Abstract 305: Association Between CYP4A11 Variant and Response to Spironolactone, but Not ENac Inhibitor Amiloride

Abstract

CYP4A11 polymorphisms have been associated with hypertension (rs1126742) and CAD (rs3890011) in humans. In mice, deficiency of the Cyp4a gene causes ENaC dysfunction and salt-sensitive hypertension that is abolished by the ENaC inhibitor amiloride. We examined the relationship between genotypes in CYP4A11 and the BP response to amiloride, spironolactone, both drugs, and placebo in 83 hypertensive African American participants in a previously published randomized clinical trial. Genotype frequencies for rs3890011 were CC:GC:GG=28:35:20. The frequency of the loss-of-function variant at rs1126742 was similar to that previously reported (CC:TC:TT=7:31:45), but too small to permit further analysis. There was no difference in baseline SBP (overall mean±SE 142±1) or number of medications (2.3±0.1) among genotype groups. RS3890011 C allele was associated with an attenuated SBP responses to spironolactone (7.3±4.5 in CC versus -9.3±2.6 in GC or GG in the spironolactone only group, p=0.002; -2.7±3.3 in CC versus -12.8±2.3 in GC or GG in subjects receiving spironolactone alone or in combination, p= 0.014, Figure) and similar for DBP (5.0±2.9 in CC versus -6.0±1.7 in GC or GG with spironolactone only, p=0.002; -1.2±2.0 in CC versus -6.3±1.4 in GC or CC in those receiving any spironolactone, p=0.043). Spironolactone reduced BP only in carriers of the rs3890011 G allele. In contrast, there was no difference among genotype groups in the BP response to ENaC inhibitor amiloride. Variation in CYP4A11 influences the response to spironolactone but not amiloride; these data are consistent with studies in genetically modified mice suggesting that a product of CYP4A11 modifies ENaC function.