Y染色体变异对男性冠心病遗传易感性影响的探讨

A sexual dimorphism exists in the incidence and prevalence of coronary artery disease-men are more commonly affected than are age-matched women. Over the last few years, genome wide association studies (GWAS) have successfully identified germline variants conferring risks of CAD at over 46 loci. These studies have not implicated variants on the Y chromosome in the risk of CAD, possibly due to the fact that very few Y chromosome SNPs have been included on most genotyping chips used to date. Several groups have specifically investigated the role of Y chromosome haplogroups in CAD risk. Although not all studies have replicated these associations, the accumulated evidence lends support to the notion that genetic variation on Y chromosome could play a part in determining cardiovascular risk in men. In view of the haploid nature of Y chromosome and its low level of recombination, the usual methods of linkage disequilibrium-based mapping applied to autosomal chromosomes cannot be used in investigation of its variation. The most appropriate strategy is the analysis of the Y chromosome phylogenetic tree. We will directly examine association between the Y chromosome and CAD. First we examined whether common Y chromosome haplogroups were associated with risk of coronary artery disease. Next we will evaluate the associated Y chromosome haplogroups in another larger sample. Finally, we will explore biological mechanisms of the signatures of Y chromosomal variants affects disease by bioinformatics and molecular biology methods, and provide clues to explain the gender differences of disease.

在过去5年里冠心病的全基因组关联研究已发现的与CAD相关的易感位点达到了46个，然而研究主要关注的是常染色体上的遗传变异对疾病发病的影响，极少关注X染色体或Y染色体上的变异与疾病的相关性。而在心血管领域，男性的冠心病发病风险显著高于同年龄的女性。一些研究提示Y染色上存在着影响男性冠心病发病的遗传变异。由于Y染色体是单倍体，因此常染色体关联研究的分析方法不能直接用于Y染色体。本课题拟在高分辨率的世界人群Y染色体谱系树的基础上研究其基本分支A-T及其亚簇上的单倍群与冠心病发病风险的相关性，以其发现风险单倍群并在大样本中进行验证。利用生物信息学和分子生物学手段，阐述Y染色体上疾病相关遗传变异影响疾病发生的生物学机制，为解释疾病发病性别差异提供线索。