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.


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.
Department of Medical Statistics, Informatics and Health Economics, Medical University of Innsbruck, Austria.
Josef
J
Fritz
Quest Diagnostics, San Juan Capistrano, CA.
Dov
D
Shiffman
Department of Clinical Sciences, Lund University, Malmö, Sweden.|Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.
Olle
O
Melander
Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
Hayato
H
Tada
Department of Medical Statistics, Informatics and Health Economics, Medical University of Innsbruck, Austria hanno.ulmer@i-med.ac.at.
Hanno
H
Ulmer
D000368:Aged; D016632:Apolipoprotein A-I / Q000235:genetics; D053299:Apolipoprotein B-100 / Q000235:genetics; D001794:Blood Pressure; D003327:Coronary Disease / Q000453:epidemiology* / Q000235:genetics; D003920:Diabetes Mellitus / Q000453:epidemiology*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008487:Medical History Taking; D008875:Middle Aged; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018570:Risk Assessment; D013548:Sweden / Q000453:epidemiology
C569471:APOB protein, human; D016632:Apolipoprotein A-I; D053299:Apolipoprotein B-100
coronary heart disease; epidemiology; family history; genetic association; risk factor