Abstract
BACKGROUND: Angiotensin-converting enzyme (ACE)-related pathways influence arrhythmias and sudden cardiac arrest (SCA) risk. OBJECTIVE: The purpose of this study was to investigate whether genetic variations in ACE-related pathways are associated with SCA risk. Because these pathways are sex dependent and are influenced by estrogen, we examined these genotype-SCA associations in the full study population and tested for interaction with gender. METHODS: In a population-based case-control study set in King County, Washington, 211 SCA cases (80% male; mean age 59 years,) and 730 age- and gender-matched controls of European descent were genotyped for 47 single nucleotide polymorphisms (SNPs) in eight genes (ACE, AGT, REN, AGTR1, AGTR2, ACE2, KNG1, BDKRB2). The association of SNPs and haplotypes with SCA risk was examined using logistic regression. RESULTS: AGTR1 SNP rs1492099 (allele frequency 15%) was associated with decreased SCA risk (odds ratio [OR] 0.62, 95% confidence interval [CI] 0.4-0.9). Haplotype variation in AGTR2 was associated with SCA risk (global haplotype test P = .001), with haplotype 2 (allele frequency 27%) associated with increased risk (OR 1.26, 95% CI 1.1-1.5). There was interaction with gender on SCA risk for variation in KNG1 (interaction P value range 0.0004-0.017 for 6/8 SNPs). KNG1 SNP rs710448 (allele frequency 42%) was associated with decreased risk (OR 0.44, 95% CI 0.3-0.8) among women but not men. Other SNPs and haplotypes in the eight genes examined were not associated with SCA risk after multiple testing correction. CONCLUSION: Variations in AGTR1 and AGTR2 are associated with SCA risk in a population-based case-control study. There was evidence of interaction with gender on SCA risk for variation in KNG1. These study findings, if replicated, suggest that variation in genes in ACE-related pathways influence SCA risk.