Linkage of Nedd4, a Regulator of the Epithelial Sodium Channel, to Primary Hypertension in Blacks

Abstract

40 Salt-sensitive hypertension is common in blacks. A primary renal mechanism may account for the increase in sodium reabsorption since levels of mineralocorticoids, including aldosterone, are often reduced in blacks. Albeit milder, the hypertension in blacks resembles Liddle s syndrome, where mutations in the epithelial sodium channel result in increased numbers of functioning channels and sodium retention. In Liddle s syndrome, molecular mutations in the PY-motif at the COOH-terminus of either the α- or β-subunit prevents binding of Nedd4, an ubiquitin ligase that targets channels for removal from the cell surface. Thus, Nedd4 is a candidate mediator of risk for hypertension in blacks. To evaluate Nedd4 s role, we performed linkage analyses in 86-88 black hypertensive sib pairs. Subjects were genotyped for two highly polymorphic markers, D15S126 and D15S1016, with heterozygosity of 79% and 89%, respectively. Both are within a 5 cM interval of chromosome 15 that contains KIAA0093 or Nedd4. Among the affected sibling pairs, we observed increased allele sharing for D15S126 (π = 0.57; p=0.01) and D15S1016 (π =0.55; p=0.07). Using only hypertensive sibling pairs (n=42-45 pairs) with BMI <32 kg/M 2 resulted in greater allele sharing for both D15S126 (π =0.63; p=0.0001) and D15S1016 (π =0.57; p=0.06). In summary, we show evidence for linkage of hypertension to a region on chromosome 15 containing the gene for Nedd4. While these results need to be confirmed in other samples, they suggest that variability in Nedd4 or a nearby gene(s) confers a strong influence on differences in sodium homeostasis and blood pressure in blacks.