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

TY - JOUR

T1 - A genetic risk score of 45 coronary artery disease risk variants associates with increased risk of myocardial infarction in 6041 Danish individuals

AU - Krarup, N T

AU - Borglykke, A

AU - Allin, K H

AU - Sandholt, C H

AU - Justesen, J M

AU - Andersson, E A

AU - Grarup, N

AU - Jørgensen, T.

AU - Pedersen, O

AU - Hansen, T

N1 - Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

PY - 2015/6/1

Y1 - 2015/6/1

N2 - 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.

AB - 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.

KW - Adult

KW - Age Factors

KW - Comorbidity

KW - Coronary Artery Disease

KW - Denmark

KW - Female

KW - Genetic Markers

KW - Genetic Predisposition to Disease

KW - Genetic Testing

KW - Humans

KW - Incidence

KW - Male

KW - Middle Aged

KW - Myocardial Infarction

KW - Phenotype

KW - Polymorphism, Single Nucleotide

KW - Predictive Value of Tests

KW - Proportional Hazards Models

KW - Prospective Studies

KW - Regression Analysis

KW - Risk Assessment

KW - Risk Factors

KW - Risk Reduction Behavior

KW - Sex Factors

KW - Smoking

U2 - 10.1016/j.atherosclerosis.2015.03.022

DO - 10.1016/j.atherosclerosis.2015.03.022

M3 - Journal article

C2 - 25864160

SN - 0021-9150

VL - 240

SP - 305

EP - 310

JO - Atherosclerosis

JF - Atherosclerosis

IS - 2

ER -