高血压表观遗传学调控机制研究及高血压并发症—脑卒中的遗传危险因素研究
发布时间：2018-08-16 13:05
【摘要】：目的：心脑血管病是人类健康的最主要威胁之一,高血压是心脑血管病的最大危险因素,并已成为我国沉重社会负担。因此阐明高血压的发生、发展和转归规律仍是高血压防治的关键。研究表明,高血压是一种遗传和环境因素相互作用的复杂疾病。候选基因策略和全基因组关联研究获得的所有易感位点均未显示出与高血压的较强关联性,高血压的病因问题仍然没有确定解释。近年来,高血压表观遗传学研究已经找到一些线索,可能在环境因素与核基因组间起到沟通桥梁作用,在没有发生基因组变异的情况下影响基因表达水平,从而影响疾病的易感性。DNA甲基化是4个表观遗传调控的重要方式之一。但是在高血压领域,DNA甲基化的研究还有很多问题亟待解答,关于人类高血压全基因组的甲基化研究还鲜有报道。本论文的第一分题从全基因组水平在极端高血压和完美对照组之间,高血压前期未转化和转化组之间比较了外周血DNA甲基化谱的差异,并从两者的交集中找到了两个可能与高血压发病机制相关的DNA甲基化差异位点,并做了初步功能研究。同时,选取与中国人群高血压相关的GWAS阳性位点,初步探索了DNA甲基化修饰作用对表型的影响。 方法：选取来自于山东省日照社区的44例完美对照,44例极端高血压患者,44例前期高血压样本,采用Illumina450K BeadChip甲基化芯片检测所有个体的外周血DNA甲基化状态。采用焦磷酸测序技术重复第一人群芯片结果,随后在扩大的70例完美对照和133例高血压病例中验证阳性的CpG甲基化位点。经两阶段的筛选找出与高血压相关的OVGP1基因。ELISA检测高血压与对照组间的血浆OVGP1蛋白水平。实时荧光定量PCR、Western-blot和免疫荧光实验用于检测OVGP1在内皮细胞的表达。进一步用pull-down实验捕获与OVGP1相互作用的蛋白,并用慢病毒转染HUVEC和THP1细胞,高表达OVGP1,检测高血压相关分子的mRNA水平变化。另一方面,用SNPshot法对第一阶段的高血压和对照人群分析rs1842896和rs7136259两个位点的基因型,结合DNA甲基化数据,分析表观遗传、遗传变异和表型的关系。 结果：在全基因组DNA甲基化筛选阶段共有14个甲基化差异位点在完美对照和极端高血压、高血压前期未转化和转化两个病例对照中均有显著差异,并且甲基化升高或降低的趋势相同。在焦磷酸测序验证后,分别位于OVGP1和CPO基因启动子区的cg20823859和cg17600943位点的甲基化水平在高血压病例中均显著降低,平均甲基化差异分别为-0.11和-0.10,校正年龄、性别和BMI后仍具有显著性(P=0.02和P=0.001)。血浆中OVGP1蛋白水平在高血压人群中也显著高于对照组。OVGP1基因的功能初探结果显示,OVGP1在HUVEC胞浆中表达,通过pull-down捕获到25个可能与OVGP1相互作用的蛋白,其中4个蛋白与高血压的病理过程显著相关。进一步研究发现OVGP1表达升高可使HUVEC和THP1中TGF-β1和GF-β2的mRNA水平分别升高。 基因分型结果显示,已知的中国高血压人群易感位点rs1842896在88例高血压病人和对照中的分布频率具有显著性差异(P0.05)。携带有TT基因型的个体中,极端高血压患者在cg21176026位点的甲基化程度也显著低于完美对照(P0.05),而TG+GG基因型的个体中两组无差异(P=0.39)。进一步我们发现,以DNA甲基化程度β=0.75为临界点,TT基因型携带者并伴随低甲基化状态发生高血压的几率增高,提示cg21176026位点的甲基化修饰可影响高血压危险等位基因rs1842896-T的作用。 结论：本研究采用全基因组甲基化研究策略,初步证明表观遗传调控可能参与高血压的发生发展,并找到两个与高血压发病相关的新靶基因OVGP1和CPO。本研究也探索了遗传变异、表观遗传修饰和高血压的关系,并推断了可能的相互作用模型。但是深入的分子机制仍需进一步研究。 目的：尿酸是嘌呤的代谢终产物。过多的摄取富含嘌呤和果糖的食物已成为目前尿酸水平升高,继而出现高尿酸血症的重要原因。高尿酸血症除了引起痛风,还被认为是高血压、心脏病、肾病和脑卒中的重要危险因素之一。尿酸水平的升高常常先于高血压出现,提示尿酸作为独立的内源性环境因素,直接参与了导致高血压的病理生理过程。本研究采用全基因组DNA甲基化差异筛选策略,研究高尿酸导致高血压的表观遗传机制。 方法：选取来自于山东省日照社区的12例高尿酸血症患者,44例完美对照,44例极端高血压患者,采用Illumina450K BeadChip甲基化芯片检测所有外周血DNA甲基化状态。首先从高尿酸血症患者和完美对照外周血DNA中寻找与高尿酸血症相关的DNA甲基化差异位点,进一步与极端高血压和完美对照间的DNA甲基化差异位点取交集,获得7个在两组比较中DNA甲基化变化一致的位点。随后,在体外用尿酸刺激细胞,检测与差异甲基化位点临近基因的mRNA表达水平的改变。 结果：获得7个可能参与高尿酸导致高血压发病机制相关的DNA甲基化差异位点。其中cg15711973、 cg23812489、 cg02157463和cg23947654位点在高尿酸血症和极端高血压患者中甲基化程度均降低,eg12252547、 cg06827234和cg16051083也在两个病例组中均升高。体外实验显示,尿酸的刺激可以使THP1和Jurkat两种免疫细胞内FLG2的mRNA表达水平显著升高。这与甲基化芯片中,位于FLG2上游TSS1500区CpG位点cg23812489的甲基化水平降低的结果是相符的。位于MAL2启动子区的cg12252547位点在芯片结果中病例组的甲基化水平高于对照组,在体外尿酸刺激下,能使THP1细胞中MAL2的mRNA水平降低,但Jurkat细胞中MAL2的表达水平没有显著改变。cg02157463位点处于JPH3基因的基因体区,在病人体内甲基化程度升高,相对应地,当尿酸刺激THP1和Jurkat细胞时,JPH3的mRNA水平显著降低。但是,我们并没有检测到其它的候选基因(TANC1, PCDHA, ZDHHC14) mRNA表达水平的改变。 结论：本研究采用全基因组DNA甲基化差异位点筛选研究策略,获得了6个可能与高尿酸导致高血压发病相关联的候选基因。这些基因多与钙离子相关通路和神经信号传递有关,提示尿酸升高有可能通过改变基因组中这些基因的DNA甲基化程度,调节基因表达水平,继而参与高尿酸导致高血压的致病过程。 