浙江汉族人群单核苷酸多态性与胸主动脉瘤遗传易感性的研究
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摘要
研究背景及目的
胸主动脉瘤是一类逐渐被引起重视的心血管疾病,具有致死致残率高、治疗难度大等特点。其发病由多种高危因素促成,虽然该病主要为散发形式,然而遗传因素在其中占有重要作用,通过遗传学水平研究由于基因多态性产生的不同程度的遗传易感性,可加深对本疾病发病机制的进一步认识,并为疾病的防治提供重要依据。随着人类基因组计划的完成和单体型图谱的构建,以及高通量基因分型技术的快速发展,全基因组关联性研究应势而生,并成为目前探索复杂疾病易感性遗传因素最为有效的方法。近年来几个国外研究中心以西方人群为主要研究对象进行了基于全基因组关联性研究,发现多组单核苷酸多态性与胸主动脉瘤发病相关。如Vasan等延续Framingham心脏研究等,通过meta分析发现rs10852932,rs17470137,rs4026608等单核苷酸多态性(SNP)位点与美国白人主动脉根部扩张程度有关,潜在相关的基因包括CCDC100, PDE3A, HMGA2,SMG6,SRR,TSR等。Wineinger等通过高血压病的多中心研究——HyperGEN研究,发现位于7号染色体的CRCP和KCTD7基因之间、以及20号染色体的SIRPA和PDYN基因之间的大片编码区域和非裔美国人主动脉根部瘤样扩张相关,关联SNP包括rs10263935、rs6045676等。LeMaire等以欧裔白人的胸主动脉真性动脉瘤及夹层患者为研究对象进行GWAS研究,发现FBN1基因多个相关SNP与之发病相关。而目前在我国,心血管疾病的遗传学研究对象主要以集中在冠心病,高血压等高发疾病为主,胸主动脉疾病发病率相对较低,引起的关注相对较小。然而,胸主动脉瘤往往起病凶险,自然病程预后不佳,对其疾病发生机制有必要进一步深入研究。进行单核苷酸多态性与胸主动脉瘤遗传易感性的相关研究,对加深此类疾病的发病机制的认识,具有重要意义。
近年来,以单核苷酸多态性为基础,通过进一步的研究方式,如单倍体型研究和基因交互作用研究等,在高血压、冠心病、腹主动脉瘤等心血管疾病研究领域取得了重要研究成果。然而在胸主动脉瘤方面,以我国汉族人群为研究对象,仍然鲜在单倍体型及基因交互作用分析水平上的研究成果,以此为研究手段,可进一步探究我国汉族人群的胸主动脉瘤疾病的致病遗传因素。
目前认为,相同疾病在不同种族、人群之间致病基因及发生机制可能会有不同。基于国外相关研究进展以我国汉族人群为研究对象,在基因水平上研究我国汉族人群遗传易感性与胸主动脉瘤的关系,确认相关高危SNP位点、进而研究高危单倍体型和潜在的基因交互关系,有望进一步加深对胸主动脉瘤的发病机理的认识,为疾病预防、诊断、治疗等方面提供新的思路。
研究对象与方法
以浙江地区汉族人群为研究对象,采用病例对照研究方法,按照成组匹配原则入组胸主动脉瘤患者病例组及健康人群对照组,获取病例组及健康人群临床信息,对病例组进行临床诊断分型。提取研究对象的血样或主动脉组织DNA,采用直接测序法检测候选SNP位点：rs10263935,rs10757278,rs1333049,rs10519177,rs9806323,rs1036477,rs2118181,rs6045676及其基因型。对对照组人群进行Hardy-Weinberg检验。运用SHESIS软件,采用Pearson卡方检验比较对照组和病例组之间8个单核苷酸多态性多态性位点及各基因型分布差异,采用logistic回归模型计算OR值和95%可信区间。对同一染色体的多态性位点进行单倍体型分析,得出与疾病相关的高危或保护性单倍体型,并采用多因素降维法(MDR)进行多因素交互作用分析,判断在胸主动脉疾病发生机制中可能的基因间交互作用。
结果
病例组51例,其中男性36例,女性15例。根据胸主动脉诊疗指南,进行病例亚组分组,其中符合胸主动脉真性动脉瘤诊断病例34例,胸主动脉夹层诊断病例35例(有18例病例符合两种共同诊断),升主动脉病变组40例,非遗传综合征病例组44例。
