Advanced

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

Fritz, Josef; Shiffman, Dov; Melander, Olle LU ; Tada, Hayato and Ulmer, Hanno (2017) In Journal of the American Heart Association 6(3).
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Coronary heart disease, Epidemiology, Family history, Genetic association, Risk factor
in
Journal of the American Heart Association
volume
6
issue
3
publisher
Wiley-Blackwell
external identifiers
  • scopus:85032574622
ISSN
2047-9980
DOI
10.1161/JAHA.116.005254
language
English
LU publication?
yes
id
143564bb-e849-4b48-a255-46430a7e469d
date added to LUP
2017-11-08 10:02:23
date last changed
2018-01-07 12:25:24
@article{143564bb-e849-4b48-a255-46430a7e469d,
  abstract     = {<p>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.</p>},
  articleno    = {e005254},
  author       = {Fritz, Josef and Shiffman, Dov and Melander, Olle and Tada, Hayato and Ulmer, Hanno},
  issn         = {2047-9980},
  keyword      = {Coronary heart disease,Epidemiology,Family history,Genetic association,Risk factor},
  language     = {eng},
  number       = {3},
  publisher    = {Wiley-Blackwell},
  series       = {Journal of the American Heart Association},
  title        = {Metabolic Mediators of the Effects of Family History and Genetic Risk Score on Coronary Heart Disease-Findings from the Malmö Diet and Cancer Study},
  url          = {http://dx.doi.org/10.1161/JAHA.116.005254},
  volume       = {6},
  year         = {2017},
}