Zhang Z, et al. - Researchers analyzed data from two human genetic studies, ADVANCE and HCHS/SOL, to determine the link of genetic variants of EPHA4 (a receptor tyrosine kinase) with hypertension. They evaluated the impact of EPHA4 signalling on mouse vascular smooth muscle cell (VSMC) contractility. Among patients with type 2 diabetes in the ADVANCE clinical trial, human female patients but not male patients demonstrated a significant association of a single nucleotide variant (SNV) (rs75843691 hg19 chr2:g.222395371 C>G), located in the third intron of EPHA4 gene, with hypertension. The contractility of VSMCs from female mice but not from male mice was increased due to siRNA knockdown of Epha4 expression in VSMCs. In type 2 diabetic patients, EPHA4 appeared to be a sex-specific hypertension risk gene. VSMC contractility was attenuated by forward EPHA4 signalling and this impact was modified by estrogen. The link between EPHA4 gene and hypertension risks in female patients was explained by the impact of EPHA4 on VSMCs contractility.