NEDD4L protein truncating variant (v13[G/A]: rs4149601) is associated with essential hypertension in a sample of the Japanese population

The ubiquitin ligase, NEDD4L, participates in plasma volume and blood pressure regulation by controlling cell surface expression of kidney epithelial sodium channel (ENaC). Impairment of ENaC internalization with disrupting Nedd4L binding PY motif in the C‐terminal of the protein showed rare Mendelian human hypertension disorder, Liddle syndrome. Therefore, possible involvements of ENaC‐Nedd4L system abnormalities were suggested in development of human hypertension. Previously, we discovered a common variant, named v13(G/A), that affects the formation of an evolutionally new C2‐encoding isoform of the Nedd4L gene in humans. The aim of this study was to test a hypothesis whether this variant is involved in essential hypertension; we performed the association study in a sample of the Japanese population. We found a gender‐specific genotypic and allelic association with statistical significance achieved only in males. Our data suggest that this genetic variation may contribute to essential hypertension in Japanese male patients through the mechanism of disrupting the C2 encoding isoform in vivo. Furthermore, molecular and functional studies will be required to elucidate the mechanism by which genetic variation in NEDD4L contributes to the development of essential hypertension.