A genetic variation associated with plasma erythropoietin and a non-coding transcript of PRKAR1A in sickle cell disease.
Blood erythropoietin (EPO) increases primarily to hypoxia. In sickle cell anaemia (homozygous HBBE6V; HbSS), plasma EPO is elevated due to hemolytic anaemia-related hypoxia. Hydroxyurea treatment reduces haemolysis and anaemia by increasing foetal haemoglobin, which leads to lower hypoxic transcriptional responses in blood mononuclear cells but paradoxically further increases EPO. To investigate this apparent hypoxia-independent EPO regulation, we assessed two sickle cell disease (SCD) cohorts for genetic associations with plasma EPO, by prioritizing 237,079 quantitative trait loci for expression level and/or transcript isoform variations of 12,727 genes derived from SCD blood mononuclear cells. We found an association between the T allele of SNP rs60684937 and increased plasma EPO (n = 567, combined P = 5.5 × 10 − 8 adjusted for haemoglobin and hydroxyurea) and validated it in independent SCD patients (n = 183, P = 0.018). The T allele of rs60684937 was associated with a relatively increased expression of a non-coding transcript of PRKAR1A (cAMP-dependent protein kinase type I-alpha regulatory subunit) in 58 SCD patients (P = 7.9 × 10 − 7) and 58 HapMap Yoruba samples (P = 0.0011). In conclusion, we demonstrate that plasma EPO elevation with hydroxyurea in SCD is independent of hypoxic responses and that genetic variation at SNP rs60684937 may contribute to EPO regulation through a cAMP-dependent protein kinase A pathway.
Comprehensive Sickle Cell Center, Section of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Xu
X
Zhang
Comprehensive Sickle Cell Center, Section of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Binal N
BN
Shah
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Wei
W
Zhang
Comprehensive Sickle Cell Center, Section of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Santosh L
SL
Saraf
Chuvash Republic Clinical Hospital 1, Cheboksary, Russia.
Galina
G
Miasnikova
Cheboksary Children's Hospital, Cheboksary, Russia.
Adelina
A
Sergueeva
Center for Sickle Cell Disease, Howard University, Washington, DC, USA.
Tatiana
T
Ammosova
Center for Sickle Cell Disease, Howard University, Washington, DC, USA.
Xiaomei
X
Niu
Center for Sickle Cell Disease, Howard University, Washington, DC, USA.
Mehdi
M
Nouraie
Center for Sickle Cell Disease, Howard University, Washington, DC, USA.
Sergei
S
Nekhai
Center for Sickle Cell Disease, Howard University, Washington, DC, USA.
Oswaldo
O
Castro
Division of Pulmonary, Allergy, and Critical Care Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA.
Mark T
MT
Gladwin
Hematology Division, University of Utah, Salt Lake City, UT, USA.
Josef T
JT
Prchal
University of Arizona, College of Medicine, Tucson, AZ, USA.
Joe G N
JG
Garcia
Department of Medicine, Pulmonary and Critical Care Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Roberto F
RF
Machado
Comprehensive Sickle Cell Center, Section of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Victor R
VR
Gordeuk
D000755:Anemia, Sickle Cell / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000986:Antisickling Agents / Q000494:pharmacology / Q000627:therapeutic use; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics*; D004921:Erythropoietin / Q000097:blood / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology* / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide
D000986:Antisickling Agents; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C554270:EPO protein, human; C517834:PRKAR1A protein, human; D004921:Erythropoietin; D006918:Hydroxyurea