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

Research output: Contribution to journalArticleScientificpeer-review

20 Citations (Scopus)


<p>Aims Genome-wide association studies (GWAS) have identified many variants associatingwith 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 Aweighted genetic risk score (GRS<sub>CAD</sub>) was formed from variants most strongly associating with CAD identified by the CARDIoGRAMplusC4D Consortium explaining 10.6% of the heritability ofCAD[153 single-nucleotide polymorphisms with r<sup>2</sup> <0.2]. The association between GRS<sub>CAD</sub> and the occurrence of SCD was studied in three independent autopsy series of consecutive cases combining altogether 1035 autopsies with 306SCDsdue toCAD(SCD<sub>CAD</sub>). Theresultswere 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<sub>CAD</sub> 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<sup>-6</sup>) for one allele increase in GRS<sub>CAD</sub>. The same association was seen in both sexes. GRS<sub>CAD</sub> predicted significantly the risk of SCD<sub>CAD</sub> 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<sup>-7</sup>]. Conclusion Genetic risk estimate for CAD may also be used to predict SCD.</p>
Original languageEnglish
Pages (from-to)1669-1675
Number of pages7
JournalEuropean Heart Journal
Issue number26
Publication statusPublished - 2015
Publication typeA1 Journal article-refereed


  • Coronary artery disease
  • Death
  • Genetics
  • Sudden

Publication forum classification

  • Publication forum level 2


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