高脂血症的遗传变异及炎症与心脑血管病关系的研究
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摘要
[研究目的]最近的全基因组关联研究已经非常明确的证明位于AP0A5/A4/C3/A1基因簇的遗传多态性能够显著的影响血甘油三酯的水平,同时也是冠心病的一个重要的危险因素。本研究目的在于对影响甘油三酯的该区域进行再测序及基因分型研究来系统的阐明该位点的临床意义及潜在的机制。
[研究方法]我们对200例高甘油三酯血症的极端患者及200例正常对照个体进行了AP0A5/A4/C3/A1区域的再测序,然后在4991例正常汉族中国人群中对20个标签SNP进行基因分型。接下来在917例早发冠心病患者和1149例晚发冠心病患者中对12个危险标签SNP进行基因分型。通过再测序我们发现了大量的并且有潜在的功能意义的位点。这些常见的和稀有的多态性位点对高甘油三酯血症具有很明显的累积效应。需要注意的是多态性位点rs2266788显著的与血浆甘油三酯水平、冠心病gensini评分以及冠心病血管病变支数具有相关性。功能研究显示rs266788C等位基因破坏了微小RNA-3201的绑定位点,导致载脂蛋白A5转录增加,血浆水平增加。
[实验结论]AP0A5/A4/C3/A1区域遗传多态性通过增加血浆载脂蛋白A5的水平在血脂调节中起着非常重要的作用,并且对冠心病的病变程度有一定的影响。Rs2266788多态性位点是一个功能性位点,该位点多态性主要通过破坏miR-3201的绑定位点,从而使载脂蛋白A5水平升高。
[研究目的]肿瘤坏死因子α是最典型的促炎细胞因子。目前越来越多的证据显示肿瘤坏死因子α在缺血性中风的发生发展过程中起着非常重要的作用,然而关于这方面的研究却始终没有定论。
[研究方法和实验结果]本次研究首先对肿瘤坏死因子α启动子区近2000碱基对的区域进行了再测序,然后选择了4个多态性位点作为随后的病例—对照研究。我们的研究显示—308G/A位点与脑卒中显著相关,并且我们也重复验证了该结果。荟萃分析的结果也证实该位点确实与脑卒中相关联。另一项基于血浆肿瘤坏死因子水平α的研究也显示脑卒中急性期时血浆中肿瘤坏死因子水平显著升高。体外功能试验说明肿瘤坏死因子启动子区三个多态性位点：-308G/A,-857C/T和1031T/C可能存在着互相作用的机制。
[实验结论]以上的结果显示肿瘤坏死因子在脑卒中的发生过程中可能起着非常重要的作用。
Aims Recent genome-wide association studies (GWAS) have identified the APOA5/A4/C3/A1gene cluster polymorphisms influencing triglyceride level and risk of coronary artery disease (CAD). In this study, we fine-mapped TG association signals in this region and then explored the clinical relevance in CAD and potential underlining mechanisms.
Methods and Results We resequenced the APOA5/A4/C3/A1cluster in200cases with extremely high TG (≥10mm/L) and200matched controls and genotyped20genetic markers among4991participants with Chinese Han ethnicity. Subsequently,12risk markers were investagated in917early onset and1149late onset CAD patients, respectively. By resequencing, a number of newly and potentially functional variants were identified and these common and rare variants have remarkable cumulative effects on HTG risk. Of important note, gene dosage of rs2266788demonstrated a robust association with TG level (p=1.39×10-19), modified gensini scores (p<0.01) and numbers of vascular lesions in CAD patients (OR:1.96,95%CI:1.31-2.14). Functional study demonstrated that rs2266788C allele destroyed miR-3201binding to the3'utr of APOA5, resulting in increase in APOA5translation, and increase plasma APOA5levels.
Conclusions Genetic variants in APOA5/A4/C3/A1gene cluster play an important role in regulation of plasma TG levels by increased APOA5concentration and contribute to the severity of CAD. Rs2266788T>C is a functional variant that elevates plasma APOA5level via destroying miR-3201binding site and therefore slowing degradation of APOA5mRNA.
Aims:Tumor necrosis factor-a (TNF-a) is one of the most typical pro-inflammatory cytokines with both beneficial and destructive properties for the central nervous system. Increasing evidences have demonstrated the important role of TNF-a in the development of ischemic stroke, but studies examining the possible association with stroke or direct functional effects of polymorphisms in TNF-a have been contradictory.
Methods and Results:In this study, a2-kb length of the proximal promoter of the TNF-a was screened and four polymorphisms were investigated in the case-control study. Our date confirmed the association between-308G/A variant with stroke in1388stroke patients and1027controls and replicated in an independent population of961stroke patients and822controls (Odds Ratio (OR)=1.34,95%confidence interval (CI)=1.02to1.77and OR=1.56,95%CI=1.09to2.23, respectively). To reconcile the association between polymorphisms and stroke and to give a comprehensive picture of the genetic architecture of this important gene, we performed a meta-analysis of15published studies in Asian population. Our results demonstrated an association between rs1800629and ischemic stroke (OR=1.43,95%CI=1.21to1.69). Another meta-analysis results of14studies demonstrated that ischemic stroke patients have higher serum TNF-a level than the control subjects (standardized mean difference (SMD)=2.33,95%CI1.85to2.81). In vitro evaluation of potential interaction between variants of the TNF-a gene (-308G/A,-857C/T and-1031T/C) demonstrated that these three polymorphisms can interact together to determine the overall activity of the TNF-a gene.
