Association And Causal Effect Between Central Obesity And Stroke

Stroke is the first cause of death among Chinese residents,has the characteristics of “four highs and one heavy”,which brings heavy burden to patients,families and society,and has become the focus of chronic disease health management.Studies have found that central obesity is a key factor leading to cardiovascular and cerebrovascular diseases,however the genetic mechanism remains unclear.In recent years,with the change of lifestyle such as dietary habits,the prevalence of central obesity has been increasing year by year.Studies have shown that compared with general obesity,central obesity and abdominal fat deposition are more strongly associated with the risk of chronic diseases.However,existing studies paid too much attention to the impact of general obesity on stroke,and insufficient attention was paid to the harm of central obesity.Furthermore,most of studies were population-based observational studies,and few of them explored the association from the perspective of genetics.Therefore,it has become a key scientific issue to correctly understand the relationship between the two diseases and explore the potential shared genetic determinants between them.Based on prospective study data and genomic data,this study intends to use epidemiological and bioinformatic methods to reveal the relationship between central obesity and stroke,pleiotropic genetic information and potential causal association,to provide novel insights for early prevention and risk factor management of stroke.Objective1.To explore the effect of central obesity on stroke incidence with prospective study data.To determine whether central obesity or waist circumference(WC)is an influential factor of stroke,and to evaluate the effect size of central obesity or WC on the incidence of stroke.2.To determine whether there is a genetic correlation between WC and stroke with genome-wide genetic data.Two different genetic pleiotropic methods are adopted to identify the pleiotropic loci(single nucleotide polymorphisms(SNPs))and genes between them and explore the common biological mechanism.By using the Mendelian Randomization(MR)approach,this study aimed to explore whether there is a causal association between them,the direction of the causal effect and the effect size.Methods1.Using the prospective study data from the Longitudinal Survey of China Health and Retirement(CHARLS)from 2011 to 2018,a total of 10335 middle-aged and elderly people aged 45 years and above were enrolled.Patients with a history of stroke and current stroke at baseline were excluded,and the incidence of stroke events during the follow-up period was observed.Different Cox regression models were used to analyze central obesity or WC on the risk of stroke.To ensure the robustness of the results,propensity score matching was performed to match the baseline characteristics,and competing risk model,subgroup analysis,and exclusion of reverse causality were conducted as sensitivity analyses.2.Using the summary statistics from genome-wide association studies(GWASs)of WC and stroke,genetic data of WC includes 462,166 subjects,genetic data of stroke consists of 446,696 subjects(40585 cases,406,111 controls).Linkage disequilibrium score regression(LDSC)was adopted to estimate the heritability of WC and stroke,and their genetic correlation.The genetic enrichment was visualized by conditional stratified Q-Q plots and fold enrichment plots,and the genetic pleiotropy was quantitatively evaluated by the likelihood ratio test(LRT).Two different genetic pleiotropic methods(conditional false discovery rate(c FDR)and genetic analysis incorporating pleiotropy and annotation(GPA))were applied to identify the genetic pleiotropic SNPs and genes between them and to explore the potential biological mechanism.3.Based on genetic data of WC and stroke,bidirectional MR approach was used to explore the causal effect,causal direction and effect size of central obesity and stroke,and to evaluate the heterogeneity and horizontal pleiotropy of instrumental variables(IVs).The inverse variance weight(IVW)method was used as the main analysis,and various sensitivity analyses such as weighted median method,maximum likelihood method,MR pleiotropy residual sum and outlier(MR-PRESSO)and Causal Analysis Using Summary Effect Estimates(CAUSE)method were used to evaluate the reliability of MR analysis.Results1.Results of population data analysisThe population-based prospective study included 10,335 subjects age 45 and older,including 4752 males and 5583 females.During the median follow-up period of 7.01 years,a total of 665 stroke events occurred,with an incidence density of 9.50/1000person-years.The cumulative incidence of stroke during the follow-up period was6.43%,the average annual incidence was 0.92%.Cox regression analysis adjusted for covariables such as social demographic data,behavior and lifestyle,and disease and health status showed that the HR [95%CI] of central obesity on stroke was 1.43 [1.21,1.68],and various sensitivity analyses also showed the stability of the association between them.The independent variable WC was set as the continuous variable,after the same analysis,multivariate Cox regression analysis showed that the risk of stroke increased by 22% for each standard deviation(SD)increase in WC,and HR [95% CI]was 1.22 [1.12,1.32].2.Results of genetic data analysisWC genetic data includes 462,166 subjects and stroke genetic data includes446,696 subjects.LDSC analysis showed that the heritability of WC and stroke was20.1%(SE=0.007)and 2.2%(SE=0.002),respectively,and the genetic correlation coefficient between them was 0.238(SE=0.034,P=1.76E-12).Pleiotropic visualization analysis revealed genetic enrichment between WC and stroke,and quantitative assessment of pleiotropy showed that pleiotropy enrichment was statistically significant(LRT=43.89,P =3.478E-11).Five pleiotropic SNPs(annotated on 5 genes)were identified by c FDR method,8 pleiotropic SNPs(annotated on 8 genes)were identified by GPA method.Five pleiotropic SNPs(annotated on 5 genes)were identified by the two genetic pleiotropic methods,among which 5 SNPs and 4 genes were newly identified.The two-sample MR analysis of WC and stroke showed that the causal effect size OR [95%CI] estimated by the primary analysis IVW method was 1.26[1.14,1.39],the risk of stroke increased by 26% for each SD increase in WC,and multiple sensitivity analyses showed stable results.Reverse MR analysis showed no causal effect between stroke and WC,and P values were greater than 0.05 in all sensitivity analyses.Conclusions1.Central obesity is a risk factor for stroke in middle-aged and elderly people.Reducing WC and preventing central obesity can help reduce the long-term risk of stroke.2.There was genetic overlap between WC and stroke.Five pleiotropic SNPs(annotated on 5 genes)were identified by two different genetic pleiotropic methods,one of the genes was previously identified,and the others were newly identified common genetic information.3.WC has a potential positive genetic correlation with stroke and may have a positive causal effect.Increased WC or central obesity will increase the risk of stroke.