Genetic Analysis Of Atrial Fibrillation In The Chinese Han Population

Atrial fibrillation(AF) is an abnormality of the heart's rhythm that is characterized by rapid and irregular activation of the atria. AF is now recognized to be the most common sustained cardiac arrhythmia in the clinic setting, which predispose to heart failure and thromboembolic stroke, making it a major public health burden. The underlying mechanism of AF is complex. By Genome-wide linkage analysis, several genetic loci have been mapped for monogenetic AF which occurs in individual families and is caused by a specific mutation in a single gene in each family; However, these loci only account for a small fraction of the genetic risk factors of AF. Most of AF cases are common complex AF which is a polygenic disease, caused by multiple genes, gene-gene interaction or gene-enviroment interaction.In recent years, genome-wide association studies(GWAS), which are conducted with cohorts comprising of hundreds of patients and controls using 500,000 to 1,000,000 single nucleotide polymorphisms (SNPs), have rapidly becoming a standard method for the discovery of genetic loci associated with risk of complex diseases. Although large scale GWAS were carried out in Caucasian population and revealed several genetic loci significantly associated with AF, the amount of data on genetic variation at these loci in populations of non-European origin is limited, my thesis research aimed to investigate genetic loci showing association in GWAS for risk of AF in the Chinese Han GeneID population.My first research is about genetic association of SNP rs2200733 with atrial fibrillation in a Chinese Han population. Approximately 13 million Chinese people are affected by AF, but the genetic basis is largely unknown. A recent genome-wide association study in Iceland identified association between SNP rs2200733 on chromosome 4q25 and AF; however, many independent replication studies are essential to unequivocally validate this association. To assess the association between SNP rs2200733 and AF as well as that between rs2200733 and ischemic stroke in a mainland Chinese Han population, we carried out case-control association studies with 383 AF patients versus 851non-AF controls and 811 ischemic stroke patients versus 688 non-stroke controls. Highly significant association was detected between rs2200733 and AF in a Chinese Han population, p-value of 3.7×10-11 (OR=1.81). There is significant association for ischemic stroke patients with age of<60 years (p=0.01, OR=1.324), but no association with patients of≥60 years and total ischemic stroke cohort (p=0.32 and 0.43 espectively). we found highly significant association between SNP rs2200733 on chromosome 4q25 and AF in the mainland Chinese Han population. The results expanded the association between rs2200733 and AF from Caucasian populations and an ethnic Hong Kong population to a more representative Chinese Han populationMy second research is about the association of SNP rs2106261 with atrial fibrillation in a Chinese Han population. Recent genome-wide association studies (GWAS) identified two single nucleotide polymorphisms (SNPs rs2106261 and rs7193343) in the zinc finger homeobox 3 gene ZFHX3 that showed significant association with AF in multiple Caucasian populations. However, an attempt to replicate the finding in a non-Caucasian population, specifically in a small Hong Kong Chinese population, failed. Here, we studied a large Chinese Han cohort consisting of 650 AF patients and 1,447 non-AF controls (GeneID) to further test whether the GWAS findings on ZFHX3 and AF can be expanded to a different ethnic population. In our study, no significant association was detected for rs7193343. However, significant association was identified between rs2106261 and AF in the GenelD population for both allelic frequencies (P=6.67×10-5; OR=1.32), and genotypic frequencies assuming either an additive or recessive model (OR=1.29, P=0.001 and OR=1.77, P=0.00018, respectively). When only lone AF cases were analyzed, the association remained significant (OR=1.50, P=0.00035 for allelic association; OR=1.45, P=0.001 for an additive model; OR=2.4, P=0.00043 for a recessive model). Our results indicate that rs2106261 in ZFHX3 confers a significant risk of AF in a Chinese Han population. The study for the first time expanded the association between ZFHX3 and AF to a non-Caucasian population and provides the first evidence of a cross-race susceptibility of the 16q22 AF locus.