健康人群对照组79例,男性53例,女性26例。对照组样本的8个SNP位点的基因型分布均符合Hardy-Weinberg平衡(p>0.05),说明本研究选取的对照组SNP位点基因型频率处于平衡状态,具有群体代表性。
对8个SNP位点检测结果在病例组及各个亚组和对照人群样本进行Pearson卡方检验,并采用logistic回归模型计算OR值和95%可信区间,结果显示CDKN2B基因相关的rs1333049GG基因型携带者增加胸主动脉瘤患病风险(OR=2.533);且各主要亚组结果也基本一致；FBN1基因相关的rs10519177的A等位基因在总体胸主动脉瘤患者病例组的分布频率高于对照组具有显著性差异,AA基因型增加胸主动脉瘤患病风险(OR=2.383),提示该基因型为危险因素,GG基因型降低胸主动脉瘤患病风险(OR=0.207),提示其为保护因素,且各主要亚组结果也基本一致；rs6045676等位基因分布频率和基因型频率在整体病例组与对照组之间无明显差异；但A等位基因在胸主动脉夹层亚组分布频率高于对照组且有显著性差异,AA基因型增加胸主动脉夹层患病风险(OR=2.684),其余亚组均无显著性差异。另5个SNP位点：rs10263935,rs10757278,rs9806323,rs1036477,rs2118181在病例组及各个亚组和对照组之间的等位基因频率及基因型频率分布无显著性差异。
连锁不平衡检验显示：CDKN2B-AS1基因相关的rs10757278,rs1333049之间存在较强水平的连锁不平衡;FBN1基因相关的rs10519177,rs9806323,rs1036477,rs2118181之间存在连锁不平衡,其中rs1036477与rs2118181之间连锁不平衡水平较强。结合各个位点在染色体的距离,结果符合预期。
单倍体型分析结果显示,部分FBN1基因相关单倍体型与浙江地区汉族人群胸主动脉瘤发病相关：AAAT组合(OR=2.291)、ATGC组合(OR=5.826)、ATGT组合(OR=11.595)以及GTGT组合增加患病风险；常见单倍体型GAGC组合(OR=0.377)降低患病风险。而CDKN2B-AS1基因相关单倍体型中少见的两种单倍体型,GG组合(OR=9.721)增加浙江汉族人群各类胸主动脉瘤患病风险,AC组合(OR=10.156)仅增加浙江地区汉族女性人群胸主动脉瘤患病风险。
多因子降维分析显示：在整体病例组中最佳多因素交互模型为二因子模型由rs1333049和rs10519177组成(Testing accuracy=0.6526, P of permutation<0.0001),十重交叉验证的一致率为10：10,“高危”人群是非上述组合的“低危”人群胸主动脉瘤发病风险的5.31倍,与FBN1相关的rs10519177位点在交互作用中起主导作用。并且此二因子模型对胸主动脉夹层亚组、非遗传综合征胸主动脉瘤亚组及升主动脉动脉瘤亚组均为最优模型。仅在胸主动脉真性动脉瘤亚组最优多因素交互模型为由rs1333049组成的单因子模型(Testing accuracy=0.5622, P of permutation=0.008),十重交叉验证的一致率为9：10,显示CDKN2B-AS1在胸主动脉真性动脉瘤致病因素中的主导作用。
结论
rs1333049、rs10519177、rs6045676多态性位点与浙江地区汉族人群胸主动脉瘤患病风险相关,FBN1基因和CDKN2B-AS1基因的部分单倍体型会产生不同程度的遗传易感性,FBN1和CDKN2B-AS1基因交互作用在胸主动脉瘤疾病发病过程中起到重要作用。胸主动脉瘤作为一大类疾病,其成因有很强的遗传因素,并且是由多种因素相互作用的复杂过程,采用不同角度的基因多态性与遗传易感性研究,将有助于阐明胸主动脉瘤发病的遗传基础。
Background
Thoracic 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 methods
We 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.