本论文的第一部分研究了高血压发生发展过程中表观遗传学调控机制,在本部分将探讨高血压引起的最为主要的并发症之一——脑卒中的遗传危险因素。由于高血压可直接引起颅内动脉瘤或血管畸形的破裂而发生出血性脑卒,且颅内动脉瘤的病因中遗传因素占据了更主导的地位,因此本部分将以颅内动脉瘤为模型,研究高血压并发症的遗传危险因素。 颅内动脉瘤的破裂能够导致严重的致死性后果。多项全基因组关联研究(genome-wide association studies, GWAS)已经在欧洲人群完成,但是迄今还没有在中国汉族人群开展颅内动脉瘤GWAS研究的报道。为验证欧洲颅内动脉瘤GWAS关联研究发现的新易感位点,本研究在大样本的中国汉人群中调查了10个单核苷酸多态性(single nucleotide polymorphism, SNP)位点与颅内动脉瘤的关联性。 选取649例中国汉族散发颅内动脉瘤患者和1682名正常人,对GWAS研究中已报道的10个候选易感位点采用时间飞行质谱生物芯片系统(Sequenom MassArray)进行基因分型。采用X2检验、logistic回归分析对SNP位点的基因型、等位基因进行相关性分析。结果显示,携带rs12413409-G和rs1980781-C等位基因的个体在病例和对照组中的频率具有显著差异(均为P=0.002),并使患颅内动脉瘤的风险分别增加1.27和1.26倍,并达到Bonferroni校正的检验水准。在加性遗传模式下,rs12413409和rs1980781也与颅内动脉瘤显著相关(分别为OR=1.27,95%CI1.09-1.48, P=0.002和OR=1.26,95%CI1.09-1.45, P=0.002)。进一步按照年龄、破裂与未破裂、动脉瘤的数量分层后发现,在小于60岁的个体中上述两个易感位点与颅内动脉瘤的关联性增强。在等位基因和加性遗传模型的关联分析中,rs12413409和rs1980781可使颅内动脉瘤的破裂风险分别增加1.25倍和1.24倍(P0.005)。携带rs12413409-G和rs1980781-C的个体也更倾向于罹患单发的颅内动脉瘤。而之前GWAS研究报道的其它8个易感基因在本研究中并未显示与中国汉人群颅内动脉瘤具有关联性。 本研究验证了欧洲人群GWAS研究获得的rs12413409和rs1980781两个易感位点,提示它们可能是中国汉人群颅内动脉瘤的遗传风险因素之一。
[Abstract]:Objective:Cardiovascular and cerebrovascular diseases are one of the most important threats to human health.Hypertension is the most important risk factor of cardiovascular and cerebrovascular diseases and has become a heavy social burden in China.Therefore,the occurrence,development and prognosis of hypertension are still the key to the prevention and treatment of hypertension.Studies have shown that hypertension is an interaction of genetic and environmental factors. Complex diseases. Candidate gene strategies and all susceptibility loci obtained from genome-wide association studies have not shown a strong association with hypertension. The etiology of hypertension remains uncertain. In recent years, epigenetic studies of hypertension have found clues that may be able to communicate environmental factors with the nuclear genome. DNA methylation is one of the four important ways of epigenetic regulation. However, in the field of hypertension, DNA methylation research has many problems to be solved urgently. The first part of this paper compares the differences of DNA methylation profiles in peripheral blood at the whole genome level between the extreme hypertension and the perfect control group, between the untransformed and untransformed pre-hypertension groups, and finds two possible sites of DNA methylation differences associated with the pathogenesis of hypertension from their intersection. At the same time, the effect of DNA methylation modification on phenotype was preliminarily explored by selecting GWAS positive sites associated with hypertension in Chinese population.
