title: Genetic variation in CYP4A11 and blood pressure response to mineralocorticoid receptor antagonism or ENaC inhibition: an exploratory pilot study in African Americans.
abstract: 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.
authors: The Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA. Electronic address: cheryl.l.laffer@vanderbilt.edu.
authors: Cheryl L
authors: CL
authors: Laffer
authors: The Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors: Fernando
authors: F
authors: Elijovich
authors: The Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: George J
authors: GJ
authors: Eckert
authors: The Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; The Regenstrief Institute, Inc., Indianapolis, IN, USA.
authors: Wanzhu
authors: W
authors: Tu
authors: The Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; The Richard L Roudebush VA Medical Center, Indianapolis, IN, USA.
authors: J Howard
authors: JH
authors: Pratt
authors: The Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors: Nancy J
authors: NJ
authors: Brown
mesh_terms: D000293:Adolescent; D000328:Adult; D001741:Black or African American; D000368:Aged; D001794:Blood Pressure / Q000187:drug effects*; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D004311:Double-Blind Method; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use*; D010865:Pilot Projects; D011863:Radioimmunoassay; D014481:United States / Q000453:epidemiology; D055815:Young Adult
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; C465478:CYP4A11 protein, human; D042926:Cytochrome P-450 CYP4A
keywords: Amiloride; epithelial sodium channel; hypertension; spironolactone