| Background Atrial fibrillation(AF)is a common tachyarrhythmia,which has become one of the most prevalent diseases and serious public health problems in Chinese population.Atrial fibrillation increases the risk of stroke and is an independent risk factor.Patients with AF of Asian origin are more susceptible to ischemic stroke than other populations whether with anticoagulation therapy or not.Currently,the scoring system of CHA2DS2-VASc recommended in the 2016 AHA/ACC/HRS AF guidelines is used to evaluate the risk of stroke in patients with nonvalvular AF.Over the past few years,extensive efforts have been devoted to the study of genetic polymorphism association analysis of atrial fibrillation,stroke and AF-related stroke in China and worldwide.Genome-wide Association studies(GWAS)have successfully identified several genetic loci.However,these loci could not account for all of the genetic variation with atrial fibrillation and stroke.The gene-gene interactions produced by multiple minor genes were underestimated and may be one of the causes for loss of heritability.By far,the report about gene-gene interactions that affect stroke in patients with AF was rare.Purpose The objective of our study is to explore the gene-gene interaction among CYP2C9,HABP2,ABO and HDAC9 and to test if any of them are associated with stroke in patients with atrial fibrillation in Dalian Han population.Ultimately the positive result of our study could be helpful to construct a genetic risk assessment model for predicting stroke in patients with AF and further develop individualized gene therapy targets for patients with AF to reduce the harmful consequences of AF.Methods Using a case-control design,99 patients with AF were recruited in the Department of Cardiology and Neurology of the Second Affiliated Hospital of Dalian Medical University.They are all Han population.They were divided into AF with ischemic stroke group(n=60)and AF without stroke group as control(n=39).AF diagnosis was confirmed by electrocardiogram in all of the patients.Patients with ischemic stroke met the WHO diagnostic criteria for ischemic stroke.Clinical data and peripheral venous blood of samples were collected.RT-PCR was used to detect the nucleotide sequences of SNPs,including rs1057910,rs11196288,rs505922 and rs2107595.Statistical analysis was performed on the gene frequency and genotype frequency by chi-square test or Fisher Exact test.Associations between genotypes and stroke in patients with AF were analyzed by logistic regression model after adjustment of potential clinical confounders,such as age,hypertension,diabetes and coronary heart disease.Association analysis based on results was carried out to evaluate the effect of each candidate SNPs on stroke in patients with atrial fibrillation.Generalized multifactor dimensionality reduction(GMDR)was used to detect gene-gene interaction among CYP2C9?HABP2?ABO and HDAC9.This method could evaluate the strength of interaction via selecting statistically significant models and comparing indicators such as cross-validation consistency among the models.Finally the best interaction model was determined.Results Compared with AF without stroke group,there were higher vascular risk factors in AF with ischemic stroke group such as older age(78.38±7.75,P=0.000),more coronary heart disease(P=0.047).By contrast,there were no statistically significant differences in hypertension and diabetes between two groups(P>0.05).In our study,the gene frequency distributions of rs1057910 at the CYP2C9 locus deviated from the Hardy-Weinberg equilibrium(P=0.00).SNP rs11196288 was not in linkage disequilibrium with SNP rs1057910(r~2<0.01).Minor allele frequency of four candidate SNPs were 0.127,0.369,0.500 and 0.020 in our study.There was a statistically significant difference in the distribution of the rs505922 with genotype CT between the AF with ischemic stroke group and the control group[P=0.045,OR=0.248,95%CI(0.063-0.970)]after correcting the effects of stroke and atrial fibrillation risk factors such as age and coronary heart disease.Further,AF with ischemic stroke cases were divided into the cardioembolic stroke subgroup(n=28)and other stroke subgroup(n=32).The two subgroups were statistically analyzed with AF without stroke group respectively.The rs505922 with genotype CT was correlated with AF patients with other stroke[P=0.045,OR=0.248,95%CI(0.063-0.970)],which had no association with cardiogenic stroke[P=0.102,OR=0.272,95%CI(0.057-1.294)].GMDR showed that the best model was composed of HABP2,ABO and HDAC9 both in AF with ischemic stroke group and other stroke subgroup.Cross-validation consistency in two groups were 10/10 but not statistically significant(sign test P>0.05).Three SNPs in the best model mentioned were analyzed by logistics regression to explore the combined effects of the three genes on the incidence of stroke in patients with AF,but the results were not statistically significant.Conclusions The results of this study indicated that in the Han population in Dalian China,the rs505922 with genotype CT at the ABO locus may be associated with ischemic stroke in patients with atrial fibrillation,which may be especially attributed to all other ischemic stroke excluding cardioembolic stroke.HDAC9 locus with stroke in patients with AF in Dalian Han population was identified.We did not find significant interactions among above SNPs that were associated with stroke susceptibility. |
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