METHODS: Forty-four perfect controls, 44 patients with extreme hypertension and 44 patients with pre-hypertension were selected from Rizhao community in Shandong Province. DNA methylation status in peripheral blood of all individuals was detected by Illumina 450K Bead Chip methylation chip. Pyrophosphate sequencing technique was used to repeat the results of the first population chip, and then the enlarged 70 cases were perfect. Positive CpG methylation sites were identified in 133 hypertensive patients and controls. OVGP1 gene associated with hypertension was identified by two-stage screening. Plasma levels of OVGP1 protein were detected by ELISA. Real-time fluorescence quantitative PCR, Western-blot and immunofluorescence assays were used to detect the expression of OVGP1 in endothelial cells. The ull-down assay captured the protein interacting with OVGP1 and transfected HUVEC and THP1 cells with lentiviruses to overexpress OVGP1 and detect the changes of mRNA levels of hypertension-related molecules. The relationship between epigenetics, genetic variation and phenotype was analyzed.
Results: A total of 14 methylation sites were found in perfect control and hypertensive patients during the whole genome DNA methylation screening stage, and there were significant differences between the untransformed and untransformed pre-hypertension patients, and the trend of methylation increased or decreased was the same. The methylation levels at Cg20823859 and Cg17600943 loci were significantly lower in hypertensive patients, with mean methylation differences of - 0.11 and - 0.10, respectively. Age, sex and BMI were adjusted for significant differences (P = 0.02 and P = 0.001). The plasma level of OVGP1 protein was also significantly higher in hypertensive patients than in the control group. The results showed that OVGP1 was expressed in the cytoplasm of HUVEC, and 25 proteins possibly interacting with OVGP1 were captured by pull-down. Four of these proteins were significantly correlated with the pathological process of hypertension.
The results of genotyping showed that the distribution frequency of the known susceptibility locus rs1842896 in 88 hypertensive patients and controls was significantly different (P 0.05). In individuals with TT genotype, the methylation level of cg21176026 locus in patients with extreme hypertension was also significantly lower than that of the perfect control (P 0.05), and the TG + GG genotype was significantly lower than that of the control (P 0.05). There was no significant difference between the two groups (P = 0.39). Further, we found that when DNA methylation level beta = 0.75 was the critical point, TT genotype carriers were more likely to develop hypertension accompanied by hypomethylation, suggesting that methylation modification at cg21176026 site could affect the role of the risk allele rs1842896-T for hypertension.
