24-h ambulatory blood pressure is linked to chromosome 18q21–22 and genetic variation of NEDD4L associates with cross-sectional and longitudinal blood pressure in Swedes

Abstract

Numerous linkage studies have indicated chromosome 18q21-22 as a locus of importance for blood pressure regulation. This locus harbors the neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) gene, which is instrumental for the regulation of the amiloride-sensitive epithelial sodium channel (ENaC). In a linkage study of 16 markers (including two single nucleotide polymorphism markers located within the NEDD4L gene) on chromosome 18 between 70-104 cM and ambulatory blood pressure (ABP), in 118 families, the strongest evidence of linkage was found for 24 h and day-time systolic ABP at the NEDD4L locus (82.25 cM) (P=0.0014). In a large population sample (n=4001), we subsequently showed that a NEDD4L gene variant (rs4149601), which by alternative splicing leads to varying expression of a functionally crucial C2 domain, was associated with diastolic blood pressure (DBP) (P=0.03) and DBP progression over time (P=0.04). A genotype combination of the rs4149601 and an intronic NEDD4L marker (rs2288774) was associated with systolic blood pressure (SBP) (P=0.01), DBP (P=0.04), and progression of both SBP (P=0.03) and DBP (P=0.05) over time. A quantitative transmission disequilibrium test in the family material of the rs4149601 supported this NEDD4L variant as being at least partially causative of the linkage result. In conclusion, our findings suggest that the chromosome 18 linkage peak at 82.25 cM is explained by genetic NEDD4L variation affecting cross-sectional and longitudinal blood pressure, possibly as a consequence of altered NEDD4L interaction with ENaC.

Intracellular Ubiquitylation of the Epithelial Na+ Channel Controls Extracellular Proteolytic Channel Activation via Conformational Change

“…Indeed, in Liddle's syndrome, mutations in the genes encoding ␤-or ␥-ENaC lead to the inactivation of cytosolic PY-motifs that serve as binding sites for the ubiquitin-protein ligase Nedd4-2 (4,5), suggesting that 1) ENaC is regulated by Nedd4-2-dependent ubiquitylation, and 2) this regulation is impaired in Liddle's syndrome. This concept was confirmed recently in a Nedd4-2 KO model, which displays salt-sensitive hypertension (6), and by a number of studies linking Nedd4-2 polymorphisms with essential hypertension (7)(8)(9)(10). Regulation of ENaC by proteolytic cleavage is the other pathway that has drawn a lot of attention in recent years (for a review see Ref.…”

A Physiologic Approach to the Pharmacogenomics of Hypertension

“…Linkage studies in hypertensive families have vaulted the chromosomal region near the neural precursor cell expressed developmentally downregulated 4-like gene (NEDD4L) to candidate gene status 71 . These investigations uncovered a variant (rs4149601) responsible for alternative splicing of NEDD4L.…”

“…One explanation is that the rs4149601 locus does not fully explain the hypertensive phenotype alone, as additional cotransmitted loci may augment or mitigate the effects observed. In the initial linkage analyses, rs4149601 was only partially causative and the presence of a second intronic variant (rs2288774) was required to account for significant differences in SBP 71 . In the PEAR and INVEST trials, a haplotype consisting of the G allele of rs4149601 and C allele of a second SNP rs292449 predicted greater BP response to hydrochlorothiazide as well as adverse cardiovascular outcomes in whites not treated by hydrochlorothiazide 74 .…”

Human Nedd4L rs4149601 G Allele Generates Evolutionary New Isoform I With C2 Domain

“…A previous report also showed that the subjects with a G allele showed significant associations for hypertension and its related phenotype. 4 In addition, in in vitro electrophysiological functional assay using Xenopus oocyte heterologous gene expression systems, we reported that isoform I would suppress ubiquitination for cell surface ENaC by 2 other isoforms. 5 …”