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

Abstract

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.

• Authors: Josef Fritz, Dov Shiffman, Olle Melander, Hayato Tada, Hanno Ulmer
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 6 Issue 3 (Mar 20 2017) ISSN: 2047-9980 [Electronic] England
• PMID: 28320750 (Publication Type: Journal Article, Observational Study)
• Copyright: © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Chemical References

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

Topics

• Aged
• Apolipoprotein A-I (genetics)
• Apolipoprotein B-100 (genetics)
• Blood Pressure
• Coronary Disease (epidemiology, 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)