Mediation Effect Of Metabolic Factors On The Association Between Sedentary Behaviors And Incident Coronary Artery Disease

Background and ObjectiveCoronary artery disease(CAD),as the leading cause of death worldwide,is driven by genetic liability,behavioral lifestyle,and metabolic factors.Due to economic growth and lifestyle changes,physical inactivity and prolonged sedentary behaviors have become prevalent worldwide,leading to an increasing burden of chronic diseases like cardiovascular disease(CVD),which has become a critical public health concern.Previous studies have found that sedentary behavior can increase the risk of CAD,while vigorous physical activity may mitigate or even offset the adverse effects of prolonged sedentariness.However,the interplay among sedentary behavior,physical activity,metabolic factors,and CAD risk is not yet fully understood,especially whether sedentary behavior affects CAD risk through metabolic factors.Besides,the combined effect of genetic susceptibility and sedentary time on CAD in the Chinese population remains unknown.Based on these findings,the following scientific questions are raised:the extent to whichphysical activity and metabolic factors contribute to the association between sedentary time and CAD,and the influence of genetic predisposition on the association.Therefore,based on a large prospective cohort study in Chinese,this study investigated the relationship between sedentary behavior and the risk of CAD,focusing on the mediation effects of physical activity and major cardiometabolic risk factors,as well as the modification effect of genetic susceptibility on the association between sedentary time and incident CAD.Subjects and MethodsStudy Subjects:The present study pooled data from three sub-cohorts with sedentary information based on the project of Prediction for Atherosclerotic Cardiovascular Disease Risk in China.Sedentary behaviors were first assessed using a unified questionnaire for all three sub-cohorts,in the 2007-2008 examination.The survey in 2007-2008 thus served as the baseline.Then,all cohorts were followed up twice during 2012-2015 and 2018-2021.Baseline Survey and Follow-up Outcomes:Under unified research protocol and stringent quality control,baseline information was collected by trained healthcare staff through standard questionnaires(demographic characteristics,lifestyles,medical records),physical examinations(height,weight,waist circumference,and blood pressure),and laboratory tests(lipid,fasting glucose).During follow-up,disease and death information was updated by interviewing participants or their proxies and ascertained using hospital records and death certificates.Incident CAD was defined as the first-ever CAD event,including unstable angina,nonfatal acute myocardial infarction,or death due to CAD.Definition of Exposure and Mediators:A standardized questionnaire was used to collect sedentary behaviors information including the average accumulated duration of time spent on television watching and other low energy expenditure activities per day during the prior year.According to the reported dose-response relationship between sedentary time and incident CAD,participants were classified into two groups:<5 and≥5 h/day.The physical activity level for each participant was assessed as the sum of the duration of each type of activity per day during the prior year multiplied by corresponding metabolic equivalent(MET)values.Based on the recommended moderate to vigorous physical activity level,the physical inactivity was defined as<10 MET-h/wk.For metabolic factors,systolic blood pressure(SBP),body mass index(BMI),total cholesterol(TC),and fasting blood glucose were all divided into two groups according to the guideline recommendations.The corresponding non-ideal group was≥140 mmHg,≥28 kg/m2,≥240 mg/dL,and≥126 mg/dL,respectively.Assessment of Genetic Susceptibility to both Metabolic Factors and CAD:For metabolic factors,significant SNPs reported in genome-wide association studies(GWAS)(P<5×10-8)were selected,and the polygenic risk score(PRS)for SBP(SNPs:37),diastolic blood pressure(36),diabetes(86),TC(50),and BMI(49)were calculated by weighting the number of risk alleles.All weights were derived from large-scale GWAS in East Asians.The PRS for BP was the mean of the PRS for SBP and diastolic BP.Genetic