Single Nucleotide Polymorphisms And Susceptibility Of Thoracic Aortic Aneurysm In Zhejiang Han Population

BackgroundThoracic aortic disease has drawn more attention in last few decades due to high mortality and increasing medical burden. A number of risk factors favor the development of thoracic aortic disease. Although most thoracic aortic disease is sporadic, genetic predisposition has a prominent role in the etiology of thoracic aortic disease. Rearching of genetic susceptibility for thoracic aortic disease will help for understanding of the pathopoiesis, screening and prevention. Genome-Wide Association Studies (GWAS) have become one of the most important method for genetic susceptibility research with the development of genetic sequencing industry. In the recent years, several GWAS highlight the candidate of single nucleotide polymorphisms (SNPs) involved thoracic aortic aneurysm disease for the western population. Vasan et al portrayed in a meta-analysis that SNPs rs10852932, rs17470137and rs4026608are involved in aortic root dilation of the population of European ancestry, associated gene including CCDC100, PDE3A, HMGA2, SMG6, SRR, TSR et al. Wineinger report a GWAS on aortic root diameter among African Americans enrolled in the HyperGEN study.Results suggest novel genetic contributors along a large region between the CRCP and KCTD7genes on chromosome7and the SIRPA and PDYN genes on chromosome20, The significant SNPs in each region is rs10263935and rs645676, respectively. Lemaire report a GWAS on thoracic aneurysm disease, results suggest several significant SNPs in FBN1region. In China, genetic susceptibility researches alway focus on high prevalence disease, like coronary disease and hypertension. However, it’s important to investigate the relation of candidate single nucleotide polymorphism identified by GWAS and susceptibility of thoracic aortic aneurysm disease for Chinese population.Recently haplotype studies and genetic interactive studies basis on single nucleotide polymorphisms have got important results in cardiovascular disease, as as hypertension, coronary artery disease and abdominal aortic aneurysm. However, few progress on thoracic aortic disease. Haplotype studies and genetic interactive studies for local population will help highlight genetic pathopoiesis factors of thoracic aortic aneurysm disease for Chinese people. Different races might not share all genetic pathopoiesis factors, therefore, further investigation focus on Chinese population in the genetic susceptibility will help to prevention and early screening of thoracic aortic aneurysm.Materials and methodsWe conducted a case-control study in Han population from Zhejiang province, and recruited51hospital based thoracic aortic disease cases and79normal controls matching to cases by age and gender as objects. Peripheral blood sample or aortic tissue from patient was collected. Sequencing analysis was used to detect the genotype and allele frequencies of8candidate SNPs (rs10263935, rs10757278, rs1333049, rs10519177, rs9806323, rs1036477, rs2118181, rs6045676). Hardy-Weinberg test for control group to confirm the sample quality. Pearson chi-square test and logistic regression were used to compare the distribution of the genotypes in8SNPs between case and control group, highlight risk factors of the thoracic aortic disease by each subgroups. Linkage disequilibrium test was performed. SHESIS software was used to detect haplotypes of2chromosomes locis. MDR analysis were applied to explore the potential high-order gene-gene interaction among the8SNPs in thoracic aortic disease.ResultsIn the case group of51samples, male was36, female was15. Diagnosis for thoracic aortic true aneurysm was34, and35cases diagnosis for thoracic aortic dissection.40cases involve ascending aorta,44cases were excluded clinical heredity syndrome. Genotyps for all8SNPs in control group were in Hardy-Weinberg equilibrium (p>0.05).rs1333049GG genotype is the risk factor of thoracic aneurysm (OR=2.533), and similar results in the subgroups of thoracic arotci true aneurysm, ascending aortic aneurysm and none-syndrome thoracic aortic aneurysm. Allele frequencies analysis showed A is the susceptibility allele type of rs10519177, AA genotype is the risk of thoracic arotic aneurysm (OR=2.383), GG genotype is protective factor of thoracic arotic aneurysm (OR=0.207), similar results in all subgroups. A allele type of rs6045676is the susceptibility allele type only for subgroup of thoracic aortic dissection, AA genotype is the risk factor thoracic aortic dissection. SNPs of rs10263935,rs10757278, rs9806323, rs1036477, rs2118181had no associated with the risk of thoracic aortic disease.Analysis showed linkage disequilibrium between rs10757278and rs1333049. Among rs10519177, rs9806323, rs1036477and rs2118181, Linkage disequilibrium level is much significant between rs1036477and rs2118181.Halpotye analysis showed FBN1susceptibility halpotype for thoracic aortic aneurysm, such as AAAT (OR=2.291), ATGC (OR=5.826), ATGT (OR=11.595), GTGT and prevalent protective halpotype of GAGC (OR=0.377). For CDKN2B-AS1, rare halpotye of GG (OR=9.721) is the susceptibility halpotype for thoracic aortic aneurysm, halpotye of AC (OR=10.156) is the susceptibility halpotype for female only.MDR analysis showed two-factor model including rs1333049and rs10519177had the highest testing accuracy and cross-validation consisitency (Testing accuracy=0.6526, P of permutation<0.0001); we thus considered the model including rs1333049and rs10519177as the best model for predicting gene-gene interaction in MDR, and similar results for subgroups of thoracic aortic dissection, none syndrome thoracic aortic aneurysm and ascending aortic aneurysm. For subgroup of thoracic aortic true aneurysm, single-factor model of rs1333049is the most accuracy model for predicting gene-gene interaction, cross-validation consisitency is9:10.ConclusionThe current results suggested rs1333049, rs10519177and rs6045676were solely associated with risk of thoracic aortic aneurysm in Zhejiang Han population. Moreover, some of halpotypes of FBN1and CDKN2B-AS1are involved in pathopoiesis of thoracic aortic aneurysm. MDR analysis showed gene-gene interaction between FBN1and CDKN2B-AS1may play important role in thoracic aortic aneurysm. As a group of disease, thoracic aortic aneurysm is deep involed with genetic factors and complex mechanism. Futher investigation for the genetic polymorphisms and susceptibility will help our understanding of pathopoiesis mechanism.