Molecular Genetic Studies Of Coronary Artery Disease In The Chinese Han Population

Coronary artery disease (CAD) and its main complication myocardial infraction (MI) are complex diseases, and are the leading cause of death worldwide. CAD and MI are caused by genetic factors and environment factors or their interactions. In China, there are more than700,000people dying from CAD each year, and the mortality of CAD increases year by year. A genome-wide association study (GWAS) is an important genetic strategy for the study of complex diseases, and can find susceptibility loci or genes for complex diseases, which may explain the pathological mechanisms of complex diseases, and will help for diseases prevention, diagnosis and treatment in the clinic. There are nearly50CAD/MI susceptibility loci that have been found, which represent great progress in genetics of CAD/MI. However, GWAS has a limitation because it relies on population statistics, and GWAS results have variability in different populations of different ancestry geographical origin. Thus, GWAS results need to be replicated in different populations to be ensured that the results are credible.My research project was carried out because inconsistent association between SNP rs17465637on chromosome1q41and CAD/MI was found. I designed a series of experiments to clarify those inconsistent results. First, I performed a case-control study with2,503CAD patients and2,920controls. The CAD population contained698MI patients. In our study, I found significant association between SNP rs17465637and CAD/MI (p=0.01, OR=1.11). Then, I collected all data on association between SNP rs17465637and CAD/MI that have been published to carry out meta-analysis. I divided the populations by ancestry into Asian populations and European populations, I also divided the populations into the CAD population that including MI patients and the MI population. My meta-analysis showed robust association between SNP rsl7465637and CAD/MI not only in Asian populations or European populations but also in the combined populations (p<1.00×10-9).I also detected association between SNP rs17465637and lipids and apoB concentration levels, which are risk factors of CAD/MI. My results showed significant association between SNP rs17465637and apoB levels (p=1.83×10-4). When I divided the apoB population by gender, the association showed only in the male group. SNP rs17465637also associates with LDL-C, TC and HDL-C levels in my study populations, Ⅰ divided the population into a male and a female group, the association with LDL-C and TC showed only in the male group.To analyze the association between SNP rs17465637and genes expression levels, Ⅰ used eQTL databases to predict possibly associated genes. I found that SNP rs17465637associate with TGFB2mRNA expression levels in my study population. SNP rs17465637is located in an intron of the MIA3, both the MIA3gene and the TGFB2gene were found to play an important role in the process of atherosclerosis (AS) that is a basic pathological mechanism of CAD/MI. Thus, I concluded that MIA3and TGFB2might be most important candidate susceptibility genes for CAD/MI.In summary, my research provided sufficient genetic evidence to establish SNP rs17465637as a CAD/MI susceptibility locus, which excluded controversial results and reach a consensus on this issue. I discovered that SNP rs17465637associates with apoB, LDL-C, TC, and HDL-C concentration levels, I also suggested that TGFB2and MIA3were the most important candidate susceptibility genes for CAD/MI.