Journal
EUROPEAN HEART JOURNAL
Volume 36, Issue 26, Pages 1669-1675Publisher
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehv106
Keywords
Death; Sudden; Coronary artery disease; Genetics
Categories
Funding
- EU [201668]
- Academy of Finland [77841, 117832, 201888]
- Social Insurance Institution of Finland
- Tampere University Foundation
- Tampere and University Hospital Medical Funds [9N035, X51401, X51001]
- Emil Aaltonen Foundation
- Juho Vainio Foundation
- Finnish Foundation of Cardiovascular Research
- Finnish Cultural Foundation
- Pirkanmaa Regional Fund of the Finnish Cultural Foundation
- Finnish Foundation for Cardiovascular Research
- Aarne Koskelo Foundation
- Tampere Tuberculosis Foundation
- Erkko Foundation
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Aims Genome-wide association studies (GWAS) have identified many variants associating with an increased risk of coronary artery disease (CAD). We studied the possible association between these variants and the risk of sudden cardiac death (SCD). Methods and results A weighted genetic risk score (GRS(CAD)) was formed from variants most strongly associating with CAD identified by the CARDIoGRAMplusC4D Consortium explaining 10.6% of the heritability of CAD [153 single-nucleotide polymorphisms with r(2) < 0.2]. The association between GRS(CAD) and the occurrence of SCD was studied in three independent autopsy series of consecutive cases combining altogether 1035 autopsies with 306 SCDs due to CAD (SCDCAD). The results were replicated in a prospective follow-up study of 2321 patients (mean follow-up time of 6.2 years with 48 incident SCDs of which 39 due to CAD) undergoing clinical exercise test at baseline. In a meta-analysis of the autopsy series, GRS(CAD) associated significantly with the risk of SCDCAD with age, body mass index, and sex adjusted odds ratio (OR) of 1.042 (1.023-1.061, P = 9.1 x 10(-6)) for one allele increase in GRS(CAD). The same association was seen in both sexes. GRS(CAD) predicted significantly the risk of SCDCAD also in a prospective study setting (Cox regression analysis adjusted with all relevant clinical data): hazard ratio 1.049 (1.010-1.090, P = 0.014). In meta-analysis of all cohorts (adjusting further for other genetic markers related to traditional risk factors and QT-interval), the association was highly significant [OR 1.045 (1.028-1.063), P = 1.7 x 10(-7)]. Conclusion Genetic risk estimate for CAD may also be used to predict SCD.
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