2.3.4. ENaC Function, CYP4A11 and Responsiveness to Amiloride Therapy

Individuals with variants affecting ENaC function and hypertension may respond preferentially to amiloride therapy. Studies from salt-sensitive hypertensive rodent models showed decreased expression of *Cyp4a* and increased ENaC activity responsive to amiloride [74,75]. Human studies on African American patients with resistant hypertension demonstrated homozygosity for the C allele at rs3890011 of Cytochrome P450 Family 4 Subfamily A Member 11 *(CYP4A11*) (1p33), which has been previously associated with blood pressure in various populations [30,76], and a positive response to amiloride therapy [77]. A large high-density admixture scan in 1670 African Americans with hypertension identified this locus as a candidate gene for hypertension [30]. *CYP4A11* encodes

a member of the cytochrome P450 superfamily of enzymes, a monooxygenase which catalyze reactions involved in the synthesis of cholesterol, steroids, and other lipids and localized to the endoplasmic reticulum. Several lines of evidence suggest that this gene serves as a modulator of ENaC function [75,77], likely through decreased epoxygenase activity and renal synthesis of epoxyeicosatrienoic acids [20,77]. Collectively, although these variants are more frequent in African Americans, their association with hypertension has been weak and/or inconsistent [50,78,79]. Further studies with a larger population size are required to study their effects on hypertension in the African American populations.
