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

J Am Heart Assoc. 2017 Mar 20;6(3):e005254. doi: 10.1161/JAHA.116.005254.


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.

Keywords: coronary heart disease; epidemiology; family history; genetic association; risk factor.

Publication types

  • Observational Study

MeSH terms

  • Aged
  • Apolipoprotein A-I / genetics
  • Apolipoprotein B-100 / genetics
  • Blood Pressure*
  • Coronary Disease / epidemiology*
  • Coronary Disease / genetics
  • Diabetes Mellitus / epidemiology*
  • Female
  • Follow-Up Studies
  • Genetic Predisposition to Disease*
  • Humans
  • Male
  • Medical History Taking*
  • Middle Aged
  • Proportional Hazards Models
  • Prospective Studies
  • Risk Assessment
  • Sweden / epidemiology


  • APOB protein, human
  • Apolipoprotein A-I
  • Apolipoprotein B-100