susceptibility to CAD was evaluated by using a validated CAD combined PRS reported in the Chinese population,involving 540 single nucleotide polymorphisms(SNPs).According to the quintiles of PRS,participants were categorized into two groups:low-intermediate genetic risk(Q1-Q4)and high genetic risk(Q5).Association Analyses Sedentary Time,Potential Mediators,and Incident CAD:To estimate the hazard ratio(HR)and 95%confidence interval(95%CI)for the associations of sedentary time and potential mediators with incident CAD,the Cox proportional hazards regression model was employed.To estimate the odds ratio(OR)and 95%CI for the association between sedentary time and each binary mediator,the logistic regression model was used.Models were all adjusted for age,sex,cohort sources,living geographical zone,urban or rural residents,education attainment,occupation,smoking status,drinking,healthy diet score,sleep duration,and family history of CVD.Furthermore,additive interaction was quantified with the relative excess risk due to interaction(RERI)and the proportion attributable to interaction(AP).Mediation Analyses of Physical Activity and Metabolic Factors:To fully clarify the roles and relative contributions of each potential mediator and all mediators combined in the association between sedentary behaviors and incident CAD,a variety of methods were utilized.Firstly,analysis with successive adjustments for covariates and potential mediators was used to preliminarily explore the contribution of each mediator and its combination.Secondly,the two-way decomposition method was conducted,using a counterfactual framework and regression analysis to decompose the association effect into natural direct effect and natural indirect effect,and a parallel multiple mediation analysis was also conducted to investigate the comprehensive contribution of multiple mediators to the association.Finally,considering the interaction between sedentary time and each mediator,the four-way decomposition method was used to decompose the total effect in a more detailed way to further analyze the mediation and interaction effects.Based on the parallel multiple mediation analysis,the proportion of CAD risk caused by sedentary behavior could be eliminated by controlling the level of mediators at the value recommended by the guidelines was also explored.Genetic Analyses of Association of Sedentary Time with Incident CAD:To explore the influence of genetic susceptibility to both metabolic factors and CAD on the association between sedentary time and incident CAD,Cox proportional hazard regression model was used.For the joint effect,participants were cross-classified according to the genetic risk(Q1-Q4 and Q5)and sedentary time(<5 and≥5 h/day),with the group of low-intermediate genetic risk and sedentary time<5 h/day as the reference.To assess the additive interaction of genetic risk and sedentary time,RERI and AP indexes were calculated.In addition,the relationship between sedentary time and CAD was explored among different genetic risks.ResultsAssociation of Sedentary Time,Potential Mediators,and Incident CAD:A total of 94,062 participants without CAD history at baseline were included.During a mean followup of 10.7 years(1,008,629 person-years),2,5 66 events of incident CAD were documented.First,compared with the group of sedentary time<5 h/day,sedentary time≥5 h/day was associated with a 62%increased risk of CAD(HR=1.62;95%CI:1.42,1.85).Compared with the physically active group,physical inactivity was also associated with a 29%increased risk of CAD(HR=1.29;95%CI:1.18,1.40).With increasing levels of metabolic factors,the risk of incident CAD was also elevated.Second,participants with sedentary time ≥5 h/day were 2.97 times more likely to be physically inactive than sedentary time<5 h/day(OR=2.97;95%CI:2.84,3.11).Obesity,high SBP,high fasting blood glucose,and high TC were also more likely to occur as sedentary time increased,with the OR(95%CI)of 1.29(1.22,1.37),1.52(1.45,1.58),1.27(1.17,1.38),and 1.48(1.33,1.65),respectively.In addition,synergistically additive interactions between sedentary time and physical activity,fasting blood glucose,and TC levels were observed.Mediation Effects of Physical Activity and Metabolic Factors:When successively adjusting for covariates and potential mediators,SBP and physical activity