Results
In 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.
Conclusion
The 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.
胸主动脉瘤是一类逐渐被引起重视的心血管疾病,具有致死致残率高、治疗难度大等特点。其发病由多种高危因素促成,虽然该病主要为散发形式,然而遗传因素在其中占有重要作用,通过遗传学水平研究由于基因多态性产生的不同程度的遗传易感性,可加深对本疾病发病机制的进一步认识,并为疾病的防治提供重要依据。随着人类基因组计划的完成和单体型图谱的构建,以及高通量基因分型技术的快速发展,全基因组关联性研究应势而生,并成为目前探索复杂疾病易感性遗传因素最为有效的方法。近年来几个国外研究中心以西方人群为主要研究对象进行了基于全基因组关联性研究,发现多组单核苷酸多态性与胸主动脉瘤发病相关。如Vasan等延续Framingham心脏研究等,通过meta分析发现rs10852932,rs17470137,rs4026608等单核苷酸多态性(SNP)位点与美国白人主动脉根部扩张程度有关,潜在相关的基因包括CCDC100, PDE3A, HMGA2,SMG6,SRR,TSR等。Wineinger等通过高血压病的多中心研究——HyperGEN研究,发现位于7号染色体的CRCP和KCTD7基因之间、以及20号染色体的SIRPA和PDYN基因之间的大片编码区域和非裔美国人主动脉根部瘤样扩张相关,关联SNP包括rs10263935、rs6045676等。LeMaire等以欧裔白人的胸主动脉真性动脉瘤及夹层患者为研究对象进行GWAS研究,发现FBN1基因多个相关SNP与之发病相关。而目前在我国,心血管疾病的遗传学研究对象主要以集中在冠心病,高血压等高发疾病为主,胸主动脉疾病发病率相对较低,引起的关注相对较小。然而,胸主动脉瘤往往起病凶险,自然病程预后不佳,对其疾病发生机制有必要进一步深入研究。进行单核苷酸多态性与胸主动脉瘤遗传易感性的相关研究,对加深此类疾病的发病机制的认识,具有重要意义。
近年来,以单核苷酸多态性为基础,通过进一步的研究方式,如单倍体型研究和基因交互作用研究等,在高血压、冠心病、腹主动脉瘤等心血管疾病研究领域取得了重要研究成果。然而在胸主动脉瘤方面,以我国汉族人群为研究对象,仍然鲜在单倍体型及基因交互作用分析水平上的研究成果,以此为研究手段,可进一步探究我国汉族人群的胸主动脉瘤疾病的致病遗传因素。
目前认为,相同疾病在不同种族、人群之间致病基因及发生机制可能会有不同。基于国外相关研究进展以我国汉族人群为研究对象,在基因水平上研究我国汉族人群遗传易感性与胸主动脉瘤的关系,确认相关高危SNP位点、进而研究高危单倍体型和潜在的基因交互关系,有望进一步加深对胸主动脉瘤的发病机理的认识,为疾病预防、诊断、治疗等方面提供新的思路。
研究对象与方法
以浙江地区汉族人群为研究对象,采用病例对照研究方法,按照成组匹配原则入组胸主动脉瘤患者病例组及健康人群对照组,获取病例组及健康人群临床信息,对病例组进行临床诊断分型。提取研究对象的血样或主动脉组织DNA,采用直接测序法检测候选SNP位点：rs10263935,rs10757278,rs1333049,rs10519177,rs9806323,rs1036477,rs2118181,rs6045676及其基因型。对对照组人群进行Hardy-Weinberg检验。运用SHESIS软件,采用Pearson卡方检验比较对照组和病例组之间8个单核苷酸多态性多态性位点及各基因型分布差异,采用logistic回归模型计算OR值和95%可信区间。对同一染色体的多态性位点进行单倍体型分析,得出与疾病相关的高危或保护性单倍体型,并采用多因素降维法(MDR)进行多因素交互作用分析,判断在胸主动脉疾病发生机制中可能的基因间交互作用。
结果
病例组51例,其中男性36例,女性15例。根据胸主动脉诊疗指南,进行病例亚组分组,其中符合胸主动脉真性动脉瘤诊断病例34例,胸主动脉夹层诊断病例35例(有18例病例符合两种共同诊断),升主动脉病变组40例,非遗传综合征病例组44例。
健康人群对照组79例,男性53例,女性26例。对照组样本的8个SNP位点的基因型分布均符合Hardy-Weinberg平衡(p>0.05),说明本研究选取的对照组SNP位点基因型频率处于平衡状态,具有群体代表性。
