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

Gudjon R Oskarsson; Ragnar P Kristjansson; Amy L Lee; Gardar Sveinbjornsson; Magnus K Magnusson; Erna V Ivarsdottir; Stefania Benonisdottir; Asmundur Oddsson; Olafur B Davidsson; Jona Saemundsdottir; Gisli H Halldorsson; Joseph Arthur; Gudny A Arnadottir; Gisli Masson; Brynjar O Jensson; Hilma Holm; Isleifur Olafsson; Pall T Onundarson; Daniel F Gudbjartsson; Gudmundur L Norddahl; Unnur Thorsteinsdottir; Patrick Sulem; Kari Stefansson

doi:10.1038/s42003-018-0053-3

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

Commun Biol. 2018 May 17:1:49. doi: 10.1038/s42003-018-0053-3. eCollection 2018.

Authors

Gudjon R Oskarsson¹, Ragnar P Kristjansson², Amy L Lee¹, Gardar Sveinbjornsson¹, Magnus K Magnusson^{1

3}, Erna V Ivarsdottir^{1

4}, Stefania Benonisdottir¹, Asmundur Oddsson¹, Olafur B Davidsson¹, Jona Saemundsdottir¹, Gisli H Halldorsson¹, Joseph Arthur¹, Gudny A Arnadottir¹, Gisli Masson¹, Brynjar O Jensson¹, Hilma Holm¹, Isleifur Olafsson⁵, Pall T Onundarson⁶, Daniel F Gudbjartsson^{1

4}, Gudmundur L Norddahl¹, Unnur Thorsteinsdottir^{1

3}, Patrick Sulem¹, Kari Stefansson^{7

8}

Affiliations

¹ deCODE genetics/Amgen, Inc, 101, Reykjavik, Iceland.
² deCODE genetics/Amgen, Inc, 101, Reykjavik, Iceland. ragnar.kristjansson@decode.is.
³ Faculty of Medicine, University of Iceland, 101, Reykjavík, Iceland.
⁴ School of Engineering and Natural Sciences, University of Iceland, 101, Reykjavík, Iceland.
⁵ Department of Clinical Biochemistry, Landspítali University Hospital, 101, Reykjavik, Iceland.
⁶ Department of Laboratory Hematology, Landspítali University Hospital, 101, Reykjavik, Iceland.
⁷ deCODE genetics/Amgen, Inc, 101, Reykjavik, Iceland. kstefans@decode.is.
⁸ Faculty of Medicine, University of Iceland, 101, Reykjavík, Iceland. kstefans@decode.is.

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.