Abstract
The vaso-occlusive crisis (VOCs) in sickle cell disease (SCD) is often associated with stress. Epinephrine released during stress acts via beta 2-adrenergic receptors (β2-AR or ADRB2) to stimulate the synthesis of cyclic adenosine monophosphate (cAMP) in the red blood cells (RBCs). Higher cAMP levels promote adhesion of sickled RBCs to vascular endothelium, a major contributor for VOCs. Several single-nucleotide polymorphisms (SNPs) of the β2-AR gene have been reported; two of them at codon 16 (rs1042713) and codon 27 (rs1042714) have been extensively studied for their clinical relevance. Therefore, we assessed the influence of polymorphism at these two sites of the β2-AR gene on the RBC cAMP concentrations with and without epinephrine stimulation in SCD subjects. We determined the frequency distribution of different genotypes of codon 16 and codon 27 of the β2-AR gene using the Sanger sequencing method in the SCD subjects. We measured the RBC-cAMP levels at baseline and after stimulation with epinephrine, to ascertain the influence of different genotypes in determining cAMP levels. There was no difference in the socio-demographic and hematological indicators in different genotypes of both codon 16 and 27. In the sham-treated erythrocytes, the cAMP levels were significantly different with three genotypes of codon 16 (F = 3.39, P = 0.036; one way ANOVA) but not with different genotypes of codon 27. A significant increase in cAMP levels was noticed with epinephrine treatment in all genotypes of codons 16 and 27 (P = 0.001; Wilcoxon signed-rank test). However, the extent of increase in the epinephrine-treated cAMP values from the sham-treated (baseline) cAMP values was significantly different between the three genotypes of codon 16 (H = 8.74; P = 0.012; Kruskal-Wallis test) but not in codon 27 genotypes. Polymorphism in codon 16 (rs1042713) of the β2-AR gene influences cAMP concentrations in the RBC both before and after epinephrine treatment. Higher cAMP levels may lead to increased adhesion of sickle cell RBCs to vascular endothelium and may increase the frequency of VOCs.
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The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgments
We would like to express our appreciation for the support from study participants, hospital nurses, and all staff members of the Sickle Cell Centre for assisting in this project.
Funding
The project was funded by the Ministry of Science and Technology, Department of Biotechnology, Government of India funding (Project Number: BT/Bio-CARe/07/551/2012). The funding agencies had no involvement in study design, data collection, data analysis, and data interpretation.
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P.D. was involved in designing of the study and conceptualizing the manuscript. P.K.M., B.P.J., S.D., and S. Sahoo were involved in the recruitment of SCD cases. B.P.J., S.S., A.R.P., and A.R. did data collection and laboratory work. P.D. and A.R.P. conducted data analysis. R.K.B., A.R.P., and P.P. provided insightful comments in the review of the manuscript. All authors had contributed intellectual input during the study period and contributed to redrafting the manuscript.
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The study was approved by the Institutional Review Board of the Asian Institute of Public health (AIPH) [ERC/No: 2014-04] [ERC/No: 2018- 29] and Veer Surendra Sai Institutional Research & Ethics Committee (VIREC) [ERC No: IEC/IRB-06/15]. Only those patients who provided written informed consent to participate in the study were included.
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Sinha, S., Jit, B.P., Patro, A.R.K. et al. Influence of rs1042713 and rs1042714 polymorphisms of β2-adrenergic receptor gene with erythrocyte cAMP in sickle cell disease patients from Odisha State, India. Ann Hematol 99, 2737–2745 (2020). https://doi.org/10.1007/s00277-020-04254-5
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DOI: https://doi.org/10.1007/s00277-020-04254-5