Association Studies Of The9p21.3Polymorphisms With Coronary Artery Disease, Type2Diabetes In A Chinese Han Population

Objective Leading by interactions among multiple genetic and environmental factors, coronary artery disease and type2diabetes are two main major disorders, which seriously reduce the people’s quality of life and become the great burden of the national economy. At present, the genome-wide association analysis studies (GWAS) based on single nucleotide polymorphisms (SNPs) become the important method of the genetic research for complex disorders. In2007, GWAS have reported that the9p21.3locus associated with coronary artery disease and myocardial infarction, as well as type2diabetes, and rsl0116277and rs1333049located separately on the two adjacent haplotype blocks (44-kb coronary artery disease block from rs10116277to rs1333049and4-kb type2diabetic block from rs10965243to rs10757283). Most recently, two studies based on European populations also reported that the two blocks might contribute to the risk of the two disorders in different ways. As type2diabetes and coronary artery disease has possible common genetic basis, we hyperthesised that there might be common genetic antecedents between type2diabetes and coronary artery disease in the type2diabetic risk locus. Therefore, we investigated a large scale case-control association analysis study in Chinese Han population, in order to further replicate type2diabetic GWAS SNPs on9p21.3, as well as to analysis the association between these SNPs and coronary artery disease.Methods Based on the Chinese Han population, we toltally selected379type2diabetes,1093coronary artery diseases and1695control subjects, used the high resolution melt analysis technology (HRM) and finished2-stage association analysis:In stage-1, we studied379type2diabetes,496coronary artery diseases and849controls in the GenelD-Central-China cohort, to analysis the association of rs2383208, rs10811661and rs10757283with coronary artery disease, as well as type2diabets. In stage-2, we studied597coronary artery diseases and846controls in the Gene1D-Northern-China cohort and to validate the association of the SNPs with coronary artery disease. We also estimated the severity of atherosclerosis in all subjects with coronary artery disease by the Gensini scoring system, and investigated the association between the selected SNPs and the Gensini scores by liner regression analysis and quartile case-controal analysis. The traditional risk factors, such as age, sex, smoking, BMI, cholestroal and so on, were adjusted by multiple logistic regression analysis and multiple linear regression analysis.Results Two SNPs (rs10811661and rs10757283) were continuously associated with type2diabetes (rs10811661-T, P=0.020, OR=1.23,95%CI:1.03-1.47, P-adj=0.021; rsl0757283-C, P=0.003, OR=1.30,95%CI:1.09-1.54, P-adj=0.004). At the same time,they also assocated with coronary artery disease (stage-1, rs10811661-T, P=0.030, OR=1.19,95%CI:1.02-1.40, P-adj=0.048; rsl0757283-C, P=0.026, OR=1.20,95%CI:1.02-1.40, P-adj=0.013; Stage-2, rs10811661-T, P=0.028, OR=1.18,95%CI:1.02-1.38, P-adj=0.031; rs10757283-C, P=0.039, OR=1.17,95%CI:1.01-1.36, P-adj=0.035). Here, the association of rs10811661and rs10757283with coronary artery disease were the most significant (rs10811661-T, P=0.002, OR=1.19,95%CI:1.06-1.33, P-adj=0.004; rs10757283-C, P=0.003, OR=1.18,95%CI:1.06-1.32, P-adj=0.001). Though negatively asscoated with the two diseases in the separate cohort with P values more than0.1, rs2383208gained a near significant association result in the combined population for coronary artery disease (rs2383208-G, P=0.058, OR=1.11,95%CI:1.00-1.24, P-adj=0.061). In the end, only rsl0757283was significantly associated with the Gensini scors in the patients with coronary artery disease (rsl0757283-C:liner regression analysis, P=2.48×10-9,(3=0.267, P-adj=0.002; case-control analysis based on Quartile analysis,4th vs.1st, P=9.50－10-10, OR=2.09,95%CI:1.65-2.64, P-adj=0.006).Conclusions Firstly, we found that rs10811661and rs10757283on9p21.3were continuously associated with type2diabetes in Chinese Han population, which was in accordance with previous studies in risk effect (OR=1.2-1.3). Secondly, we demonstrated that the same diabetic region was a novel risk locus for coronary artery disease, which might function in a different way. Finally, we found that rs10757283might both influence the atherosclerosis development and increase coronary artery disease risk in Chinese Han population. Further studies based on the UCSC and Genevar database indicated the9p21.3locus represented by rs10757283and rs10811661has no known genes, but lots of gene expression regulation elements, such as enhancer. And rs10757283could regulate the expression of its downstream gene DMTRA1. Therefore, we may conclude that the9p21.3risk locus, represented by rs10811661and rs10757283, might influence the development of coronary artery diseases and type2diabetes by regulating the expression of DTMRA1. Further studies are needed to clarify the specific molecular biological mechanisms,Above all, based on the previous GWAS works, we performed the large scale case-control association analysis, and for the first time found the common genetic risk locus (9p21.3represented by rs10811661and rs10757283) for coronary artery disease and type2diabetes. And rs10757283was also correlated with the severity of coronary atherosclerosis. This is an important breakthrough in the field of studies on the two complex disorders in China even all over the world, which provides a new scientific basis for the further prevention and treatment research on coronary artery disease and type2diabetes.