Conclusions:These findings strongly implicate the involvement of TNF-a in the pathogenesis of stroke.
[研究方法]我们对200例高甘油三酯血症的极端患者及200例正常对照个体进行了AP0A5/A4/C3/A1区域的再测序,然后在4991例正常汉族中国人群中对20个标签SNP进行基因分型。接下来在917例早发冠心病患者和1149例晚发冠心病患者中对12个危险标签SNP进行基因分型。通过再测序我们发现了大量的并且有潜在的功能意义的位点。这些常见的和稀有的多态性位点对高甘油三酯血症具有很明显的累积效应。需要注意的是多态性位点rs2266788显著的与血浆甘油三酯水平、冠心病gensini评分以及冠心病血管病变支数具有相关性。功能研究显示rs266788C等位基因破坏了微小RNA-3201的绑定位点,导致载脂蛋白A5转录增加,血浆水平增加。
[实验结论]AP0A5/A4/C3/A1区域遗传多态性通过增加血浆载脂蛋白A5的水平在血脂调节中起着非常重要的作用,并且对冠心病的病变程度有一定的影响。Rs2266788多态性位点是一个功能性位点,该位点多态性主要通过破坏miR-3201的绑定位点,从而使载脂蛋白A5水平升高。
[研究目的]肿瘤坏死因子α是最典型的促炎细胞因子。目前越来越多的证据显示肿瘤坏死因子α在缺血性中风的发生发展过程中起着非常重要的作用,然而关于这方面的研究却始终没有定论。
[研究方法和实验结果]本次研究首先对肿瘤坏死因子α启动子区近2000碱基对的区域进行了再测序,然后选择了4个多态性位点作为随后的病例—对照研究。我们的研究显示—308G/A位点与脑卒中显著相关,并且我们也重复验证了该结果。荟萃分析的结果也证实该位点确实与脑卒中相关联。另一项基于血浆肿瘤坏死因子水平α的研究也显示脑卒中急性期时血浆中肿瘤坏死因子水平显著升高。体外功能试验说明肿瘤坏死因子启动子区三个多态性位点：-308G/A,-857C/T和1031T/C可能存在着互相作用的机制。
[实验结论]以上的结果显示肿瘤坏死因子在脑卒中的发生过程中可能起着非常重要的作用。
Aims Recent genome-wide association studies (GWAS) have identified the APOA5/A4/C3/A1gene cluster polymorphisms influencing triglyceride level and risk of coronary artery disease (CAD). In this study, we fine-mapped TG association signals in this region and then explored the clinical relevance in CAD and potential underlining mechanisms.
Methods and Results We resequenced the APOA5/A4/C3/A1cluster in200cases with extremely high TG (≥10mm/L) and200matched controls and genotyped20genetic markers among4991participants with Chinese Han ethnicity. Subsequently,12risk markers were investagated in917early onset and1149late onset CAD patients, respectively. By resequencing, a number of newly and potentially functional variants were identified and these common and rare variants have remarkable cumulative effects on HTG risk. Of important note, gene dosage of rs2266788demonstrated a robust association with TG level (p=1.39×10-19), modified gensini scores (p<0.01) and numbers of vascular lesions in CAD patients (OR:1.96,95%CI:1.31-2.14). Functional study demonstrated that rs2266788C allele destroyed miR-3201binding to the3'utr of APOA5, resulting in increase in APOA5translation, and increase plasma APOA5levels.
Conclusions Genetic variants in APOA5/A4/C3/A1gene cluster play an important role in regulation of plasma TG levels by increased APOA5concentration and contribute to the severity of CAD. Rs2266788T>C is a functional variant that elevates plasma APOA5level via destroying miR-3201binding site and therefore slowing degradation of APOA5mRNA.
Aims:Tumor necrosis factor-a (TNF-a) is one of the most typical pro-inflammatory cytokines with both beneficial and destructive properties for the central nervous system. Increasing evidences have demonstrated the important role of TNF-a in the development of ischemic stroke, but studies examining the possible association with stroke or direct functional effects of polymorphisms in TNF-a have been contradictory.
Methods and Results:In this study, a2-kb length of the proximal promoter of the TNF-a was screened and four polymorphisms were investigated in the case-control study. Our date confirmed the association between-308G/A variant with stroke in1388stroke patients and1027controls and replicated in an independent population of961stroke patients and822controls (Odds Ratio (OR)=1.34,95%confidence interval (CI)=1.02to1.77and OR=1.56,95%CI=1.09to2.23, respectively). To reconcile the association between polymorphisms and stroke and to give a comprehensive picture of the genetic architecture of this important gene, we performed a meta-analysis of15published studies in Asian population. Our results demonstrated an association between rs1800629and ischemic stroke (OR=1.43,95%CI=1.21to1.69). Another meta-analysis results of14studies demonstrated that ischemic stroke patients have higher serum TNF-a level than the control subjects (standardized mean difference (SMD)=2.33,95%CI1.85to2.81). In vitro evaluation of potential interaction between variants of the TNF-a gene (-308G/A,-857C/T and-1031T/C) demonstrated that these three polymorphisms can interact together to determine the overall activity of the TNF-a gene.
Conclusions:These findings strongly implicate the involvement of TNF-a in the pathogenesis of stroke.
引文
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