Predicting sudden cardiac death using common genetic risk variants for coronary artery disease

Jussi A Hernesniemi; Leo-Pekka Lyytikäinen; Niku Oksala; Ilkka Seppälä; Marcus E Kleber; Nina Mononen; Winfried März; Jussi Mikkelsson; Tanja Pessi; Anne-Mari Louhelainen; Mika Martiskainen; Kjell Nikus; Norman Klopp; Melanie Waldenberger; Thomas Illig; Mika Kähönen; Reijo Laaksonen; Pekka J Karhunen; Terho Lehtimäki

doi:10.1093/eurheartj/ehv106

Predicting sudden cardiac death using common genetic risk variants for coronary artery disease

Eur Heart J. 2015 Jul 7;36(26):1669-75. doi: 10.1093/eurheartj/ehv106. Epub 2015 Apr 23.

Authors

Jussi A Hernesniemi¹, Leo-Pekka Lyytikäinen², Niku Oksala³, Ilkka Seppälä², Marcus E Kleber⁴, Nina Mononen², Winfried März⁵, Jussi Mikkelsson⁶, Tanja Pessi⁷, Anne-Mari Louhelainen⁸, Mika Martiskainen⁸, Kjell Nikus⁹, Norman Klopp¹⁰, Melanie Waldenberger¹¹, Thomas Illig¹², Mika Kähönen¹³, Reijo Laaksonen², Pekka J Karhunen⁸, Terho Lehtimäki²

Affiliations

¹ Department of Clinical Chemistry, University of Tampere, Tampere University Hospital and Fimlab Laboratories, Tampere, Finland North Karelia Central Hospital, Tikkamäentie 16, Joensuu 80210, Finland jussi.hernesniemi@uta.fi.
² Department of Clinical Chemistry, University of Tampere, Tampere University Hospital and Fimlab Laboratories, Tampere, Finland.
³ Department of Clinical Chemistry, University of Tampere, Tampere University Hospital and Fimlab Laboratories, Tampere, Finland Department of Vascular Surgery, University of Tampere, Tampere University Hospital and Fimlab Laboratories, Tampere, Finland.
⁴ Department of Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
⁵ Department of Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany Synlab Academy, Synlab Services GmbH, Mannheim, Germany Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
⁶ Department of Forensic Medicine, University of Tampere, Tampere University Hospital and Fimlab Laboratories, Tampere, Finland Satakunta Central Hospital, Pori, Finland.
⁷ Department of Forensic Medicine, University of Tampere, Tampere University Hospital and Fimlab Laboratories, Tampere, Finland The Pirkanmaa Hospital District's Science Centre, Tampere, Finland.
⁸ Department of Forensic Medicine, University of Tampere, Tampere University Hospital and Fimlab Laboratories, Tampere, Finland.
⁹ Department of Cardiology, Heart Hospital and University of Tampere Medical School, Tampere, Finland.
¹⁰ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Munich, Germany Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.
¹¹ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Munich, Germany Institute of Epidemiology II, Helmholtz Zentrum München, Munich, Germany.
¹² Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Munich, Germany Hannover Unified Biobank, Hannover Medical School, Hannover, Germany Institute for Human Genetics, Hannover Medical School, Hanover, Germany.
¹³ Department of Clinical Physiology, University of Tampere, Tampere University Hospital and Fimlab Laboratories, Tampere, Finland.

PMID: 25908775
DOI: 10.1093/eurheartj/ehv106

Abstract

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 (GRSCAD) 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 GRSCAD 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, GRSCAD 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 × 10(-6)) for one allele increase in GRSCAD. The same association was seen in both sexes. GRSCAD 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 × 10(-7)].

Conclusion: Genetic risk estimate for CAD may also be used to predict SCD.

Keywords: Coronary artery disease; Death; Genetics; Sudden.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Autopsy
Coronary Artery Disease / genetics*
Death, Sudden, Cardiac / etiology
Death, Sudden, Cardiac / prevention & control*
Epidemiologic Methods
Female
Genetic Predisposition to Disease / genetics
Genetic Variation
Genotype
Humans
Male
Middle Aged
Polymorphism, Single Nucleotide / genetics