Blood erythropoietin (EPO) increases primarily to hypoxia. In sickle cell anemia (homozygous HBBE6V ; HbSS), plasma EPO is elevated due to hemolytic anemia-related hypoxia. Hydroxyurea treatment reduces hemolysis and anemia by increasing fetal hemoglobin, 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 hemoglobin and hydroxyurea) and validated it in independent SCD patients (n=183, P=0.018). The T allele of rs60684937 was associated with 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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