A genetic variation associated with plasma erythropoietin and a non-coding transcript of PRKAR1A in sickle cell disease.

TitleA genetic variation associated with plasma erythropoietin and a non-coding transcript of PRKAR1A in sickle cell disease.
Publication TypeJournal Article
Year of Publication2016
AuthorsZhang X, Shah BN, Zhang W, Saraf SL, Miasnikova G, Sergueeva A, Ammosova T, Niu X, Nouraie M, Nekhai S, Castro O, Gladwin MT, Prchal JT, Garcia JGN, Machado RF, Gordeuk VR
JournalHum Mol Genet
Date Published2016 10 15
ISSN Number1460-2083
KeywordsAnemia, Sickle Cell, Antisickling Agents, Cyclic AMP-Dependent Protein Kinase RIalpha Subunit, Erythropoietin, Female, Gene Expression Profiling, Gene Expression Regulation, Genetic Association Studies, Humans, Hydroxyurea, Leukocytes, Mononuclear, Male, Pharmacogenomic Variants, Polymorphism, Single Nucleotide

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.

Alternate JournalHum. Mol. Genet.
PubMed ID28173069
Grant ListK23 HL125984 / HL / NHLBI NIH HHS / United States
P50 HL118006 / HL / NHLBI NIH HHS / United States
R01 HL111656 / HL / NHLBI NIH HHS / United States