| Coronary artery disease (CAD) is the leading cause of morbidity and mortality all over the world, and causes more than 700,000 deaths each year in China. As the main pathological process of CAD, atherosclerosis (AS) can lead to vascular stenosis and blood supply insufficiency, which causes a consequence of cardiac dysfunction and pathologies. With the completion of the human genome project and development of the HapMap and the world-wide practice of high throughput SNP genotyping method based on chips, the genome-wide association study (GWAS) has become a popular way to identify susceptibility loci or genes of complex diseases or traits nowadays. Since the year of 2007, over seven GWAS have identified several SNPs associated with CAD or its major complication myocardial infarction (MI). Among these, only a few SNPs, including SNPs at the 9p21.3 locus, have been replicated successfully in almost every ethnic population. However, most published GWAS mainly focus on the populations of European ancestry and no GWAS has been reported in the Chinese population.This study focuses in GWAS for CAD in the Chinese population. I and my colleagues have established an large ongoing cardiovascular related genetic database named GenelD. I selected 4583 CAD cases and 3470 controls (all are of Han origin), and then carried out a three stage GWAS starting with the Affymetrix Genome-Wide SNP 5.0 arrays. My study includes two independent discovery populations (Dis-Hubei,100 cases vs 100 controls; Dis-Beijing,130 cases vs 130 controls) that were genotyped for approximately 500,000 SNPs by the arrays. Only 9 SNPs showing a nominal P value of <0.01 and in both discovery populations with a same allele as the risk allele have been selected for further analysis. After the Stage 2 validation (572 cases vs 436 controls) and stage 3 replication (Rep-Shandong,811 cases vs 818contorl; Rep-Hubei,1,012 cases vs 1,732 controls; Rep-North,845 cases vs 1,367 controls), I finally identified two susceptibility loci for CAD one on 9p21.3 and the other on 6p24.1. Breslow-Day tests showed that SNP rs6903956 at the 6p24.1 locus had a homogenous effect in all replication populations, thus, all populations can be combined for association analysis, After adjusting for significant risk factors as covariates, I showed that SNP rs6903956 was statistically associated with CAD in the combined population with 3240 cases vs 4353 controls(Padj=2.55×10-13, Odds Ratio=1.65).SNP rs6903956 is located in a putative gene c6orf105, which is expressed widely in human tissues or organs (heart, stomach, Kidney) and many typess of cells (leukocytes. Hela cells, HepG2 cell). Real-time PCR analysis showed that the risk allele A of SNP rs6903956 was significantly associated with the decreased expression levels of c6orf105 mRNA (study 1,P=4.00×10-3; study 2, P=3.56×10-4), which suggested that the expression level of c6orf105 might be involved in the pathological progress of CAD, although the precise mechanism remains to be investigated in the future. In conclusion, in this present study, I performed a three stage GWAS and finally identified a new susceptibility locus on 6p24.1 that is associated with risk of CAD in the Chinese population. |
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