N T Krarup1, A Borglykke2, K H Allin3, C H Sandholt3, J M Justesen3, E A Andersson3, N Grarup3, T Jørgensen4, O Pedersen3, T Hansen5. 1. The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: nikolaj.krarup@sund.ku.dk. 2. Research Center for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark. 3. The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 4. Research Center for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Faculty of Medicine, University of Aalborg, Aalborg, Denmark. 5. The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
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.
RCT Entities:
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.
Authors: Bohdan B Khomtchouk; Diem-Trang Tran; Kasra A Vand; Matthew Might; Or Gozani; Themistocles L Assimes Journal: Brief Bioinform Date: 2020-12-01 Impact factor: 11.622
Authors: Bartłomiej Kisiel; Robert Kruszewski; Aleksandra Juszkiewicz; Anna Raczkiewicz; Artur Bachta; Krzysztof Kłos; Krzysztof Duda; Artur Maliborski; Konrad Szymański; Rafał Płoski; Marek Saracyn; Stanisław Niemczyk; Katarzyna Kisiel; Małgorzata Tłustochowicz; Witold Tłustochowicz Journal: Rheumatol Int Date: 2018-10-29 Impact factor: 2.631