The Association Between Coronary Artery Disease And Gene Polymorphism In Chinese Han Population

Coronary artery disease (CAD) and its main complication, myocardial infarction, are leading causes of death and disability worldwide. CAD is considered to be a typical complex disease with multifactorial etiology, which leads to inconsistent findings in genetic studies. In the past two decades, genetic association analyses have been performed in many studies and have implicated many candidate genes single-nucleotide polymorphisms determine the susceptibility to CAD, as well as to the progression of atherosclerosis. One possibility of failure to replicate some single-locus results is that the underlying genetics of CAD are not only based on multiple genes with minor effects but also on gene– gene and gene-environment interactions. However, these results are often not reproducible. These inconsistent findings might be explained in part by the genetic and environmental heterogeneity among different ethnic groups. And each SNP may not have a discernible main independent effect on disease risk, but its effect may be dependent on other genetic variations (gene–gene interaction or epistasis).To test this hypothesis, a case–control study was conducted in a large Chinese Han population, and both single locus and gene–gene interactions on CAD were investigated.Objective CAD is considered to be a typical complex disease with multifactorial etiology, which leads to inconsistent findings in genetic studies. One possibility of failure to replicate some single-locus results is that the underlying genetics of CAD are not only based on multiple genes with minor effects but also on gene– gene interactions. In order to investigate the association of the SNPs and angiographically proven CAD in the Chinese Han population, a case–control study was constructed to detect both single locus and multilocus effects. Gene-environment interactions were also studied.Methods Totally 508 CAD patients and 521 controls were recruited in this study. A case–control study was conducted. Coronary artery disease (CAD) group, defined as the presence of one or more stenosis≥50% in at least one major coronary artery, was identified in 508 patients. As a control group, 66 unrelated patients free of CAD (defined as <10% stenosis) were included. Another 455 healthy individuals were also recruited as control, which had an annual medical examination. There are 47 SNPs in 43 candidate genes were selected from biochemical pathways that have been implicated in the development and progression of CAD. We genotyped 1029 subjects, using SNPstream technique and high resolution melting method (HRM). The frequencies distribution of allele and genotype in patients and controls were compared by using chi-square test. Logistic regression analyses were used to detect single-locus associations in dominant, recessive and additive genetic models. Ordinal logistic regression analyses were used to detecting numbers of significantly diseased vessels risk and different types of CAD according to the models of inheritance of the alleles.The gene-gene and gene- environment interaction effects of multiple SNPs were detected by multifactor dimensionality reduction (MDR) method. Bonferroni correction was used to adjust the P values for multiple testing. Results The present study was the first to show a significant association between variant PPARG(rs1152002-GA) in patients with CAD in an additive genetic model after Bonferroni correction and adjustment for the conventional risk factors for CAD(P=0.001, Bonferroni correction p=0.047). Analysis showed that three SNPs on 9p21.3 (rs10757278-GA, rs2383206-GA and rs10757274-GA) were significant association with premature MI risk in a recessive model. No significant associationwas observed between single-locus and the number of significantly diseased vessels on CAD. In the additive genetic model, variants PPARG (rs1152002-GA) were significant association with the plaque stability in patients with CAD. The MDR analysis showed potential interactions of NPY(rs16147-GA),MAGI1(rs1495448-GT) and RANTES(rs2107538-CT) variants on the susceptibility of CAD(P<0.001). The MDR analysis also showed potential interactions of PPARG (rs1152002-GA) variant and smoking on the susceptibility of CAD (P<0.0001).Conclusion The present study was the first to show a significant association between variants PPARG (rs1152002-GA) in patients with CAD in an additive genetic model after Bonferroni correction and adjustment for the conventional risk factors for CAD. We provide evidences for gene-gene and gene- environment interaction which exert combination effects on the susceptibility of CAD. This finding proposed a potential gene– gene interactive model for future studies.