Document Detail

Genetic variation in CYP4A11 and blood pressure response to mineralocorticoid receptor antagonism or ENaC inhibition: an exploratory pilot study in African Americans.
MedLine Citation:
PMID:  25064769     Owner:  NLM     Status:  In-Data-Review    
An rs3890011 variant of CYP4A11, which is in linkage disequilibrium with the loss-of-function variant rs1126742, is associated with hypertension in humans. In mice, Cyp4a deficiency results in salt-sensitive hypertension through activation of ENaC. We tested the hypothesis that the rs3890011 variant is associated with blood pressure response to drugs acting via the ENaC pathway. African Americans with volume-dependent, resistant hypertension were randomized to treatment with placebo, spironolactone, amiloride, or combination. Blood pressure responses were analyzed by CYP4A11 genotypes. Rs3890011 (GG:GC:CC = 20:35:28) and rs1126742 (TT:TC:CC = 45:31:7) were in linkage disequilibrium (D' = 1, r = 0.561). Expected small number of rs1126742 CC homozygotes precluded analysis of the effect of this genotype on treatment responses. Spironolactone reduced blood pressure in rs3890011 GG and GC individuals, but not in CC homozygotes (P = .002), whereas amiloride reduced blood pressure similarly in all rs3890011 genotypes. The antihypertensive effects of spironolactone and amiloride were comparable in GG and GC participants, but only amiloride reduced pressure in CC homozygotes (-6.3 ± 7.3/-3.2 ± 4.0 vs. +6.8 ± 7.9/+4.8 ± 8.6 mm Hg, P < .01/<.05). The aldosterone response to spironolactone was also blunted in the CC genotype. In individuals homozygous for the CYP4A11 rs3890011 C allele, blood pressure is resistant to mineralocorticoid receptor antagonism, but sensitive to ENaC inhibition, consistent with ENaC activation. Studies in a larger population are needed to replicate these findings.
Cheryl L Laffer; Fernando Elijovich; George J Eckert; Wanzhu Tu; J Howard Pratt; Nancy J Brown
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Publication Detail:
Type:  Journal Article     Date:  2014-05-09
Journal Detail:
Title:  Journal of the American Society of Hypertension : JASH     Volume:  8     ISSN:  1878-7436     ISO Abbreviation:  J Am Soc Hypertens     Publication Date:  2014 Jul 
Date Detail:
Created Date:  2014-07-28     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101312518     Medline TA:  J Am Soc Hypertens     Country:  United States    
Other Details:
Languages:  eng     Pagination:  475-80     Citation Subset:  IM    
Copyright Information:
Copyright © 2014 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.
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