Genetic variation in CYP11B2 and AT1R influences heart rate variability conditional on sodium excretion

Sympathetic tone increases with stimulation of the renin-angiotensin system and is under the influence of salt intake. In the European Project On Genes in Hypertension (EPOGH), we investigated whether polymorphisms in the genes encoding aldosterone synthase (CYP11B2 C-344T) and the type-1 angiotensin II receptor (AT1R A1166C) affect the autonomic modulation of heart rate at varying levels of salt intake. We measured the low frequency (LF) and high frequency (HF) components of heart rate variability and their ratio (LF:HF) in the supine and standing positions in 1797 participants (401 families and 320 unrelated subjects) randomly selected from 6 European populations, whose average urinary sodium excretion ranged from 163 to 245 mmol/d. In multivariate analyses with sodium excretion analyzed as a continuous variable, we explored the phenotype-genotype associations using generalized estimating equations and quantitative transmission disequilibrium tests. Across populations, there was no heterogeneity in the phenotype-genotype relations. The genotypic effects differed according to sodium excretion. In subjects with sodium excretion <190 mmol/d (median), supine heart rate, LF, and LF:HF increased and HF decreased with the number of CYP11B2 -344T alleles, and the orthostatic changes in LF, HF, and LF:HF were blunted in carriers of the AT1R 1166C allele. In subjects with sodium excretion >190 mmol/d, these associations with the CYP11B2 and AT1R polymorphisms were nonsignificant or in the opposite direction, respectively. Thus, CYP11B2 C-344T and AT1R A1166C polymorphisms affect the autonomic modulation of heart rate, but these genetic effects depend on sodium excretion.