Molecular Genetic Analysis Of Atherosclerosis In Chinese Population

Atherosclerosis is the most common disease affecting the health of humans, and causes coronary artery diseas (CAD), myocardial infarction (MI), and strokes which represent the leading causes of morbidity, mortality and disability worldwide. Atherosclerosis is a complex disease which is caused by genetic factors, environmental factors, and their interactions. During the past few years, epidemiological studies have identified multiple genetic factors for atherosclerosis. Recent genome-wide association studies (GWAS) identified several candidate genes associated with atherosclerosis, and improved the understanding of the pathogenic pathways of atherosclerosis. However, most GWAS were carried out in Caucasions, and their results may or may not hold true for the Chinese population. One of the most impartant aspect of our molecular genetcal research of atherosclerosis is to find the specific genetic loci or factors that affect the Chinese population, and to assess whether the reported risk loci in Caucasions play any role in the Chinese population or in a different pattern. In my thesis research, I analyzed the association of two single nucleotide polymorphisms (SNPs) with atherosclerosis in a Chinese Han population.PartⅠ:The association of SNP rs11206510 on chromosome 1p32 with LDL-c,CAD and ischemic stroke in a Chinese Han populationSeveral genome-wide association studies found that the common allele T of SNP rs11206510 on chromosome 1p32 was associated with increased low-density lipoprotein-cholesterol levels (LDL-C) and with risk of coronary artery disease (CAD) in Caucasian populations. The goals of this study are:(1) to determine whether rs11206510 is associated with LDL-C and CAD in a different ethnic population, namely a Chinese cohort; (2) to investigate whether rs11206510 is associated with ischemic stroke.The association of rs11206510 with LDL-C was analyzed in 1,415 Chinese Han subjects. The CAD study utilized a GeneID cohort with 1,543 CAD patients and 1,240 controls. For stroke studies, two independent cohorts were used, and included the GenelD-North cohort with 1,205 cases and 1,205 controls and the GenelD-Central cohort with 692 cases and 882 controls.Different from Caucasian populations, the rare allele C of rs11206510 was associated with increased LDL-C levels in the Chinese Han population (adjusted P-adj=0.002), and conferred risk of early-onset CAD (380 cases vs.1,240 controls; P-adj=0.002, odds ratio (OR)=1.89), but not with overall CAD (P-adj=0.82). The allelic association with ischemic stroke was highly significant in two independent cohorts with P-adj=1.13x10-5 (OR=1.71) in the GeneID-North cohort, P-adj=9.32x10-5 (OR=1.70) in GeneID-Central cohort. Genotypic association was also significant for both early-onset CAD and ischemic stroke.Our results indicate that SNP rs11206510 is associated with LDL-C levels and early-onset CAD in the Chinese Han population. For the first time, this study also demonstrates that rs11206510 confers a significant risk of ischemic stroke.PartⅡ:Association of rs9943582 with ischemic stroke, CAD and left ventricular systolic dysfunctionPrevious in vitro and in vivo studies revealed that the pathway of apelin and its receptor, APJ were involved in heart failure, blood pressure levels and atherosclerosis. A GWAS in a Japanese population also showed that a series of SNPs in the 5'upstream of the APJ gene were associated with stroke, SNP rs9943582, one of the positive polymorphisms, was located in the key promoter region, and affected the transcription level of APJ through changing the binding site of SP1 transcriptional factor. SNP ss9943582 may be a causal popymorphism that has a functional effect to the APJ gene. The association of rs9943582 with atherosclerosis needs further investigations. Considering the relationship of the APJ gene with heart failure, we also assessted the association of rs9943582 with heart failure in a Chinese population.In a cohort of CAD with 1751 cases and 1022 controls and an ischemic stroke cohort with 1158 cases and 1265 controls, we found that rs9943582 had no obviouse association with atherosclerosis in both the CAD cohort and ischemic stroke cohort (CAD cohort: P-adj=0.22, ischemic stroke cohort:P-adj=0.86). After dividing the CAD patients into a left ventricular systolic dysfunction group and a normal left ventricular systolic function group according the left ventricular eject fraction (LVEF), we performed a case cvontorl association study by considering the two groups as cases (LVEF<40%, N=431) and controls (LVEF>50%,N=1046). Our analysis found that rs9943582 had highly significant association with left ventricular systolic dysfunction in CAD patients (P-adj=6.71×10-5, OR=1.43). SNP rs9943582 also showed association with the echocardiographic traits including the left ventricular end-diastolic diameter, the left atrial diameter and LVEF.In this study, we showed that the allele A of rs9943582 (-154G/A) in the 5'UTR region of the APJ gene was not associated with CAD, but associated with left ventricular systolic dysfunction after coronary artery disease in a Chinese Han population. This is the first time that a variant in the apelin/APJ system is found to confer risk factor for occurrence of heart failure in the context of CAD. The results suggest an important role of the apelin/APJ system in the pathology of ischemic heart disease, and the pathway might constitute an important therapic target.