PIII-21Prevalence of NEDD4L Cryptic Splice Site Polymorphism in African-Americans with Hypertension

BACKGROUND The ubiquitin ligase NEDD4L is a candidate gene for essential hypertension based on both physiological and genetic evidence. NEDD4L ubiquinates the distal renal tubule epithelial sodium channel (ENaC) and therefore plays an important role in regulating the trafficking of ENaC from the plasma membrane. Genetic linkage studies of hypertension have also been reported to show linkage to a region 18q which includes the NEDD4L gene. A high prevalence (30%) polymorphism in NEDD4L at G82723A has been recently identified which codes for a cryptic splice site which yields a nonfunctional protein. This polymorphism would presumably lead to an increase in the plasma membrane residence time of ENaC, enhanced distal tubule sodium and water reabsorption, and hypertension. METHODS We tested this hypothesis by determining the frequency of the NEDD4L A allele in African-Americans with hypertension using a case-control design. We studied the frequency of the NEDD4L A allele in 93 hypertensive African-Americans and 98 healthy African-Americans to determine whether there was an association of A allele with hypertension. The DNA was isolated from blood and then genotyped for the variant NEDD4L 82723 A allele using TaqMan-based allelic discrimination assays. RESULTS The patient demographics and NEDD4L A allele frequency is shown in the table below. CONCLUSIONS We found no association between this cryptic splice site NEDD4L 82723 A polymorphism and hypertension in African-Americans. Healthy HTN P value N 98 93 Female 47.9% 56.9% NS Age (years) 42.2 +/− 11.6 48.5 +/− 11.6 0.0002 A allele 34.2% 35.5% NS Clinical Pharmacology & Therapeutics (2005) 79, P64–P64; doi: 10.1016/j.clpt.2005.12.229