Role of CYP2C9 genetic variants for salt sensitivity and the regulation of the renin-angiotensin-aldosterone system in normotensive men.
OBJECTIVE
Cytochrome P450 (CYP) 2C9 gene polymorphisms have been implicated in regulation of the renin-angiotensin-aldosterone system (RAAS) and salt sensitivity in hypertensive patients. We tested the relevance of CYP2C9 genotypes for regulation of plasma renin activity (PRA), plasma aldosterone concentrations and blood pressure (BP) in response to changes in salt intake in normotensive individuals.


METHODS
Three hundred and ten normotensive men (mean age 24.9 ± 0.1) were studied after a standardized low = 20 mmol/day or high = 220 mmol/day sodium intake for 7 days. Individuals were classified as salt sensitive when the mean arterial BP was more than 3 mmHg higher after high compared with low-salt exposure.


RESULTS
CYP2C9*2 and CYP2C9*3 alleles were not associated with salt-sensitivity status or BP phenotypes; CYP2C9*2 had no effect on PRA or plasma aldosterone. CYP2C9*3 carriers showed a significantly lower PRA compared with CYP2C9*1/*1 individuals in the overall study cohort (high salt: 0.39 ± 0.05 vs. 0.62 ± 0.04 ng/ml per h, P = 0.009; low salt: 2.19 ± 0.27 vs. 2.87 ± 0.13 ng/ml per h, P = 0.013). Salt-sensitive CYP2C9*3 carriers exhibited the lowest PRA values and significantly lower 24 h sodium excretion rates during high-salt intake (P = 0.005 vs. CYP2C9*1/*1). Lower plasma aldosterone concentrations were only observed in salt-resistant CYP2C9*3 carriers under low salt (P = 0.039).


CONCLUSIONS
The present study confirms an association between CYP2C9 polymorphism and activity of the RAAS. Specifically, we detected an overall effect of CYP2C9*3 on lower PRA, but not on salt-sensitive BP regulation in normotensive men. Further studies are needed to analyze the long-term effects of CYP2C9*3 for salt sensitivity and hypertensive diseases.
Bolbrinker
Juliane
J
Institute of Clinical Pharmacology and Toxicology, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany. juliane.bolbrinker@charite.de
Beige
Joachim
J
Huber
Matthias
M
Sharma
Arya M
AM
Thomas
Alexander
A
Deter
Hans-Christian
HC
Kreutz
Reinhold
R
D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001794:Blood Pressure; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D006801:Humans; D008297:Male; D012084:Renin-Angiotensin System; D017673:Sodium Chloride, Dietary / Q000009:adverse effects*
D017673:Sodium Chloride, Dietary; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases