A genetic risk score of 45 coronary artery disease risk variants associates with increased risk of myocardial infarction in 6041 Danish individuals

Atherosclerosis. 2015 Jun;240(2):305-10. doi: 10.1016/j.atherosclerosis.2015.03.022. Epub 2015 Mar 16.


Background: In Europeans, 45 genetic risk variants for coronary artery disease (CAD) have been identified in genome-wide association studies. We constructed a genetic risk score (GRS) of these variants to estimate the effect on incidence and clinical predictability of myocardial infarction (MI) and CAD.

Methods: Genotype was available from 6041 Danes. An unweighted GRS was constructed by making a summated score of the 45 known genetic CAD risk variants. Registries provided information (mean follow-up = 11.6 years) on CAD (n = 374) and MI (n = 124) events. Cox proportional hazard estimates with age as time scale was adjusted for sex, BMI, type 2 diabetes mellitus and smoking status. Analyses were also stratified either by sex or median age (below or above 45 years of age). We estimated GRS contribution to MI prediction by assessing net reclassification index (NRI) and integrated discrimination improvement (IDI) added to the European SCORE for 10-year MI risk prediction.

Results: The GRS associated significantly with risk of incident MI (allele-dependent hazard ratio (95%CI): 1.06 (1.02-1.11), p = 0.01) but not with CAD (p = 0.39). Stratification revealed association of GRS with MI in men (1.06 (1.01-1.12), p = 0.02) and in individuals above the median of 45.11 years of age (1.06 (1.00-1.12), p = 0.03). There was no interaction between GRS and gender (p = 0.90) or age (p = 0.83). The GRS improved neither NRI nor IDI.

Conclusion: The GRS of 45 GWAS identified risk variants increase the risk of MI in a Danish cohort. The GRS did not improve NRI or IDI beyond the performance of conventional European SCORE risk factors.

Trial registration: ClinicalTrials.gov NCT00289237.

Keywords: Coronary artery disease; Genetic risk score; Myocardial infarction; Single-nucleotide polymorphism.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Comorbidity
  • Coronary Artery Disease / diagnosis
  • Coronary Artery Disease / epidemiology
  • Coronary Artery Disease / genetics*
  • Coronary Artery Disease / prevention & control
  • Denmark / epidemiology
  • Female
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Genetic Testing / methods
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Myocardial Infarction / diagnosis
  • Myocardial Infarction / epidemiology
  • Myocardial Infarction / genetics*
  • Myocardial Infarction / prevention & control
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Predictive Value of Tests
  • Proportional Hazards Models
  • Prospective Studies
  • Regression Analysis
  • Risk Assessment
  • Risk Factors
  • Risk Reduction Behavior
  • Sex Factors
  • Smoking / adverse effects
  • Smoking / epidemiology


  • Genetic Markers

Associated data

  • ClinicalTrials.gov/NCT00289237