Novel Loci Associated with Increased Risk of Sudden Cardiac Death in the Context of Coronary Artery Disease

Adriana Huertas-Vázquez ,Katherine Jerger,Christopher P Nelson,Jerome I Rotter,Kyndaron Reinier,Kent D Taylor,Sumeet S Chugh,Alistair S Hall,Harpriya Chugh,Panos Deloukas,Sara L Pulit,Carmen Teodorescu,Jo Ayala,Peter S Braund,Anthony J Balmforth,Karen Gunson,Nilesh J Samani,Xiuqing Guo,Jonathan Jui,Audrey Uy‐Evanado ,Albert Chen ,Christopher Newton‐Cheh ,L A Jones ,Wtccc

doi:10.1371/journal.pone.0059905

Abstract

BackgroundRecent genome-wide association studies (GWAS) have identified novel loci associated with sudden cardiac death (SCD). Despite this progress, identified DNA variants account for a relatively small portion of overall SCD risk, suggesting that additional loci contributing to SCD susceptibility await discovery. The objective of this study was to identify novel DNA variation associated with SCD in the context of coronary artery disease (CAD).Methods and FindingsUsing the MetaboChip custom array we conducted a case-control association analysis of 119,117 SNPs in 948 SCD cases (with underlying CAD) from the Oregon Sudden Unexpected Death Study (Oregon-SUDS) and 3,050 controls with CAD from the Wellcome Trust Case-Control Consortium (WTCCC). Two newly identified loci were significantly associated with increased risk of SCD after correction for multiple comparisons at: rs6730157 in the RAB3GAP1 gene on chromosome 2 (P = 4.93×10−12, OR = 1.60) and rs2077316 in the ZNF365 gene on chromosome 10 (P = 3.64×10−8, OR = 2.41).ConclusionsOur findings suggest that RAB3GAP1 and ZNF365 are relevant candidate genes for SCD and will contribute to the mechanistic understanding of SCD susceptibility.

Highlights

Sudden cardiac death (SCD) remains a significant public health problem with an estimated annual incidence of 250,000–300,000 in the US and 4–5 million around the globe [1,2,3]
Our findings suggest that RAB3GAP1 and zinc finger protein 365 gene (ZNF365) are relevant candidate genes for sudden cardiac death (SCD) and will contribute to the mechanistic understanding of SCD susceptibility
We hypothesized that the distinct configuration of the MetaboChip custom array which contains variants nominally associated (P,0.01) with coronary artery disease (CAD), QT interval, systolic and diastolic blood pressure, diabetes, glycemic traits, lipids, height and weight in large-scale metaanalyses of genome-wide association (GWA) studies [14] would enable the identification of additional novel genetic variation associated with SCD in the context of CAD

Summary

Introduction

Sudden cardiac death (SCD) remains a significant public health problem with an estimated annual incidence of 250,000–300,000 in the US and 4–5 million around the globe [1,2,3]. Recent collaborative genome-wide association (GWA) efforts have identified susceptibility loci associated with SCD [8,9,10] but only two DNA variants on chromosomes 2q24 (BAZ2B) [10] and 21q21 (near CXADR) [9] have crossed the stringent threshold of genomewide statistical significance. Recent genome-wide association studies (GWAS) have identified novel loci associated with sudden cardiac death (SCD). Despite this progress, identified DNA variants account for a relatively small portion of overall SCD risk, suggesting that additional loci contributing to SCD susceptibility await discovery. The objective of this study was to identify novel DNA variation associated with SCD in the context of coronary artery disease (CAD)

Objectives

Methods

Results

Discussion

Conclusion