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

Xu Zhang, Binal N. Shah, Wei Zhang, Santosh L. Saraf, Galina Miasnikova, Adelina Sergueeva, Tatiana Ammosova, Xiaomei Niu, Mehdi Nouraie, Sergei Nekhai, Oswaldo Castro, Mark T. Gladwin, Josef T. Prchal, Joe G.N. Garcia, Roberto Machado, Victor R. Gordeuk

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4601-4609
Number of pages9
JournalHuman Molecular Genetics
Volume25
Issue number20
StatePublished - Jan 1 2016
Externally publishedYes

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Sickle Cell Anemia
Erythropoietin
Hydroxyurea
Cyclic AMP-Dependent Protein Kinases
Single Nucleotide Polymorphism
Blood Cells
Alleles
HapMap Project
Fetal Hemoglobin
Quantitative Trait Loci
Hemolytic Anemia
Hemolysis
Anemia
Protein Isoforms
Hemoglobins
Genes
Hypoxia

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Zhang, X., Shah, B. N., Zhang, W., Saraf, S. L., Miasnikova, G., Sergueeva, A., ... Gordeuk, V. R. (2016). A genetic variation associated with plasma erythropoietin and a non-coding transcript of PRKAR1A in sickle cell disease. Human Molecular Genetics, 25(20), 4601-4609.

A genetic variation associated with plasma erythropoietin and a non-coding transcript of PRKAR1A in sickle cell disease. / Zhang, Xu; Shah, Binal N.; Zhang, Wei; Saraf, Santosh L.; Miasnikova, Galina; Sergueeva, Adelina; Ammosova, Tatiana; Niu, Xiaomei; Nouraie, Mehdi; Nekhai, Sergei; Castro, Oswaldo; Gladwin, Mark T.; Prchal, Josef T.; Garcia, Joe G.N.; Machado, Roberto; Gordeuk, Victor R.

In: Human Molecular Genetics, Vol. 25, No. 20, 01.01.2016, p. 4601-4609.

Research output: Contribution to journalArticle

Zhang, 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, R & Gordeuk, VR 2016, 'A genetic variation associated with plasma erythropoietin and a non-coding transcript of PRKAR1A in sickle cell disease', Human Molecular Genetics, vol. 25, no. 20, pp. 4601-4609.
Zhang X, Shah BN, Zhang W, Saraf SL, Miasnikova G, Sergueeva A et al. A genetic variation associated with plasma erythropoietin and a non-coding transcript of PRKAR1A in sickle cell disease. Human Molecular Genetics. 2016 Jan 1;25(20):4601-4609.
Zhang, Xu ; Shah, Binal N. ; Zhang, Wei ; Saraf, Santosh L. ; Miasnikova, Galina ; Sergueeva, Adelina ; Ammosova, Tatiana ; Niu, Xiaomei ; Nouraie, Mehdi ; Nekhai, Sergei ; Castro, Oswaldo ; Gladwin, Mark T. ; Prchal, Josef T. ; Garcia, Joe G.N. ; Machado, Roberto ; Gordeuk, Victor R. / A genetic variation associated with plasma erythropoietin and a non-coding transcript of PRKAR1A in sickle cell disease. In: Human Molecular Genetics. 2016 ; Vol. 25, No. 20. pp. 4601-4609.
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AU - Saraf, Santosh L.

AU - Miasnikova, Galina

AU - Sergueeva, Adelina

AU - Ammosova, Tatiana

AU - Niu, Xiaomei

AU - Nouraie, Mehdi

AU - Nekhai, Sergei

AU - Castro, Oswaldo

AU - Gladwin, Mark T.

AU - Prchal, Josef T.

AU - Garcia, Joe G.N.

AU - Machado, Roberto

AU - Gordeuk, Victor R.

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N2 - 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.

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