中国汉族人群心脑血管病遗传易感性的研究

发布时间：2018-03-27 15:36

本文选题：遗传　切入点：缺血胜脑卒中　出处：《华中科技大学》2010年博士论文

【摘要】： [研究目的]对白种人缺血性脑卒中的第一个全基因组关联研究(GWAS)确定了多个易感性基因座位。我们在中国汉族人中重复验证了这些位点和缺血性脑卒中的关联性。 [研究方法]采用TaqMan-MGB探针法,在包括1123个缺血性脑卒中病例(血栓性卒中716例,腔隙性脑梗塞407例)和557个正常对照的样本中,对上述报道的25个常见阳性位点进行了基因分型。并在单核甘酸多态性和单体型水平进行了关联分析,还使用了错误发现率(FDR)q值来进行多重检验的校正。 [实验结果]rs11052413,一个位于基因之间的单核甘酸多态性,在加性模型(OR=1.51,95%CI=1.19-1.92,p=7.4×10-4,q=0.018)和显性模型(OR=1.59,95%CI=1.20-2.08,p=9.2×10-4,q=0.023)中独立于传统的心脑血管病危险因素与缺血性脑卒中显著关联。位于ZNF650基因内含子的rs10204475和基因间的单核甘酸多态性rs10486776都在显性模型中均独立于传统的心血管危险因素与缺血性脑卒中相关联(OR=1.47,95%CI=1.12-1.96,p=0.005,q=0.040和OR=1.53,95%CI=1.15-2.02,p=0.003,q=0.036)。卒中亚型分析在多重校正后未发现有统计学意义的阳性结果。 [实验结论]我们在中国汉族人中证实了之前报道的缺血性脑卒中和rs11052413、rs10486776、和ZNF650基因的rs10204475之间的关联。然而,这些遗传变异在脑卒中发挥作用的机制有待进一步阐明。中文摘要 [研究目的]非对称甲基精氨酸(ADMA),一种内源性的精氨酸的类似物,通过抑制一氧化氮的生成在内皮功能失调中发挥着非常重要的作用。在本研究中,我们考察了位于非对称甲基精氨酸水解酶(DDAH1)基因启动子区一个新的多态性位点是否改变了脑卒中与冠心病的遗传易感性。 [研究方法和实验结果]通过对DDAH1基因再测序,在该基因的启动子区我们发现了一个4个碱基插入／缺失的新的多态性位点。其中插入型等位基因破坏了金属调节转录因子1(MTF1)与多态性位点结合,能引起体外DDAH1基因体外转录活性和体内mRNA水平的显著降低,并造成血浆ADMA水平和ADMA/L-精氨酸比值升高。我们首先用TaqMan探针法,在包括1388个脑卒中和1027个对照的样本中以及576个冠心病和557个对照样本中进行基因分型,然后在在包括961个脑卒中和822个对照的样本中以及482个冠心病和1072个对照样本中重复验证上述关联性。我们发现DDAH1基因的启动子区-396位的4个碱基插入等位基因独立于传统的心脑血管病危险因素与血栓性脑卒中和冠心病显著关联。(血栓性脑卒中发现人群：OR=1.35,p=0.032；重复人群：和OR=1.51,p=0.006；冠心病发现人群,OR=1.45,p=0.035；重复人群：和OR=1.47,p=0.003)。 [实验结论]我们的研究提示DDAH1基因功能失活的多态性与血栓性脑卒中和冠心病的遗传易感性相关。
[Abstract]:[objective] multiple susceptibility loci were identified in the first genome-wide association study of ischemic stroke in Caucasians. We have repeatedly demonstrated the association between these loci and ischemic stroke in Chinese Han Chinese. [methods] using TaqMan-MGB probe method, a total of 1123 patients with ischemic stroke (716 thrombotic stroke, 407 lacunar infarction) and 557 normal controls were studied. The 25 common positive loci reported above were genotyped. The association analysis between mononuclear glycolic acid polymorphism and haplotype level was carried out, and the error detection rate (FDRQ) was used to correct the multiple tests. [results] rs11052413, a mononuclear glycosylated polymorphism located between genes, 1.19-1.92p7.4 脳 10 ~ (-4) Q ~ (0.018)) and a dominant model (Orr _ (1.20-2.08) p _ (9.2) 脳 10 ~ (-4) Q _ (0.023)) were significantly associated with ischemic stroke. Both rs10204475 located in the intron of ZNF650 gene and intergenic monoglyceric acid polymorphism rs10486776 were associated with ischemic stroke in the adductive model. Both rs10204475 located in the intron of the ZNF650 gene and monoglyceric acid polymorphisms among genes were associated with ischemic stroke in the dominant model, which was independent of the traditional cardiovascular and cerebrovascular disease risk factors. All of them were independent of traditional cardiovascular risk factors and ischemic stroke. No significant positive results were found in stroke subtype analysis after multiple recalculations. [conclusion] We have confirmed the association between previously reported ischemic stroke and rs11052413 rs10486776, and the rs10204475 of ZNF650 gene in Chinese Han population. However, the mechanism of these genetic variations in stroke needs to be further elucidated. [objective] asymmetric methylarginine (ADMAA), an endogenous arginine analogue, plays a very important role in endothelial dysfunction by inhibiting the production of nitric oxide. We investigated whether a new polymorphic locus located in the promoter of asymmetric methylarginine hydrolase (DDAH1) gene changed the genetic susceptibility to stroke and coronary heart disease (CHD). [methods and experimental results] by resequencing the DDAH1 gene, In the promoter region of the gene, we found a new polymorphic locus with four base inserts / deletions, in which the insertion allele destroyed the binding of metal-regulated transcription factor 1 (MTF1) to the polymorphic locus. In vitro, the transcription activity of DDAH1 gene in vitro and the level of mRNA in vivo were significantly decreased, and the plasma ADMA level and ADMA / L- arginine ratio were increased. Genotyping was performed in 1388 stroke and 1027 controls, 576 coronary heart disease and 557 control samples. The association was then repeatedly validated in 961 stroke and 822 control samples, 482 coronary heart disease and 1072 control samples. We found 4 base insertion alleles at -396-position of the promoter region of the DDAH1 gene. Independent of traditional cardiovascular and cerebrovascular disease risk factors were significantly associated with thrombotic stroke and coronary heart disease. [conclusion] our study suggests that the polymorphism of inactivation of DDAH1 gene is associated with genetic susceptibility to thrombotic stroke and coronary heart disease.
【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2010
【分类号】：R54;R743;R394

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