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

• Published in: Communications biology Vol. 1; no. 1; p. 49
• Main Authors: Oskarsson, Gudjon R., Kristjansson, Ragnar P., Lee, Amy L., Sveinbjornsson, Gardar, Magnusson, Magnus K., Ivarsdottir, Erna V., Benonisdottir, Stefania, Oddsson, Asmundur, Davidsson, Olafur B., Saemundsdottir, Jona, Halldorsson, Gisli H., Arthur, Joseph, Arnadottir, Gudny A., Masson, Gisli, Jensson, Brynjar O., Holm, Hilma, Olafsson, Isleifur, Onundarson, Pall T., Gudbjartsson, Daniel F., Norddahl, Gudmundur L., Thorsteinsdottir, Unnur, Sulem, Patrick, Stefansson, Kari
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.05.2018; Nature Publishing Group
• Subjects: 45/43; 45/91; 631/208/205/2138; 631/208/2489/144; 82; 82/80; Biology; Biomedical and Life Sciences; Erythrocytes; Erythropoietin; Genome-wide association studies; Genomes; Hemoglobin; Life Sciences; Mutation; Nucleotide sequence
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-018-0053-3

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. Gudjon Oskarsson et al. report the association of a rare variant in the erythropoietin (EPO) receptor gene, EPOR , with serum EPO levels in the Icelandic population. The variant leads to a truncation of EPO-R without an effect on hemoglobin levels, indicating a possible feedback mechanism in the generation of red blood cells.