本文選題：遺傳　切入點：缺血勝腦卒中　出處：《華中科技大學(xué)》2010年博士論文

【摘要】： [研究目的]對白種人缺血性腦卒中的第一個全基因組關(guān)聯(lián)研究(GWAS)確定了多個易感性基因座位。我們在中國漢族人中重復(fù)驗證了這些位點和缺血性腦卒中的關(guān)聯(lián)性。 [研究方法]采用TaqMan-MGB探針法,在包括1123個缺血性腦卒中病例(血栓性卒中716例,腔隙性腦梗塞407例)和557個正常對照的樣本中,對上述報道的25個常見陽性位點進行了基因分型。并在單核甘酸多態(tài)性和單體型水平進行了關(guān)聯(lián)分析,還使用了錯誤發(fā)現(xiàn)率(FDR)q值來進行多重檢驗的校正。 [實驗結(jié)果]rs11052413,一個位于基因之間的單核甘酸多態(tài)性,在加性模型(OR=1.51,95%CI=1.19-1.92,p=7.4×10-4,q=0.018)和顯性模型(OR=1.59,95%CI=1.20-2.08,p=9.2×10-4,q=0.023)中獨立于傳統(tǒng)的心腦血管病危險因素與缺血性腦卒中顯著關(guān)聯(lián)。位于ZNF650基因內(nèi)含子的rs10204475和基因間的單核甘酸多態(tài)性rs10486776都在顯性模型中均獨立于傳統(tǒng)的心血管危險因素與缺血性腦卒中相關(guān)聯(lián)(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)。卒中亞型分析在多重校正后未發(fā)現(xiàn)有統(tǒng)計學(xué)意義的陽性結(jié)果。 [實驗結(jié)論]我們在中國漢族人中證實了之前報道的缺血性腦卒中和rs11052413、rs10486776、和ZNF650基因的rs10204475之間的關(guān)聯(lián)。然而,這些遺傳變異在腦卒中發(fā)揮作用的機制有待進一步闡明。中文摘要 [研究目的]非對稱甲基精氨酸(ADMA),一種內(nèi)源性的精氨酸的類似物,通過抑制一氧化氮的生成在內(nèi)皮功能失調(diào)中發(fā)揮著非常重要的作用。在本研究中,我們考察了位于非對稱甲基精氨酸水解酶(DDAH1)基因啟動子區(qū)一個新的多態(tài)性位點是否改變了腦卒中與冠心病的遺傳易感性。 [研究方法和實驗結(jié)果]通過對DDAH1基因再測序,在該基因的啟動子區(qū)我們發(fā)現(xiàn)了一個4個堿基插入／缺失的新的多態(tài)性位點。其中插入型等位基因破壞了金屬調(diào)節(jié)轉(zhuǎn)錄因子1(MTF1)與多態(tài)性位點結(jié)合,能引起體外DDAH1基因體外轉(zhuǎn)錄活性和體內(nèi)mRNA水平的顯著降低,并造成血漿ADMA水平和ADMA/L-精氨酸比值升高。我們首先用TaqMan探針法,在包括1388個腦卒中和1027個對照的樣本中以及576個冠心病和557個對照樣本中進行基因分型,然后在在包括961個腦卒中和822個對照的樣本中以及482個冠心病和1072個對照樣本中重復(fù)驗證上述關(guān)聯(lián)性。我們發(fā)現(xiàn)DDAH1基因的啟動子區(qū)-396位的4個堿基插入等位基因獨立于傳統(tǒng)的心腦血管病危險因素與血栓性腦卒中和冠心病顯著關(guān)聯(lián)。(血栓性腦卒中發(fā)現(xiàn)人群：OR=1.35,p=0.032；重復(fù)人群：和OR=1.51,p=0.006；冠心病發(fā)現(xiàn)人群,OR=1.45,p=0.035；重復(fù)人群：和OR=1.47,p=0.003)。 [實驗結(jié)論]我們的研究提示DDAH1基因功能失活的多態(tài)性與血栓性腦卒中和冠心病的遺傳易感性相關(guān)。
[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.
【學(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2010
【分類號】：R54;R743;R394

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