Several members of the EPH
kinase family and their
ligands are involved in blood pressure regulation, and such regulation is often sex- or
sex hormone-dependent, based on animal and human genetic studies. EPHB6 gene knockout (KO) in mice leads to
hypertension in castrated males but not in un-manipulated KO males or females. To assess whether this finding in mice is relevant to human
hypertension, we conducted a human genetic study for the association of EPHB6 and its two
ligands,
EFNB1 and
EFNB3, with
hypertension in hypogonadic patients. Seven hundred and fifty hypertensive and 750 normotensive Han Chinese patients, all of whom were hypogonadic, were genotyped for single nucleotide polymorphisms (SNPs) within the regions of the genes, plus an additional 50 kb 5' of the genes for EPHB6,
EFNB1 and
EFNB3. An imputed insertion/deletion polymorphism, rs35530071, was found to be associated with
hypertension at p-values below the Bonferroni-corrected significance level of 0.0024. This marker is located 5' upstream of the
EFNB3 gene start site. Previous animal studies showed that while male
EFNB3 gene knockout mice were normotensive,
castration of these mice resulted in
hypertension, corroborating the results of the human genetic study. Considering the significant associations of
EFNB3 SNPs with
hypertension in hypogonadic males and supporting evidence from castrated
EFNB3 KO mice, we conclude that loss-of-function variants of molecules in the EPHB6 signaling pathway in the presence of
testosterone are protective against
hypertension in humans.