CONCLUSION: The genome-wide methylation strategy was used to preliminarily demonstrate that epigenetic regulation may be involved in the development of hypertension, and two novel target genes, OVGP1 and CPO, were identified. The relationship between genetic variation, epigenetic modification and hypertension was explored, and possible interactions were inferred. However, further research is needed on the molecular mechanism.
Objective: Uric acid is the end product of purine metabolism. Excessive intake of food rich in purine and fructose has become an important cause of increased uric acid levels and subsequent hyperuricemia. Hyperuricemia is considered to be an important risk factor for hypertension, heart disease, kidney disease and stroke in addition to gout. High levels often precede hypertension, suggesting that uric acid, as an independent endogenous environmental factor, is directly involved in the pathophysiological process leading to hypertension.
Methods: 12 hyperuricemia patients, 44 perfect controls and 44 hypertensive patients were selected from Rizhao community of Shandong Province. DNA methylation status of all peripheral blood samples was detected by Illumina 450K Bead Chip methylation chip. DNA related to hyperuricemia was first searched from the DNA of hyperuricemia patients and perfect control peripheral blood samples. The methylation difference sites were further intersected with the DNA methylation difference sites between extreme hypertension and perfect control to obtain seven sites with the same changes in DNA methylation in both groups.
Results: Seven different DNA methylation sites were identified, including Cg15711973, Cg23812489, Cg02157463 and Cg23947654, which may be involved in the pathogenesis of hyperuricemia and hypertension. The levels of DNA methylation were decreased in both hyperuricemia and hypertensive patients, and increased in eg12252547, cg06827234 and cg16051083. In vitro experiments showed that uric acid stimulation significantly increased the expression of FLG2 mRNA in THP1 and Jurkat immune cells. This was consistent with the decrease of methylation level at CpG site cg23812489 in TSS1500 region upstream of FLG2 on the methylation chip. The cg12252547 site in the promoter region of MAL2 was found in the case group. The level of methylation was higher than that of the control group. Under uric acid stimulation in vitro, the level of MAL2 mRNA in THP1 cells decreased, but the level of MAL2 expression in Jurkat cells did not change significantly. However, we did not detect any changes in the expression levels of other candidate genes (TANC1, PCDHA, ZDHHC14).
CONCLUSION: Six candidate genes were identified by genome-wide DNA methylation differential site screening strategy. These genes are mostly related to calcium ion-related pathways and neural signal transduction, suggesting that elevated uric acid may alter the DNA methylation of these genes in the genome. Degree of regulation, gene expression level, and then participate in the pathogenesis of hypertension induced by hyperuricemia.
The first part of this paper studies the epigenetic regulation mechanism in the development of hypertension. In this part, we will explore the genetic risk factors of stroke, one of the most important complications of hypertension. Hereditary factors play a more dominant role in the etiology of intracranial aneurysms, so this part will study the genetic risk factors of hypertension complications with intracranial aneurysms as a model.
Several genome-wide association studies (GWAS) have been performed in European populations, but so far no GWAS studies have been carried out in Chinese Han population. To verify the new findings of the GWAS association study for intracranial aneurysms in Europe This study investigated the association of 10 single nucleotide polymorphism (SNP) loci with intracranial aneurysms in a large sample of Chinese Han population.
A total of 649 Chinese Han sporadic intracranial aneurysms and 1682 normal subjects were selected for genotyping of 10 candidate susceptibility sites reported in the GWAS study using Sequenom Mass Array. The results showed that the frequencies of rs12413409-G and rs1980781-C alleles were significantly different between the case group and the control group (both P = 0.002), and the risk of intracranial aneurysms was increased by 1.27 and 1.26 times respectively, reaching the Bonferroni-calibrated test level. There was a significant association (OR = 1.27, 95% CI 1.09-1.48, P = 0.002 and OR = 1.26, 95% CI 1.09-1.45, P = 0.002, respectively). Further stratification of ruptured and unruptured aneurysms by age and number of aneurysms revealed an increased association between these two susceptibility loci and intracranial aneurysms in individuals younger than 60 years of age. In the analysis, rs12413409 and rs1980781 increased the risk of rupture of intracranial aneurysms by 1.25 and 1.24 times respectively (P 0.005). Individuals carrying rs12413409-G and rs1980781-C were also more likely to develop single intracranial aneurysms. The other eight susceptibility genes reported in the previous GWAS study did not show intracranial motility in Chinese Han population. Aneurysms are associated.
