the efflux of cholesterol and phospholipids. ABCA1 has a major impact on atherosclerosis and plays a critical role in the prevention of CHD. Many studies have shown that single nucleotide polymorphisms (SNPs) of ABCA1 gene were related to CHD, but their results were inconsistent in different ethnic populations, and need to be studied further.ObjectiveOur study aimed to investigate the association of ABCAl gene polymorphisms with CHD and plasma lipid variability; screen out the related risk factors of CHD; and explore the gene-environment interactions in the development of CHD.MethodsA case-control study was used to collect the information of 754 CHD patients and 760 controls. Four ABCA1 SNPs (rs363717, rs4149339, rs4149338 and rs2230808) were genotyped by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS). Quantitative variables were presented using mean and standard deviation, and student’s t test was applied for comparison between cases and controls. Qualitative variables were presented as frequency and percentage. Hardy-Weinberg equilibriumtest was performed by goodness-of-fit chi-square test. The differences of genotype and allele frequencies between cases and controls were assessed by chi-square test. Unconditional logistic regression analysis was used to confirm the association between ABCA1 SNPs and CHD under five genetic models. Haplotype analysis was performed with the online SNPS tats program. Analysis of covariance was used to assessing the effect of different genotypes on plasma lipid levels. Linkage disequilibrium (LD) between SNPs was tested by Haploview 4.2 software. Chi-square test was also used to screen out the related risk factors of CHD. Gene-environment interaction analysis was evaluated by unconditional logistic regression.Results①A total of 754 CHD patients and 760 controls were recruited in our study, and significant differences in age and gender distributions between two groups were not observed (P>0.05). ②Genotype distributions of the four ABCA1 SNPs in control subjects were consisitent with Hardy-Weinberg equilibrium (P>0.05). ③ The genotypic and allelic frequencies of rs363717 between cases and controls were significantly different (P<0.05). Significant association was observed between rs363717 polymorphism and CHD risk, and carriers of the AG/GG had a significantly decreased risk of CHD as compared to those with the wild-type genotype AA under dominant model of inheritant (OR=0.73,95% CI 0.59-0.90, P=0.003). No significant association between other three SNPs and CHD risk was observed (P>0.05). ④The degree of LD between rs363717, rs4149339 and rs4149338 with each other was strong (0.9<D’<1.0,0.5<r2<1.0), but the LD between rs2230808 and other three SNPs with each other was weak (0.2<D’<0.5, 0.04<r2<0.08). ⑤The haplotypes A-C (rs363717-rs4149339/rs4149338), A-C-C(rs363717-rs4149339-rs4149338), A-C-G (rs363717-rs4149339/ rs4149338-rs2230808) and A-C-C-G (rs363717-rs4149339-rs4149338-rs2230808) were associated with a significantly increased risk of CHD, and G-C(rs363717-rs4149338), G-G (rs363717-rs2230808), G-C-C(rs363717-rs4149339-rs4149338), G-C-G (rs363717-rs4149339/rs4149338-rs2230808) and G-C-C-G (rs363717-rs4149339-rs4149338-rs2230808) haplotypes may play a protective role in CHD. ⑥SNP rs2230808 was associated with higher TC levels in control subjects, carriers of the A allele had a higher TC level than noncarriers (4.17±0.79 vs 4.03± 0.81, P=0.025). ⑦The percentages of smokers and drinkers in CHD patients were greater than controls, and both smoking and drinking were risk factors for CHD (P<0.001); Patients with CHD had higher plasma lipid levels than controls, and dyslipidemia was risk factor for CHD (P<0.001). ⑧rs363717 polymorphism interacted with drinking to increase CHD risk, and significant interaction was observed between this SNP and diabetes (Pinteraction<0.05).Conclusion①Significant association was found between ABCA1 rs363717 polymorphism and CHD risk, and G allele might be a protective factor for CHD. ②Haplotypes A-C, A-C-C, A-C-G and A-C-C-G were associated with increased risk of CHD, and haplotypes G-C, G-G, G-C-C, G-C-G and G-C-C-G may play a protective role in CHD. ③SNP rs2230808 was associated with higher TC levels in control subjects, carriers of the A allele had a higher TC level than noncarriers. ④Smoking, drinking and dyslipidemia were risk factors for CHD. ⑤There was interaction between rs363717 polymorphism and drinking, and this SNP also interacted with diabetes.