Genome-wide assessment for genetic variants associated with ventricular dysfunction after primary coronary artery bypass graft surgery

Abstract

Background: Postoperative ventricular dysfunction (VnD) occurs in 9-20% of coronary artery bypass graft (CABG) surgical patients and is associated with increased postoperative morbidity and mortality. Understanding genetic causes of postoperative VnD should enhance patient risk stratification and improve treatment and prevention strategies. We aimed to determine if genetic variants associate with occurrence of in-hospital VnD after CABG surgery.

Methods: A genome-wide association study identified single nucleotide polymorphisms (SNPs) associated with postoperative VnD in male subjects of European ancestry undergoing isolated primary CABG surgery with cardiopulmonary bypass. VnD was defined as the need for ≥2 inotropes or mechanical ventricular support after CABG surgery. Validated SNPs were assessed further in two replication CABG cohorts and meta-analysis was performed.

Results: Over 100 SNPs were associated with VnD (P<10(-4)), with one SNP (rs17691914) encoded at 3p22.3 reaching genome-wide significance (P(additive model) = 2.14×10(-8)). Meta-analysis of validation and replication study data for 17 SNPs identified three SNPs associated with increased risk for developing postoperative VnD after adjusting for clinical risk factors. These SNPs are located at 3p22.3 (rs17691914, OR(additive model) = 2.01, P = 0.0002), 3p14.2 (rs17061085, OR(additive model) = 1.70, P = 0.0001) and 11q23.2 (rs12279572, OR(recessive model) = 2.19, P = 0.001).

Conclusions: No SNPs were consistently associated with strong risk (OR(additive model)>2.1) of developing in-hospital VnD after CABG surgery. However, three genetic loci identified by meta-analysis were more modestly associated with development of postoperative VnD. Studies of larger cohorts to assess these loci as well as to define other genetic mechanisms and related biology that link genetic variants to postoperative ventricular dysfunction are warranted.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Schematic illustrating sequence of GWAS study followed by validation study, replication studies, and meta-analysis.

All subjects were of European ancestry and were male unless otherwise specified. * 39 Affymetrix 6.0 SNPs associated with VnD in the GWAS (P−4) or SNPs in strong linkage disequilibrium (r2>0.80; estimated using HaploView 4.1.) with these GWAS SNPs were genotyped from 34 genetic loci for further validation study assessment. † In order to identify SNPs with potentially stronger associations with VnD within some of the genetic loci identified in the GWAS, additional SNPs were genotyped that were in moderate linkage disequilibrium with associated GWAS SNPs (r2 = 0.30–0.70). Correlations (r2) were estimated using HaploView 4.1. ‡ SNP associations with VnD were analyzed by enrolling institution (BWH, THI, and Vanderbilt University Medical Center) with adjustments for age, preoperative LVEF, and duration of CPB time, and then combined by meta-analysis.

Figure 2. The –log P value (lambda adjusted) of the allelic genetic model for each single nucleotide polymorphism (SNP) according to location on the 22 autosomal chromosomes.

Horizontal line indicates the 5×10−8 P value threshold for genome-wide significance.