Genetic Polymorphism Of HERG Confers Predisposition Of Acquired Atrial Fibrillation In Chinese

BackgroundAtrial Fibrillation,as one of the most common arrhythmia diseases,could cause palpitation,heart failure,and even artery infarction,especially cerebral artery infarction.Patients with AF are also facing tremendous economic pressure.However, current clinical treatment upon AF hasn't been satisfying.Hence,deeper understanding of the mechanisms of AF development will no doubt significantly benefit its diagnostic and therapeutic improvement.The most AF cases are required AF,not familial AF.For this type of AF,the occurrence was certainly related to the fundamental heart diseases,and also had some genetic susceptibility.And the studies of the required AF haven't got enough attention by scientists.Some groups in China Taiwan have demonstrated that KCNE1 gene's 38G SNP is associated with the required AF.However,a more complete study is definitely in need right now.IKs and IKr is the major current in cardiac muscle cells.And their decrease could cause the LQTS,while their increase would lead to the reduction of the ERP,which could initiate AF.These years,the study of familial AF has achieved great advancement,most of the assured genes are related to the potassium channel.These researches have prompted the study of acquired AF.IKr channel is encoded by KCNH2 and KCNE2.Hong el.demonstrated that one mutation(N588K) on KCNH2 was associated with AF and SQTS.Therefore,we believe that IKr is dosed related with AF.And focusing on the Shanghai Han Nationality,we aimed to study the association of KCNH2 gene polymorphisms with the required AF.ObjectivesA hospital based case-control study was set up to observe the association of polymorphisms of Health Economics Research Group(HERG) gene with nonfamily atrial fibrillation(AF) in Chinese.Besides,we aim to assess the interaction effect between HERG gene and other factors in order to have a better comprehension of the nosogenesis.Subjects and MethodsIn a fine-designed pair-matched hospital-based case control study,we selected four tagging single nucleotide polymorphisms(tSNPs) in HERG for association study with AF Consecutive patients were recruited from April 1st 2007 to February 31st 2008 from XINHUA hospital.Blood were taken and anticoagulated by ACD.Genomic DNA was extracted by phenol-chloroform extraction method.All selected SNPs were genotyped by the SNPStream technology platform(Beckman).Multiple logistic regression analyses was employed to adjust for the confounding factors.Association study of haplotypes of these tSNPs was also performed by Haploview4.0.The interactions between genetic polymorphisms and environment was explored by MDR software.ResultsAll factors matched well except LAD(left atrail dimension),which in control group is significantly less than case(P＜0.001).None of the loci was deviated from Hardy-weinberg equilibrium.We observed that both genotype and allele frequencies of rs1805120 in exon 6 of HERG were significantly different between AF and controls(P=0.0289 and P=0.0172,respectively).Individuals with TT genotype have a higher risk of AF in the dominant model(OR=2.16,95%CI:1.22-3.85,P=0.0070) comparing to other genotypes.The significance remained after Bonferroni correction. The risk of TT genotype with AF is even higher through hierarchic analysis, OR=6.29(95%CI:1.43-27.78,P=0.004)limiting to the increased LAD subjects. Logistic regression analyses indicated that the HR in rs1805120 increased from 2.19 (95%CI:1.21-3.95,P=0.0095)to 3.55(95%CI 1.12-11.24,P=0.0319) after controlling for covariates.No significant difference is observed in haplotype analysis.The model of 5 factors including LAD,rs1805120,rs2968857,rs3807375 and diabetes was the best one revealed by MDR.ConclusionsWe report a new genetic variation(rs1805120) in HERG gene predisposition to the risk of acquired atrial fibrillation.People with TT genotype may have a higher risk to atrial fibrillation,especially in those with enlarged left atrial.Atrial enlargement may also be a risk to atrial fibrillation.There may be interactions among LAD,rs1805120, rs2968857,rs3807375 and diabetes.However,the functional SNPs need further investigation.