A truncating mutation in EPOR leads to hypo-responsiveness to erythropoietin with normal haemoglobin.

ABSTRACT: The cytokine erythropoietin (EPO), signalling through the EPO receptor (EPO-R), is essential for the formation of red blood cells. We performed a genome-wide association study (GWAS) testing 32.5 million sequence variants for association with serum EPO levels in a set of 4187 individuals. We detect an association between a rare and well imputed stop-gained variant rs370865377[A] (p.Gln82Ter) in EPOR, carried by 1 in 550 Icelanders, and increased serum EPO levels (MAF?=?0.09%, Effect?=?1.47 SD, P?=?3.3?×?10-7). We validated these findings by measuring serum EPO levels in 34 additional pairs of carriers and matched controls and found carriers to have 3.23-fold higher EPO levels than controls (P?=?1.7?×?10-6; P combined?=?1.6?×?10-11). In contrast to previously reported EPOR mutations, p.Gln82Ter does not associate with haemoglobin levels (Effect?=?-0.045 SD, P?=?0.32, N?=?273,160), probably due to a compensatory EPO upregulation in response to EPO-R hypo-responsiveness.

SUBMITTER: Oskarsson GR 

PROVIDER: S-EPMC6123817 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature