| Background and objective Atrial fibrillation(AF)is a common and complex disease caused by multiple factors.Clarifying the etiology and pathogenesis of AF will provide scientific basis and new ideas for the prediction,prevention,diagnosis,classification,evaluation and treatment of AF.At present,the traditional risk factors based on cardiovascular diseases,such as gender,age,diabetes,hypertension,coronary heart disease,smoking and so on,have been explored quite mature with AF.In recent years,the vigorous development of molecular genetics research,such as candidate gene association analysis,whole genome association analysis,exon sequencing and genome sequencing,have gradually become the focus.High mobility group box(HMGB)is a nuclear protein,named after its high migration ability in polyacrylamide gel electrophoresis.HMGB1 is the only molecule that can release to extracellular and has cytokine activity.Clinical studies have found that HMGB1,as one of the inflammatory mediators,might participate in the inflammatory reaction process of acute and chronic diseases such as sepsis,myocardial ischemia-reperfusion injury,trauma,acute lung injury and arthritis,and may induce the occurrence and development of AF.Therefore,we speculate that the gene HMGB1 is likely to be one of the important candidate genes of AF.Exploring the possible AF susceptibility sites on HMGB1 might provide a new intervention target for the prevention and treatment of AF.Methods We collected Chinese Han population from Yichang Central People’s Hospital in Hubei Province by stages,and analyzed the possible susceptibility sites of AF on the candidate gene HMGB1 by case-control association analysis.In the first stage,from December 2012 to June 2013,we collected 396 patients with AF diagnosed by chief physician of cardiology department or above in Yichang Central People’s Hospital of Hubei Province,as the case group;at the same time,we collected 726 cases of non AF population who underwent physical examination in the hospital during this period as the control group.At this stage,we selected the single nucleotide polymorphism(SNP)rs1412125c/t that may have function reported in previous studies on the candidate gene HMGB1,which located in the promoter region;we first verified the correlation between this SNP and AF in Chinese Han population.In the second stage,from January 2016 to January 2019,we collected 576 AF patients and 869 non AF people.At this stage,we not only replicated the correlation between SNP rs1412125c/t and AF again,but also tested the correlation between SNP rs1045411t/c located in the 3’UTR region of HMGB1 and AF.We genotyped these two SNPs in Chinese Han population by high resolution melt analysis(HRM).In the second stage,we also used SPSS(v.21.0,Inc.,Chicago,IL)for haplotype analysis to explore the interaction between the selected SNPs sites in AF.Furthermore,we made a stratified analysis,and used multivariate logistic regression analysis and multiple linear regression analysis to correct the impact of traditional risk factors of AF on the correlation between the selected SNPs and AF.Results In the first stage,we found that the minimum allele frequency of rs1412125c/t in the promoter region of HMGB1 was significantly higher in the case group than in the control group,and the observed p value was less than 0.05.However,when the traditional risk factors of AF were corrected,the p value was greater than 0.05,and the difference was not statistically significant,suggesting that rs1412125 allele C might not be an independent risk factor of AF;in genotype analysis,under the dominant,additive and recessive modes of rs1412125c/t,the observed p value and the adjusted p value with traditional risk factors were greater than 0.05;in the stratified analysis,gender and rheumatic heart disease interacted with the SNPs were significantly correlated with AF with the adjusted p values less than 0.05.In the second stage,in the allele association analysis,after adjusting the traditional risk factors of AF,rs1412125 was not associated with AF(Padj=0.715),which confirmed the reliability of the results of the first stage;we also found that after adjusting for the traditional risk factors of AF,rs 1045411 was not associated with AF;in genotype association analysis,in all modes(additive,dominant and recessive),rs1412125c/t was not associated with AF,and the Padj value was greater than 0.1,but SNP rs1045411t/c was weakly associated with AF in recessive mode,Padj=0.056;in haplotype association analysis,there was no difference in the distribution frequency of all haplotypes composed of two SNPs between AF group and control group,and the Padj value was greater than 0.1;in gender subgroups:rs1045411t/c showed a weak correlation with AF in the implicit model of male subgroups(pobs=0.065),however,after adjusting for traditional risk factors,the Padj value was greater than 0.1;in the female subgroup,the haplotype rs1045411t-rs1412125t combination was weakly correlated with AF(Padj=0.097,OR=0.67,95%CI:0.42-1.07);rs1045411c-rs1412125c combination was also weakly correlated with AF(Padj=0.086,OR=0.71,95%CI:0.48-1.05);in the age stratified analysis,patients with AF younger than 65 years old were defined as early-onset AF subgroup,and other patients were defined as late-onset AF subgroup:under the implicit model,rs1045411t was significantly correlated with AF in the late-onset subgroup(Padj=0.009,OR=11.1,95%CI:1.82-50.0).Conclusion For the first time,we detected the correlation between two SNPs located on the candidate gene HMGB1(rs1045411t/c and rs1412125c/t)and AF in Chinese Han population.Rs 1412125c/t might increase the risk of AF in patients with rheumatic heart disease;rs1045411t/c might regulate the occurrence and development of AF in male and elderly patients;haplotypes rs1045411t-rs1412125t and rs1045411c-rs1412125c might be involved in the occurrence and development of female AF.Clarifying the molecular genetic mechanism will provide new ideas and intervention targets for the in-depth research on the prediction,prevention,diagnosis,classification,evaluation and treatment of AF,and finally promote the development of AF precision medicine. |
PDF Full Text Request