Association Of C47T Polymorphism In SOD2Gene With Coronary Heart Disease

BackgroundCoronary heart disease (CHD) cause great damage to human, and is the leading cause of death and disability. Evidence suggested that the established risk factors, like hypertension, hyperlipemia and smoke, etc, explain only50%of the population occurrence of CHD, indicating that other risk factors also deserve much attention. Considering CHD is a typical multi-factorial genetic diseases, exploration for multiple genes involved in the CHD could help identify high-risk population, and further provide foundation for CHD control and prevention, thus has great academic and practical significance.Oxidative stress induced by reactive oxygen species (ROS) plays an important role in atherosclerosis, which is the pathogenesis of CHD. SOD2, also known as manganese superoxide dismutase (MnSOD), translates in cytosol and translocates into mitochondria, where it catalyses dismutation of superoxide radicals to oxygen and hydrogen peroxide. In recent years, several studies had been performed to evaluate the relationship between C47T polymorphism in SOD2gene and CHD risk. However, the results in the publications were conflicting. Besides, no much information is currently available for the relation of C47T polymorphism in SOD2gene to premature CHD risk.Objectives1. To detect the association of SOD2gene C47T polymorphism with CHD, premature CHD and late-onset CHD risk.2. To explore the possible genetic model of inheritance for C47T polymorphism involved in CHD. Methods1. A hospital-based case-control study was performed with newly-diagnosed CHD patients at Qilu Hospital, who were further divided into premature CHD and late-onset CHD groups. Healthy controls were recruited from the healthy persons examined in the Physical Examination Center at Qilu Hospital. The SOD2gene C47T polymorphism was analyzed by Pyrosequencing. Genetic mode of inheritance was selected based on the heterozygote log odds ratio as a proportion of the homozygote log odds ratio. Univariate and multivariate Logistic regression models were performed to estimate the effect of SOD2gene C47T polymorphism on CHD risk. Univariate and multivariate multinomial Logistic regression models were performed to estimate the effect of SOD2gene C47T polymorphism on premature CHD and late-onset CHD risk, respectively.2. A Meta-analysis was performed with comprehensive search for relevant publications. Genetic mode of inheritance was selected based on the heterozygote log odds ratio as a proportion of the homozygote log odds ratio. Fixed or random effect pooled measure was selected on the basis of homogeneity test among studies. Heterogeneity among studies was evaluated using I2. Meta-regression was used to explore potential sources of between-study heterogeneity (publication year, sex, age and ethnicity). An influence analysis was conducted to describe how robust the pooled estimator is to removal of individual studies. Publication bias was estimated using Harbord test.Main results1. The case-control study:the results from the multivariate logistic regression suggested a dominant model, because of log(OR TC vs. TT)/log(ORCC vs. TT)=1(P=0.579); the mutant genotype of CC+TC was significantly associated with a reduced CHD risk in multivariate logistic regression:OR(95%CI)=0.605(0.426-0.961), and the effect was stronger for premature CHD:OR(95%CI)=0.561(0.380-0.829) that for late-onset CHD:OR(95%CI)=0.705(0.468-1.061) risk.2. The Meta-analysis:results from the Meta-analysis also indicated a dominant model, because of log(ORTC vs. TT)/log(ORCC vs. TT)=1(P=0.784). After excluding the article that deviated from Hardy-Weinberg equilibrium in controls, this Meta-analysis showed a significant association of the CC+TC genotype with reduced CHD risk OR(95%CI)=0.69(0.61-0.78). No individual study was found to have excessive influence on the pooled effect. No significant publication bias was detected. The article deviating from Hardy-Weinberg equilibrium in controls was the main contributor to the between-study heterogeneity.Conclusions1. The SOD2gene C47T polymorphism might serve as a protective factor to CHD risk, and the protection was much significant for premature CHD that that for late-onset CHD.2. The dominant model might be present for SOD2gene C47T polymorphism involved in CHD.