This study confirmed two susceptibility loci, rs12413409 and rs1980781, obtained from the GWAS study in European populations, suggesting that they may be one of the genetic risk factors for intracranial aneurysms in Chinese Han population.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R743.2
本文编号：2186068
[Abstract]:Objective:Cardiovascular and cerebrovascular diseases are one of the most important threats to human health.Hypertension is the most important risk factor of cardiovascular and cerebrovascular diseases and has become a heavy social burden in China.Therefore,the occurrence,development and prognosis of hypertension are still the key to the prevention and treatment of hypertension.Studies have shown that hypertension is an interaction of genetic and environmental factors. Complex diseases. Candidate gene strategies and all susceptibility loci obtained from genome-wide association studies have not shown a strong association with hypertension. The etiology of hypertension remains uncertain. In recent years, epigenetic studies of hypertension have found clues that may be able to communicate environmental factors with the nuclear genome. DNA methylation is one of the four important ways of epigenetic regulation. However, in the field of hypertension, DNA methylation research has many problems to be solved urgently. The first part of this paper compares the differences of DNA methylation profiles in peripheral blood at the whole genome level between the extreme hypertension and the perfect control group, between the untransformed and untransformed pre-hypertension groups, and finds two possible sites of DNA methylation differences associated with the pathogenesis of hypertension from their intersection. At the same time, the effect of DNA methylation modification on phenotype was preliminarily explored by selecting GWAS positive sites associated with hypertension in Chinese population.
METHODS: Forty-four perfect controls, 44 patients with extreme hypertension and 44 patients with pre-hypertension were selected from Rizhao community in Shandong Province. DNA methylation status in peripheral blood of all individuals was detected by Illumina 450K Bead Chip methylation chip. Pyrophosphate sequencing technique was used to repeat the results of the first population chip, and then the enlarged 70 cases were perfect. Positive CpG methylation sites were identified in 133 hypertensive patients and controls. OVGP1 gene associated with hypertension was identified by two-stage screening. Plasma levels of OVGP1 protein were detected by ELISA. Real-time fluorescence quantitative PCR, Western-blot and immunofluorescence assays were used to detect the expression of OVGP1 in endothelial cells. The ull-down assay captured the protein interacting with OVGP1 and transfected HUVEC and THP1 cells with lentiviruses to overexpress OVGP1 and detect the changes of mRNA levels of hypertension-related molecules. The relationship between epigenetics, genetic variation and phenotype was analyzed.
Results: A total of 14 methylation sites were found in perfect control and hypertensive patients during the whole genome DNA methylation screening stage, and there were significant differences between the untransformed and untransformed pre-hypertension patients, and the trend of methylation increased or decreased was the same. The methylation levels at Cg20823859 and Cg17600943 loci were significantly lower in hypertensive patients, with mean methylation differences of - 0.11 and - 0.10, respectively. Age, sex and BMI were adjusted for significant differences (P = 0.02 and P = 0.001). The plasma level of OVGP1 protein was also significantly higher in hypertensive patients than in the control group. The results showed that OVGP1 was expressed in the cytoplasm of HUVEC, and 25 proteins possibly interacting with OVGP1 were captured by pull-down. Four of these proteins were significantly correlated with the pathological process of hypertension.
The results of genotyping showed that the distribution frequency of the known susceptibility locus rs1842896 in 88 hypertensive patients and controls was significantly different (P 0.05). In individuals with TT genotype, the methylation level of cg21176026 locus in patients with extreme hypertension was also significantly lower than that of the perfect control (P 0.05), and the TG + GG genotype was significantly lower than that of the control (P 0.05). There was no significant difference between the two groups (P = 0.39). Further, we found that when DNA methylation level beta = 0.75 was the critical point, TT genotype carriers were more likely to develop hypertension accompanied by hypomethylation, suggesting that methylation modification at cg21176026 site could affect the role of the risk allele rs1842896-T for hypertension.
CONCLUSION: The genome-wide methylation strategy was used to preliminarily demonstrate that epigenetic regulation may be involved in the development of hypertension, and two novel target genes, OVGP1 and CPO, were identified. The relationship between genetic variation, epigenetic modification and hypertension was explored, and possible interactions were inferred. However, further research is needed on the molecular mechanism.
