Elsevier

Atherosclerosis

Volume 240, Issue 2, June 2015, Pages 305-310
Atherosclerosis

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

https://doi.org/10.1016/j.atherosclerosis.2015.03.022Get rights and content

Highlights

  • This study extends the knowledge of genetic risk of coronary artery disease in Danes.

  • A genetic risk score of 45 CAD risk-variants associate with myocardial infarction.

  • The genetic risk score improves C-index but not reclassification by European SCORE risk factors.

Abstract

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.

Section snippets

Background

Cardiovascular disease is the leading cause of death due to non-communicable disease and is projected to cause 23.3 million deaths globally in 2030 [1]. Cardiovascular disease includes coronary artery disease (CAD) caused by atherosclerosis of the coronary arteries, ultimately leading to myocardial infarction (MI). Several modifiable lifestyle-related risk factors such as smoking, dyslipidemia, type 2 diabetes mellitus and elevated blood pressure have been firmly established to increase the

Study samples

The Inter99 study is a randomized, non-pharmacological intervention study for the prevention of ischemic heart disease on 13,016 participants between 30 and 60 years randomly selected from the Civil Registration System. These individuals were randomized to high-intensity (90%) or low-intensity (10%) lifestyle intervention. The study was conducted at the Research Centre for Prevention and Health in Glostrup, Denmark (ClinicalTrials.gov: NCT00289237). 6784 (52%) showed up at the

Results

Table 1 shows the baseline characteristics of the Inter99 study sample. As expected, significant differences between non-cases and cases are evident for all metabolic traits. The SNPs used in the GRS are listed in Supplementary Table 1. Correlation coefficients are presented in Supplementary Table 2.

Discussion

The present study includes 45 known CAD risk variants and found an allele- and tertile-dependent increase in risk of incident MI in a prospective Danish study sample. We did not observe association with CAD risk although we had more cases than for MI. Our analyses of clinical predictive capacity did not reveal improved reclassification of MI cases and non-cases for the GRS.

Acknowledgments

We thank A. Forman, T. Lorentzen, B. Andreasen and G.J. Klavsen for technical assistance and A.L. Nielsen, G. Lademann and M.M.H. Kristensen for management assistance. The study was supported by grants from The Lundbeck Foundation Center for Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care (LuCamp; http://www.lucamp.org) and The Novo Nordisk Foundation Center for Basic Metabolic Research, which is an independent research center at the University of Copenhagen

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