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

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

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Abstract

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 (GRSCAD) 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 r2 <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 306SCDsdue toCAD(SCDCAD). 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, 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.

Original language	English
Pages (from-to)	1669-1675
Number of pages	7
Journal	European Heart Journal
Volume	36
Issue number	26
DOIs	https://doi.org/10.1093/eurheartj/ehv106
Publication status	Published - 2015
Publication type	A1 Journal article-refereed

Keywords

Coronary artery disease
Death
Genetics
Sudden

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Publication forum level 2

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10.1093/eurheartj/ehv106

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Hernesniemi, J. A., Lyytikäinen, L. P., Oksala, N., Seppälä, I., Kleber, M. E., Mononen, N., März, W., Mikkelsson, J., Pessi, T., Louhelainen, A. M., Martiskainen, M., Nikus, K., Klopp, N., Waldenberger, M., Illig, T., Kähönen, M., Laaksonen, R., Karhunen, P. J., & Lehtimäki, T. (2015). Predicting sudden cardiac death using common genetic risk variants for coronary artery disease. European Heart Journal, 36(26), 1669-1675. https://doi.org/10.1093/eurheartj/ehv106

@article{d12e44f8d9a64eeb8c9134a6a946d67b,

title = "Predicting sudden cardiac death using common genetic risk variants for coronary artery disease",

abstract = "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 (GRSCAD) 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 r2 <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 306SCDsdue toCAD(SCDCAD). 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, 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, Coronary artery disease, Death, Genetics, Sudden",

author = "Hernesniemi, {Jussi A.} and Lyytik{\"a}inen, {Leo Pekka} and Niku Oksala and Ilkka Sepp{\"a}l{\"a} and Kleber, {Marcus E.} and Nina Mononen and Winfried M{\"a}rz and Jussi Mikkelsson and Tanja Pessi and Louhelainen, {Anne Mari} and Mika Martiskainen and Kjell Nikus and Norman Klopp and Melanie Waldenberger and Thomas Illig and Mika K{\"a}h{\"o}nen and Reijo Laaksonen and Karhunen, {Pekka J.} and Terho Lehtim{\"a}ki",

year = "2015",

doi = "10.1093/eurheartj/ehv106",

language = "English",

volume = "36",

pages = "1669--1675",

number = "26",

}

Hernesniemi, JA , Lyytikäinen, LP , Oksala, N, Seppälä, I, Kleber, ME, Mononen, N, März, W, Mikkelsson, J, Pessi, T, Louhelainen, AM, Martiskainen, M , Nikus, K, Klopp, N, Waldenberger, M, Illig, T, Kähönen, M , Laaksonen, R , Karhunen, PJ & Lehtimäki, T 2015, 'Predicting sudden cardiac death using common genetic risk variants for coronary artery disease', European Heart Journal, vol. 36, no. 26, pp. 1669-1675. https://doi.org/10.1093/eurheartj/ehv106

TY - JOUR

T1 - Predicting sudden cardiac death using common genetic risk variants for coronary artery disease

AU - Hernesniemi, Jussi A.

AU - Lyytikäinen, Leo Pekka

AU - Oksala, Niku

AU - Seppälä, Ilkka

AU - Kleber, Marcus E.

AU - Mononen, Nina

AU - März, Winfried

AU - Mikkelsson, Jussi

AU - Pessi, Tanja

AU - Louhelainen, Anne Mari

AU - Martiskainen, Mika

AU - Nikus, Kjell

AU - Klopp, Norman

AU - Waldenberger, Melanie

AU - Illig, Thomas

AU - Kähönen, Mika

AU - Laaksonen, Reijo

AU - Karhunen, Pekka J.

AU - Lehtimäki, Terho

PY - 2015

Y1 - 2015

N2 - 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 (GRSCAD) 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 r2 <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 306SCDsdue toCAD(SCDCAD). 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, 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.

AB - 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 (GRSCAD) 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 r2 <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 306SCDsdue toCAD(SCDCAD). 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, 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.

KW - Coronary artery disease

KW - Death

KW - Genetics

KW - Sudden

KW - Coronary artery disease

KW - Death

KW - Genetics

KW - Sudden

U2 - 10.1093/eurheartj/ehv106

DO - 10.1093/eurheartj/ehv106

M3 - Article

AN - SCOPUS:84942420556

VL - 36

SP - 1669

EP - 1675

IS - 26

ER -

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

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