1-s2.0-S2352906715000317-main.pdf (234 kB)
Download file

Cumulative effects of common genetic variants on risk of sudden cardiac death.

Download (234 kB)
journal contribution
posted on 22.07.2015, 11:27 by A. Huertas-Vazquez, Christopher P. Nelson, J. S. Sinsheimer, K. Reinier, A. Uy-Evanado, C. Teodorescu, J. Ayala, A. S. Hall, K. Gunson, J. Jui, Nilesh J. Samani, S. S. Chugh
Background Genome-wide association studies and candidate-gene based approaches have identified multiple common variants associated with increased risk of sudden cardiac death (SCD). However, the independent contribution of these individual loci to disease risk is modest. Objective To investigate the cumulative effects of genetic variants previously associated with SCD risk. Methods A total of 966 SCD cases from the Oregon-Sudden Unexpected Death Study and 1926 coronary artery disease controls from the Wellcome Trust Case–Control Consortium were investigated. We generated genetic risk scores (GRSs) for each trait composed of variants previously associated with SCD or with abnormalities in specific electrocardiographic traits such as QRS duration, QTc interval and heart rate. GRSs were calculated using a weighted approach based on the number of risk alleles weighted by the beta coefficients derived from the original studies. We also compared the highest and lowest quintiles for the GRS composed of SCD SNPs. Results Increased cumulative risk was observed for a GRS composed of 14 SCD-SNPs (OR = 1.17 [1.05–1.29], P = 0.002). The risk for SCD was 1.5 fold greater in the highest risk quintile when compared to the lowest risk quintile (OR = 1.46 [1.11–1.92]). We did not observe significant associations with SCD for SNPs that determine electrocardiographic traits. Conclusions A modest but significant effect on SCD risk was identified for a GRS composed of 14 previously associated SCD SNPs. While next generation sequencing methodology will continue to identify additional novel variants, these findings represent proof of concept for the additive effects of gene variants on SCD risk.

Funding

Dr. Adriana Huertas-Vazquez is supported by the American Heart Association Scientist Development Grant (13SDG14640052) and Dr. Janet S. Sinsheimer by the NIH Grant GM05275. Dr. Chistopher P. Nelson and Dr. Nilesh J. Samani are funded by the British Heart Foundation and Dr. Nilesh J. Samani is a NIHR Senior Investigator. Dr. Sumeet S. Chugh is funded by grants from the US National Heart Lung and Blood Institute (R01HL105170 and R01HL122492), and holds the Pauline and Harold Price Endowed Chair in Cardiac Electrophysiology as the Cedars-Sinai Heart Institute, Los Angeles.

History

Citation

IJC Heart & Vasculature, 2015, 7, pp. 88-91

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cardiovascular Sciences

Version

VoR (Version of Record)

Published in

IJC Heart & Vasculature

Publisher

Elsevier Ireland Ltd.

issn

2352-9067

eissn

2352-9067

Acceptance date

01/03/2015

Copyright date

2015

Available date

22/07/2015

Publisher version

http://www.sciencedirect.com/science/article/pii/S2352906715000317

Notes

PMCID: PMC4476546

Language

en

Usage metrics

Categories

Exports