Objective: Uric acid is the end product of purine metabolism. Excessive intake of food rich in purine and fructose has become an important cause of increased uric acid levels and subsequent hyperuricemia. Hyperuricemia is considered to be an important risk factor for hypertension, heart disease, kidney disease and stroke in addition to gout. High levels often precede hypertension, suggesting that uric acid, as an independent endogenous environmental factor, is directly involved in the pathophysiological process leading to hypertension.
Methods: 12 hyperuricemia patients, 44 perfect controls and 44 hypertensive patients were selected from Rizhao community of Shandong Province. DNA methylation status of all peripheral blood samples was detected by Illumina 450K Bead Chip methylation chip. DNA related to hyperuricemia was first searched from the DNA of hyperuricemia patients and perfect control peripheral blood samples. The methylation difference sites were further intersected with the DNA methylation difference sites between extreme hypertension and perfect control to obtain seven sites with the same changes in DNA methylation in both groups.
Results: Seven different DNA methylation sites were identified, including Cg15711973, Cg23812489, Cg02157463 and Cg23947654, which may be involved in the pathogenesis of hyperuricemia and hypertension. The levels of DNA methylation were decreased in both hyperuricemia and hypertensive patients, and increased in eg12252547, cg06827234 and cg16051083. In vitro experiments showed that uric acid stimulation significantly increased the expression of FLG2 mRNA in THP1 and Jurkat immune cells. This was consistent with the decrease of methylation level at CpG site cg23812489 in TSS1500 region upstream of FLG2 on the methylation chip. The cg12252547 site in the promoter region of MAL2 was found in the case group. The level of methylation was higher than that of the control group. Under uric acid stimulation in vitro, the level of MAL2 mRNA in THP1 cells decreased, but the level of MAL2 expression in Jurkat cells did not change significantly. However, we did not detect any changes in the expression levels of other candidate genes (TANC1, PCDHA, ZDHHC14).
CONCLUSION: Six candidate genes were identified by genome-wide DNA methylation differential site screening strategy. These genes are mostly related to calcium ion-related pathways and neural signal transduction, suggesting that elevated uric acid may alter the DNA methylation of these genes in the genome. Degree of regulation, gene expression level, and then participate in the pathogenesis of hypertension induced by hyperuricemia.
The first part of this paper studies the epigenetic regulation mechanism in the development of hypertension. In this part, we will explore the genetic risk factors of stroke, one of the most important complications of hypertension. Hereditary factors play a more dominant role in the etiology of intracranial aneurysms, so this part will study the genetic risk factors of hypertension complications with intracranial aneurysms as a model.
Several genome-wide association studies (GWAS) have been performed in European populations, but so far no GWAS studies have been carried out in Chinese Han population. To verify the new findings of the GWAS association study for intracranial aneurysms in Europe This study investigated the association of 10 single nucleotide polymorphism (SNP) loci with intracranial aneurysms in a large sample of Chinese Han population.
A total of 649 Chinese Han sporadic intracranial aneurysms and 1682 normal subjects were selected for genotyping of 10 candidate susceptibility sites reported in the GWAS study using Sequenom Mass Array. The results showed that the frequencies of rs12413409-G and rs1980781-C alleles were significantly different between the case group and the control group (both P = 0.002), and the risk of intracranial aneurysms was increased by 1.27 and 1.26 times respectively, reaching the Bonferroni-calibrated test level. There was a significant association (OR = 1.27, 95% CI 1.09-1.48, P = 0.002 and OR = 1.26, 95% CI 1.09-1.45, P = 0.002, respectively). Further stratification of ruptured and unruptured aneurysms by age and number of aneurysms revealed an increased association between these two susceptibility loci and intracranial aneurysms in individuals younger than 60 years of age. In the analysis, rs12413409 and rs1980781 increased the risk of rupture of intracranial aneurysms by 1.25 and 1.24 times respectively (P 0.005). Individuals carrying rs12413409-G and rs1980781-C were also more likely to develop single intracranial aneurysms. The other eight susceptibility genes reported in the previous GWAS study did not show intracranial motility in Chinese Han population. Aneurysms are associated.
This study confirmed two susceptibility loci, rs12413409 and rs1980781, obtained from the GWAS study in European populations, suggesting that they may be one of the genetic risk factors for intracranial aneurysms in Chinese Han population.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R743.2
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