中国汉族人群ALDH2基因多态性与缺血性卒中易感性及其机制研究

Ischemic stroke is characterized by high incidence, high mortality, high morbidity and high recurrence rate characteristics, which severely impairs the patient’s health and life quality. At present, the pathogenesis of ischemic stroke is unclear. Recently, a large-scale genome-wide association study (GWAS) of Caucasians reported that a single nucleotide polymorphism (rs10744777) on chromosome 12q24 were associated with risk of ischemic stroke. In our previous study, we found that the frequency of this locus in Han Chinese population is very low. The relationship between ALDH2 genetic variance and Chinese Han population susceptibility and prognosis of ischemic stroke is still not clear. Moreover, the known locus (rs10744777) associated with susceptibility to ischemic stroke does not affect the transcriptional activity of the ALDH2 gene. Thus, we aim to carry out case-control and cohort study based on Nanjing stroke registry to assess the associations between the variants in this region and ischemic stroke risk and prognosis. Moreover, we will explore the roles of these variants on transcriptional regulation. Our results could be used to screen high-risk groups and susceptible individuals for ischemic stroke. And they have important academic values for improving the diagnosis and predicting of disease development.

缺血性卒中具有高发病率、高死亡率、高致残率和高复发率的特点，严重危害广大患者的生活质量和生命健康。目前，缺血性卒中的发病机制尚不清楚。近期，一项基于欧美人群的全基因组关联研究显示，位于染色体 12q24 区域的ALDH2基因rs10744777与缺血性卒中易感性显著相关。在前期研究中，我们发现该位点在中国汉族人群中的频率较低，ALDH2基因遗传变异与中国汉族人群缺血性卒中易感性及预后的关系仍不清楚，且已知的与缺血性卒中易感性显著相关rs10744777位点并不影响ALDH2基因的转录活性。因此，本课题在前期研究的基础上，结合南京卒中注册系统，采用病例-对照和队列研究设计，分析ALDH2基因遗传变异与中国汉族缺血性卒中易感性和预后之间的关系，同时探讨功能性SNP位点对该基因转录调控的作用。研究结果对于缺血性卒中高危人群的明确、疾病的早期诊断和治疗具有重要意义和实用价值。

全基因组关联研究发现染色体12q24区域遗传变异与欧洲人群脑卒中相关。本课题主要探讨12q24区域的两个遗传变异（rs10744777和rs886205）与中国人群缺血性卒中的关联和可能的生物学机制。我们纳入了1195名缺血性卒中患者和642名健康对照，ALDH2基因的rs10744777和rs886205多态性进行了基因分型，并用多元logistic回归进行了比较。结果我们发现rs10744777（CT/TT）基因型与男性卒中危险性有关（OR=1.99，95%CI=1.15-3.42，P=0.013）。相反，没有在女性卒中人群中发现显著相关。单倍型分析表明单倍型“TA”与缺血性卒中风险增加（OR=1.85，95%CI=1.10-3.12,P=0.042)相关。进一步的亚型分析显示，rs10744777(CT/TT)基因型与男性动脉粥样硬化亚型卒中密切相关(OR=2.27,95%CI=1.30-3.95,P=0.004)。经过三个月的随访，我们发现携带rs886205 GA基因型的男性缺血性卒中的功能预后较差(OR=1.76,95%CI 1.03-3.00)。根据表达量性状位点（eQTL）的研究，我们发现rs886205是脑内ALDH2的表达量性状位点（P=3.02×10-6）。进一步的生物信息学分析表明rs886205可显著影响转录因子(E-twenty six)_known3的结合亲和力。上述结果表明，ALDH2基因多态性可改变中国男性缺血性脑卒中的危险性和预后。