title: Association of NEDD4L ubiquitin ligase with essential hypertension.
abstract: NEDD4L is a ubiquitin ligase that controls cell surface expression of kidney epithelial Na+ channels by ubiquitin-mediated endocytosis and lysosome targeting. Thus, it is a significant determinant of Na+ reabsorption in the distal nephron. The NEDD4L gene is located on human chromosome 18q21 within several blood pressure quantitative trait loci, including those for familial orthostatic hypotension, essential hypertension, pulse pressure, and systolic blood pressure response to postural challenge. Because of the importance of NEDD4L to Na+ balance, many of these studies have proposed that mutations in NEDD4L may be responsible for these blood pressure phenotypes. To test this hypothesis, we fine-mapped the NEDD4L region in 2 families with orthostatic hypotension, which we previously reported to be linked to human chromosome 18q21 but failed to implicate NEDD4L in these families. We also typed multiple NEDD4L single-nucleotide polymorphisms (SNPs) in a collection of US whites, Greek whites, and African-Americans individuals with essential hypertension. A significant association between several SNPs and hypertension was observed in all 3 populations. One of the SNPs associated in African Americans is known to result in premature truncation of the NEDD4L protein. Thus, genetic variation in NEDD4L may play a role in the development or progression of some forms of abnormal blood pressure.
authors.affiliation: Center for Human Genetics, Boston University School of Medicine, 715 Albany St, Boston, MA 02118, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Russo
authors.forename: Efthymia
authors.initials: E
authors.lastname: Melista
authors.forename: Jing
authors.initials: J
authors.lastname: Cui
authors.forename: Anita L
authors.initials: AL
authors.lastname: DeStefano
authors.forename: George L
authors.initials: GL
authors.lastname: Bakris
authors.forename: Athanasios J
authors.initials: AJ
authors.lastname: Manolis
authors.forename: Haralambos
authors.initials: H
authors.lastname: Gavras
authors.forename: Clinton T
authors.initials: CT
authors.lastname: Baldwin
mesh_terms: D001741:Black or African American / Q000235:genetics; D016022:Case-Control Studies; D002874:Chromosome Mapping; D056827:Endosomal Sorting Complexes Required for Transport; D005260:Female; D006115:Greece / Q000208:ethnology; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D007024:Hypotension, Orthostatic / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D000075702:Nedd4 Ubiquitin Protein Ligases; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D014481:United States / Q000208:ethnology; D044465:White People / Q000235:genetics
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618485:Nedd4L protein, human; D044767:Ubiquitin-Protein Ligases