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(P<0.05)。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(P<0.05),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(P<0.005)。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。
Object:Cardiovascular and cerebrovascular diseases are significant healthcare issues around the world. Hypertension is leading risk factor for the diseases It has long been known that hypertension is a multifactorial disease caused by environmental and genetic risk factors. Lots of susceptibility loci associated with blood pressure have been identified using candidate gene approach and genome-wide association studies(GWAS), but only accounted for10%of the heritability in population levels. Hypertension has been estimated to be40%-60%contributed by genetic factors, but for which responsible are still unknown. GWAS studies told us that there maybe the mishersitability could explain why GWAS can only discover10%of the susceptible genetic factors in common diseases such as hypertension. One of the reason for misheristablility is epigenetics referning to hentable changes in gene expression float occur without a change in DNA sequence. To date, the best understood epigenetic mechanisms are CpG DNA methylation, histone modifications and microRNA. It has been known that epigenetic mechanism, such as DNA methylation can be modified by environment factors such highsalt diet, smoking, alcohol, methylation could change the DNA expression. DNA methylation in patients has been the subject of inheres interest because of its recently recognized role in disease as well as in the development in normal function of organisms. From1958to now the hypertension prevalence was increased from5.88%to22%. What we changed mostly are our lifestyle and environment not our gene mutations. Therefore we hypothesized that changes in lifestyle and environmental factors as through epigenetic mechanism such as DNA methylation to change gene expression, therefore disease such as hypertension susceptibility. Our hypothesis was tested in two cohorts perfect control(age>50years old; BP<120/80mmHg; no other major CVD nor major risk factors). The aim of present studies was designed to explore the DNA methylation difference in two case-controls (hypertensive vs. perfect control and prehyertensive untransform vs. transform). As well the preliminary functional research about novel target were performed. We also confirmed the rs1842896reported by pervious GWAS in our case-control. Further, the relation among epigenetic, genetic variation and hypertension was analyzed.
Method:we conducted a genome-wide methylation analysis on44severe hypertensive cases,44pre-hypertensive cases and44perfect controls using Illumina450K BeadChip. Pyrosequence was performed on136cases and70controls to validate the most significant CpG sites. The serum level of OVGP1were detected in hypertensives and normotensives by ELISA method, and the expression of OVGP1in endothelial cell(HUVEC) were investigated by real-time PCR, western blot and immunoflourence techniques. Further, pull-down technique was employed in order to capture the proteins interacted possibly with OVGP1from HUVEC. HUVEC was tranfected with lentivirus with OVGP1gene to detect expression changes of genes related with hypertension. In addition, two variants previously reported by GWAS among Chinese hypertensives were genotyped in44server hypertension cases and44perfect controls. We analyzed the relativeship between genotype and epigenetic modification.
Results:In discovery step,14CpG sites were significant difference either between sever hypertension and perfect controls or between pre-hypertensive untransform and transform. cg20823859and cg17600943, in the promoter of OVGP1and CPO respectively, were confirmed in an independent sample of136hypertensives and70normotensives. The two CpG sites showed lower methylation levels in case than in controls, indicating beta value difference were-0.11and-0.10, respectively.(adjusted P=0.02and0.001respectively) The serum level of OVGP1was significantly increased in hypertensives. Our results showed that OVGP1was expressed in the cytoplasm of HUVEC. Twenty five proteins potentially interacted with OVGP1were captured by pull-down method, four of which were associated with the mechanism of hypertension in reported studies. Further, the mRNA levels of TGF-fil and TGF-β2were increased when OVGP1was overexpressed in HUVEC and THP1, respectively.
Comparied44hypertensives well as that of44normotensives, rs1842896was significantly associated with hypertension in allelic and additive genetic models.(P＜0.05) By integrating the genetic and genome-wide DNA methylation data, we found the subjects who were carrying rsl842896TT genotype and showed a value of beta less than0.75on cg21176026sites were prone to hypertension.
Conclusion:Two difference sites identified in peripheral blood genome DNA were associated with hypertension, supporting that changes in DNA methylation may play roles in the pathogenesis of hypertension.
Object:Uric acid is the end product of nucleic acid metabolism. Diets heavy in purine or fructose, or exposure to lead can also contribute to high uric acid levels, which is defined as hyperuricemia. Hyperuricemia is not only the major etiological factor of gout, but also the independent risk factor of hypertension, nephrosis, cardiovascular and cerebrovascular disease. Although it seems possible that high uric acid levels are a mere consequence of disease, high uric acid levels always precede the development of hypertension. It is speculated that uric acid, as endogenous environmental risk factor, participants in the pathogenesis of essential hypertension. In this present study, the genome-wide DNA methylation difference was investigated on hyperuricemic hypertension.
Method:Here we describe the genome-wide pattern of DNA methylation change in human peripheral blood leucocyte from12hyeruricemia patients and44perfect control using Illumina450K BeadChip. We also investigated the differences of DNA methylation between44sever hypertensive patients and44perfect control. Seven DNA methylation difference loci were associated with both hyperuricemia and hypertension. Further, in vitro we detected the expression change of mRNA level of adjacent genes after THP1and Jurkat cell lines were treated with uric acid.
Results:Four significant CpG low methylation sites, including cg15711973、 cg23812489、 cg02157463and cg23947654, were identified in both hyperuricemia and hypertensive cases than in control. The increasing DNA methylation level were observed in cg12252547、 cg06827234and cg16051083. A simultaneous change in mRNA expression was seen for3of those adjacent genes in THP1and Jurkat cell lines treated with uric acid.
Conclusion:Six DNA methylation sites identified were associated with both hyperuricemic and hypertension suggesting that changes in DNA methylation may play an important role in the pathogenesis of hyperuricemic hypertension.
Intracranial aneurysms (IAs) cause a catastrophic consequence when ruptured. Several genome-wide association studies have been performed in European, but these susceptibility loci to IAs have not been validated in Chinese Han patients. To further investigate the roles of these newly identified variants, we replicated individually the previous association of single nucleotide polymorphism(SNP) with the risk of IAs in a large sample size of the Chinese Han race.
Using the Sequenom MassARRAY system, we replicated ten susceptible loci reported in previous genome-wide investigations in649sporadic patients with IAs and1682controls of Chinese. The significant association of rs12413409and rs1980781with sporadic IAs were replicated and shown by allelic association (P=0.002and P=0.002, respectively), as well as by the additive model (adjusted P=0.002and P=0.003, respectively). In younger subgroup, these two variants showed an even stronger association with IAs. Based on the analysis of allele and genotype, rsl2413409-G of CNNM2and rs1980781-C of STARD13increased the risk of IA rupture (adjusted OR=1.25and OR=1.24, respectively). Furthermore, the genotype distributions of rs12413409and rs1980781were marked difference between patients with single IAs and controls (adjusted P=0.001for rs12413409and P=0.001for rs1980781, respectively) after adjustment of modifiable risk factors.
In sporadic IAs, two variants of ten loci identified in previous genome-wide association studies are associated with increased risk of IAs among Chinese Han population.
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