A Molecular Epidemiological Study Of Genetic Polymorphisms In Complement Component3gene And Ischemic Stroke Susceptibility

Cerebrovascular disease has become a leading cause of morbidity and mortality,and the incidence is increasing. About70%of our existing patients withcerebrovascular disease are Ischemic stroke (IS), the incidence of IS with anatherosclerosis trigger is growing. Traditional risk factors such as high bloodpressure, smoking, diabetes, atrial fibrillation, and obesity can explain only part ofthe pathogenesis of Stroke. IS, a heterogeneous, multifactor, and polygeneticdisorder of genetic heterogeneity, is the result of mutual interaction betweenindividual’s genetic background (gene-gene) and various environmental factors(gene-environment). Inflammatory response as a major pathological mechanism ofIS has received much attention. There are a little more research filed focusing on therole of the complement system in the pathogenesis of IS in recent years. Thecomplement system involved in the inflammatory response can promote theformation and rupture of AS plaque by initiating the inflammatory response,accelerating the course of IS. As the gene polymorphism has gradually become a hottopic, the Sahlgrenska Academy of Sweden has studied the two C3genetic singlepolymorphisms (SNPs) locs: rs2277984and rs3745565for the first time in2011,but little is known about the relationship between the C3genetic polymorphism andIS susceptibility in Chinese population.This study was a molecular epidemiological study of the relationship betweenthe two complement C3(SNPs), rs2277984and rs3745565, selected by the strokeresearch team of Sweden and IS risk. It was aimed to explore the association of genetic polymorphisms in C3gene with IS susceptibility in Eastern Han Chinese.,and compared with the results of the research team in Sweden. At the same time,it can provide data resource for the relevant genetic study in Eastern Han Chineseabout the human genome epidemiology and make a scientific contribution to thefurther research of IS genetic etiology as well as the individual-specific ISprevention and treatment.[Objective] This study was aimed to explore the association of geneticpolymorphisms in C3gene and IS susceptibility in Eastern Han Chinese.[Method]A case-control study was conducted with a total of700unrelated patientsthat were clinically diagnosed IS and a control group of700non-stroke individuals.All subjects were genetically-unrelated Eastern Han Chinese (mainly from Jiangsuand Anhui provinces) and recruited from the First Affiliated Hospital of NanjingMedical University (Nanjing) from February2009to February2011under a strictinclusion criterion. Carefully designed structural questionnaires of epidemiologywere distributed among them and the relevant clinical indexes, blood samples andgenome DNA were collected. And with tight quality supervision, TaqMan probetechnology was used to genotype and identify the two SNPs of C3gene,i.e.rs2277984and rs3745565, and single locus analysis was employed to explore theeffect of genetic variations in C3on IS risk.[Results]1. Clinical characteristics of subjectsThe present study finished a complete and thorough epidemiology and genotypeinvestigation in700IS cases and a control group of700subjects. The mean age was67.96±9.31for the cases and63.27±9.623for the controls respectively with nostatistically significant difference between the two groups (P=0.133). However, IScases had a higher prevalence of conventional risk factors including sex (male), long-term smoking, people with hypertension and diabetes and were significantlydistinct from the controls (P <0.05). Meanwhile, average clinical indexes such asBMI, SBP, DBP, FPG, TC, TG, LDL-C, UA, and Lp(a) were significantly higher inIS cases than that in controls while the average HDL-C were lower in IS cases thanthat in controls(P<0.05)..2. Single-locus analysisThere was no significant difference between the two groups in genotypicdistributions and allelic frequencies of rs2277984G/A (P>0.05). But in locus ofrs3745565G>C, the frequencies of three genotypes in the case and control groupswere significantly different (P=0.037).,the frequency of C allele in controls washigher than that in IS cases (91.7%vs.88.9%, P=0.043), and also higher than thatin other IS subtypes (except for LAA、CE、SAO)(91.7%VS89.7%, P=0.007).Unadjusted χ2test and Multivariable Logistic regression analysis adjusted for age,sex, BMI were performed under co-dominant, dominant and recessive geneticmodel, it suggested that rs2277984G/A showed no significant relationship with ISsusceptibility. Rs3745565G>C showed a positive with IS susceptibility only underthe recessive genetic model and unadjusted the confounding factors. It shownthat,compared with the GG genotype, rs3745565GC and CC genotype can increasethe IS risk by37%(unadjusted OR=1.37,95%CI1.04-1.80, P=0.026. But therewas no significant association with IS risk after correction (P>0.05).[Conclusion] The two SNPs (rs2277984and rs3745565) of C3gene may not exertan influence on the IS risk in Eastern Han Chinese. The study provides the IS geneticresearch in Eastern Han Chinese with the relevance information about thecomplement gene for the first time, it is expected that further research of other populations could verify the relationship between the C3gene polymorphism and ISsusceptibility.