The Hyperlipidemia Genetic Variation As Well As The Inflammation With The Relationship Of Cardiovascular And Cerebrovascular Disease

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.