level seemed to be the most important mediators for the influence of sedentary time on incident CAD.After adjustment for physical activity,the excess risk of CAD associated with sedentary time≥5 h/day decreased by 12.18%(95%CI:7.47%,18.08%).For SBP,the excess risk of CAD decreased by 13.20%(95%CI:9.76%,17.89%),significantly greater than the contribution of other metabolic factors.Moreover,the five mediators collectively explained 26.40%(95%CI:19.85%,35.38%)of excess risk.For the two-way decomposition method,SBP also contributed the most to the association between sedentary time and incident CAD,followed by physical activity,fasting glucose,BMI,and TC levels,respectively.The indirect effect via each mediator can increase the risk of CAD by 1%-5%.For multiple mediators,26.05%(95%CI:19.35%,34.41%)risk of CAD associated with sedentary time≥5 h/day was mediated by a combination of physical activity levels and metabolic factors.For the four-way decomposition method,when exposure-mediator interaction was considered,physical activity,SBP,fasting blood glucose,BMI,and TC levels can explain 12.19%(95%CI:7.77%,19.37%),12.88%(9.93%,17.82%),3.31%(1.50%,4.65%),2.96%(1.84%,4.86%)and 2.74%(1.45%,4.12%)of the total effect of sedentary time>5 hours/day on CAD,respectively.Notably,the interaction effects of sedentary time with physical activity and TC level on the risk of CAD accounted for 39.24%(95%CI:20.50%,66.71%)and 10.03%(2.52%,16.73%)of the total effect,respectively.In addition,when SBP,physical activity,fasting blood glucose,BMI,and TC levels all met the guideline recommendation,the risk of CAD associated with sedentary time was approximately eliminated by 51.48%(95%CI:32.85%,70.39%).Modification Effects of Genetic Risk on Sedentary Time with Incident CAD:A total of 34,388 participants were included in the current genetic analyses,recording 955 CAD events.For genetic susceptibility to CAD,compared with the participants with lowintermediate genetic risk and sedentary time<5 h/day,those with high genetic risk and sedentary time≥5 h/day had the highest risk of CAD,with the HR(95%CI)of 3.04(2.32,3.98).The results were similar for genetic susceptibility to metabolic factors.A synergistically additive effect between genetic susceptibility to CAD and sedentary time was observed(RERI=1.19;95%CI:0.50,1.89).For those at high genetic risk with sedentary time≥5 h/day,39%(AP=0.39;95%CI:0.17,0.62)of the elevated risk could be attributed to the additive effect.No interaction was found between genetic susceptibility to metabolic factors and sedentary time.When stratified by CAD genetic risk,the effect of sedentary time was more pronounced among those with high genetic risk.Specifically,among individuals with low-intermediate genetic risk,the HR(95%CI)of CAD was 1.41(1.08,1.82)for those with sedentary time≥5 h/day in comparison with individuals with sedentary time<5 h/day.The corresponding HR(95%CI)was 2.23(1.44,3.45)among those with high genetic risk.For metabolic factors,associations between sedentary time and incident CAD were similar among different genetic risk groups.ConclusionsOur findings suggested some key points.(1)Prolonged sedentary time,physical inactivity,and elevated metabolic factors(SBP,fasting blood glucose,BMI,and TC)were associated with increased incident CAD.(2)The association between sedentary time and CAD may be accentuated by physical inactivity.(3)Five mediators together might explain about one-quarter of the CAD risk associated with sedentary time≥5 h/day,with SBP and physical activity contributing the most.(4)When SBP,physical activity,fasting blood glucose,BMI,and TC levels were all controlled as guideline recommendations,the detrimental effect of sedentary behaviors was roughly halved.If prolonged sedentary behaviors cannot be controlled effectively,consider intervening in metabolic risk factors such as SBP,hoping to eliminate adverse health effects as much as possible.(5)The results support population-wide efforts to limit sedentary time to prevent CAD,and individuals with a high genetic risk of CAD may benefit more from reduced sedentary time.This study provides population evidence for the potential biological pathway of the association between sedentary time and incident CAD and provides evidence support for the intervention of risk factors and policy making.