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

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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.


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.



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

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


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IJC Heart & Vasculature


Elsevier Ireland Ltd.





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PMCID: PMC4476546



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