Metabolic Mediators of the Effects of Family History and Genetic Risk Score on Coronary Heart Disease-Findings from the Malmö Diet and Cancer Study

Background--family history of coronary heart disease (chd) as well as genetic predisposition to chd assessed by a genetic risk score (grs) are predictors of chd risk. it is,however,uncertain to what extent these risk predictors are mediated by major metabolic pathways. methods and results--total effects of self-reported family history and a 50-variant grs (grs50),as well as effects mediated by apolipoprotein b and a-i (apob,apoa-i),blood pressure,and diabetes mellitus,on incidence of chd were estimated in 23 595 participants of the malmö diet and cancer study (a prospective,population-based study). during a median follow-up of 14.4 years,2213 participants experienced a first chd event. family history of chd and grs50 (highest versus other quintiles) were associated with incident chd,with hazard ratios of 1.52 (95% ci: 1.39-1.65) and 1.53 (95% ci: 1.39-1.68),respectively,after adjusting for age,sex,and smoking status. small proportions of the family history effect were mediated by metabolic risk factors: 8.3% (95% ci: 5.8-11.7%) by the apob pathway,1.7% (95% ci: 0.2-3.4%) by apoa-i,8.5% (95% ci: 5.9-12.0%) by blood pressure,and 1.5% (95% ci: 0.8% to 3.8%) by diabetes mellitus. similarly,small proportions of grs50 were mediated: 8.1% (95% ci: 5.5-11.8%) by apob,1.2% (95% ci: 0.5-3.0%) by apoa-i,4.2% (95% ci: 1.3-7.5%) by blood pressure,and 0.9% (95% ci: 3.7% to 1.6%) by diabetes mellitus. conclusions--a fraction of the chd risk associated with family history or with grs50 is mediated through elevated blood lipids and hypertension,but not through diabetes mellitus. however,a major part (≥80%) of the genetic effect operates independently of established metabolic risk factor pathways. © 2017 the authors.