染色体6p21.1区遗传变异与缺血性脑卒中/大动脉粥样硬化型脑梗死的相关性

Two genome-wide association studies have found that two variants rs11572061 and rs556621, which are located in the same intergenic region at 6p21.1, are associated with ischemic stroke (IS) and IS subtype--large artery atherosclerosis stroke (LAA-S), respectively, suggesting that neighboring genes of the two variants may play an important role in the occurrence and development of IS/LAA-S. But what are those genes involved have not been clarified. The two studies also showed that genetic polymorphisms at 6p21.1 are different between different ethnic groups, which may cause different variants associated with IS/LAA-S in different ethnic groups. At present, genetic variants at 6p21.1 associated with IS/LAA-S have not yet been clarified in Chinese Han population. Through comprehensive literature reading of all genes within 1Mbp distance of the two variants, this project preliminarily screened out six suspicious genes, and designed a case-control study to search for genetic variants in the six genes related to IS/LAA-S in Chinese Han population of Hainan Island, which include patients with IS/LAA-S, age-matched control individuals and long-lived individuals. This project will lay the foundation for further study of the molecular mechanism of IS/LAA-S, and has important significance in the prevention, early diagnosis, early intervention and treatment of IS/LAA-S.

两项全基因组关联分析发现位于6p21.1区同一基因间隔区的多态性位点rs11572061和rs556621分别与缺血性脑卒中（IS）和IS亚型大动脉粥样硬化型脑梗死（LAA-S）相关，提示这两个位点邻近基因很可能在IS/LAA-S的发生发展过程中起作用，但究竟是那些基因并未阐明。这两项研究还显示不同种族6p21.1区基因多态性存在差异，会引起不同种族该区与IS/LAA-S相关的位点不同。目前中国汉族人群该区与IS/LAA-S相关的多态性位点尚未阐明。本项目对距离这两个位点1Mbp内的邻近基因进行全面的文献阅读，初步筛查出6个可疑基因，并计划在海南地区汉族群体（IS/LAA-S患者、年龄匹配对照组和长寿老人）中进行病例对照研究，寻找这6个基因与IS/LAA-S相关的遗传变异，为IS/LAA-S发生发展的分子机制研究奠定基础，对IS/LAA-S的预防、早期诊断、早期干预和治疗具有重要的意义。

脑卒中是一种在世界范围内均普遍高发的疾病。缺血性脑卒中（ischemic stroke，IS）是脑卒中的主要亚型，IS的遗传机制错综复杂，极小比例的IS是一些单基因遗传病的临床表现，绝大多数IS是多种作用微小的遗传因素和环境因素共同作用的多因子遗传的复杂疾病，因此了解IS的遗传危险因素是阐明IS发病机制、优化预防策略、确定新的治疗靶点的重要步骤。本项目对组蛋白脱乙酰基酶9（histone deacetylase 9，HDAC9）基因上游14个和下游59个常见遗传变异与IS主要亚型大动脉粥样硬化型脑卒中（large artery atherosclerosis stroke，LAA-S）的相关性进行了初探，得到了一些阳性位点，并讨论和总结了染色体6p21.1区遗传变异对IS/LAA-S易感性的影响，结果显示染色体6p21.1区遗传变异rs556621与中国人群IS/LAA-S易感性相关。同时对单基因遗传病引起的IS和多因子遗传的复杂IS的遗传风险因素的研究进行了综述，进一步加深了对IS遗传结构的理解，为下一步研究拓展思路。简而言之，本项目通过IS/LAA-S易感基因多态性研究，为后续IS/LAA-S的遗传发病机制的研究奠定了基础，即为后续的功能研究提供线索，有重要的科学意义；同时，有助于IS/LAA-S易感人群的发现，为IS/LAA-S的预防、早期诊断和干预、治疗提供指导，以期降低IS/LAA-S的发病率，提高患者生命质量，减少医疗费用，即有一定的临床应用价值。