Hypertension (HTN) is a major global health challenge, with 50-60% of patients estimated to have salt-sensitive HTN (ssHTN). Despite decades of research, the genetic basis of ssHTN remains poorly understood. The ubiquitin ligase NEDD4L is a key regulator of the epithelial sodium channel (ENaC), central to renal sodium handling. Given NEDD4L’s role in sodium homeostasis, population variants may significantly influence BP regulation. Unpublished work from our lab has identified three unrelated patients harbouring rare, compounded heterozygous or homozygous variants in the NEDD4L gene, who exhibit symptoms characteristic of Liddle syndrome, a rare form of ssHTN. My current preliminary findings from All of Us (AoU) identified several rare variants that may contribute to ssHTN, and these have been functionally validated in our lab. Moreover, common NEDD4L variants such as rs4149601 and rs2288774 have been associated with BP regulation and salt-sensitivity in multiple populations, which I have also confirmed in AoU. Interestingly, homozygotes of the rs4149601 variant are thought to express a different isoform of NEDD4L, which is traditionally considered the “canonical” isoform, as labelled by genetic databases and experimentally used in basic science settings. Therefore, we have several research questions and objectives for this research project.
Research Questions:
1. How do rs4149601 and rs2288774, as well as rarer NEDD4L variants, associate with BP, salt-sensitivity, and respond to diuretics in UKB?
2. How do these associations compare with findings from AoU, where preliminary data suggest functional impact of several NEDD4L variants?
Objectives
– Perform systematic genotype-phenotype analyses of NEDD4L variants in UKB, integrating BP phenotypes, HTN diagnoses, and extend findings from AoU
– Prioritize variants for functional characterization in cell models
This work will identify clinically relevant NEDD4L variants and support precision medicine approaches.
