Polymorphisms in multiple genes are associated with resting heart rate in a stepwise allele-dependent manner.

OBJECTIVE: The purpose of this study was to use a candidate gene approach to identify common polymorphisms that are associated with resting sinus heart rate in a population without overt cardiovascular disease. BACKGROUND: Increased resting heart rate is significantly associated with susceptibility to development of myocardial infarction, sudden cardiac death, and overall cardiac mortality. METHODS: A longitudinal cohort of 1468 individuals (active and retired middle-aged Canadian firefighters) who were enrolled in the Firefighters and Their Endothelium (FATE) study was evaluated. Resting heart rate was recorded from the electrocardiogram (ECG) obtained at enrollment. Candidate genes were selected for their known roles in sinus node automaticity and/or its regulation, and single nucleotide polymorphisms (SNPs) with a minor allele frequency of > or =0.20 were targeted. A total of 53 SNPs in 46 genes were selected and analyzed in a screening sample, and 33 SNPs in 29 genes were evaluated in the full population. RESULTS: Univariate analysis detected five putative associations between HR and SNPs. As expected, environmental covariates were identified. Three polymorphisms, ADRB1 G389R, SCN5a H558R, and CASQ1 intron 2, remained statistically significant and independent of covariates. Some alleles were associated with higher and some with lower heart rates. A stepwise increase in heart rate was observed that was dependent on the number of tachycardia-associated alleles with progressive increases in mean heart rate from 51 to 66 bpm. CONCLUSIONS: Common polymorphisms are associated with heart rate in a stepwise allele-dependent manner.