对8个SNP位点检测结果在病例组及各个亚组和对照人群样本进行Pearson卡方检验,并采用logistic回归模型计算OR值和95%可信区间,结果显示CDKN2B基因相关的rs1333049GG基因型携带者增加胸主动脉瘤患病风险(OR=2.533);且各主要亚组结果也基本一致；FBN1基因相关的rs10519177的A等位基因在总体胸主动脉瘤患者病例组的分布频率高于对照组具有显著性差异,AA基因型增加胸主动脉瘤患病风险(OR=2.383),提示该基因型为危险因素,GG基因型降低胸主动脉瘤患病风险(OR=0.207),提示其为保护因素,且各主要亚组结果也基本一致；rs6045676等位基因分布频率和基因型频率在整体病例组与对照组之间无明显差异；但A等位基因在胸主动脉夹层亚组分布频率高于对照组且有显著性差异,AA基因型增加胸主动脉夹层患病风险(OR=2.684),其余亚组均无显著性差异。另5个SNP位点：rs10263935,rs10757278,rs9806323,rs1036477,rs2118181在病例组及各个亚组和对照组之间的等位基因频率及基因型频率分布无显著性差异。
连锁不平衡检验显示：CDKN2B-AS1基因相关的rs10757278,rs1333049之间存在较强水平的连锁不平衡;FBN1基因相关的rs10519177,rs9806323,rs1036477,rs2118181之间存在连锁不平衡,其中rs1036477与rs2118181之间连锁不平衡水平较强。结合各个位点在染色体的距离,结果符合预期。
单倍体型分析结果显示,部分FBN1基因相关单倍体型与浙江地区汉族人群胸主动脉瘤发病相关：AAAT组合(OR=2.291)、ATGC组合(OR=5.826)、ATGT组合(OR=11.595)以及GTGT组合增加患病风险；常见单倍体型GAGC组合(OR=0.377)降低患病风险。而CDKN2B-AS1基因相关单倍体型中少见的两种单倍体型,GG组合(OR=9.721)增加浙江汉族人群各类胸主动脉瘤患病风险,AC组合(OR=10.156)仅增加浙江地区汉族女性人群胸主动脉瘤患病风险。
多因子降维分析显示：在整体病例组中最佳多因素交互模型为二因子模型由rs1333049和rs10519177组成(Testing accuracy=0.6526, P of permutation<0.0001),十重交叉验证的一致率为10：10,“高危”人群是非上述组合的“低危”人群胸主动脉瘤发病风险的5.31倍,与FBN1相关的rs10519177位点在交互作用中起主导作用。并且此二因子模型对胸主动脉夹层亚组、非遗传综合征胸主动脉瘤亚组及升主动脉动脉瘤亚组均为最优模型。仅在胸主动脉真性动脉瘤亚组最优多因素交互模型为由rs1333049组成的单因子模型(Testing accuracy=0.5622, P of permutation=0.008),十重交叉验证的一致率为9：10,显示CDKN2B-AS1在胸主动脉真性动脉瘤致病因素中的主导作用。
结论
rs1333049、rs10519177、rs6045676多态性位点与浙江地区汉族人群胸主动脉瘤患病风险相关,FBN1基因和CDKN2B-AS1基因的部分单倍体型会产生不同程度的遗传易感性,FBN1和CDKN2B-AS1基因交互作用在胸主动脉瘤疾病发病过程中起到重要作用。胸主动脉瘤作为一大类疾病,其成因有很强的遗传因素,并且是由多种因素相互作用的复杂过程,采用不同角度的基因多态性与遗传易感性研究,将有助于阐明胸主动脉瘤发病的遗传基础。
Background
Thoracic 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 methods
We 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.
Results
In 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.
Conclusion
The 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.
引文
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