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Front Pharmacol. 2019 Feb 7;10:84. doi: 10.3389/fphar.2019.00084. eCollection 2019.

Beta2-Adrenergic Receptor Polymorphisms and Haplotypes Associate With Chronic Pain in Sickle Cell Disease.

Jhun EH1, Sadhu N1, Hu X1, Yao Y2,3, He Y1,4, Wilkie DJ2,3, Molokie RE1,4,5,6, Wang ZJ1,4.

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Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, United States.
Department of Biobehavioral Health Science, College of Nursing, University of Illinois at Chicago, Chicago, IL, United States.
Department of Biobehavioral Nursing Science, College of Nursing, University of Florida, Gainesville, FL, United States.
Comprehensive Sickle Cell Center, University of Illinois at Chicago, Chicago, IL, United States.
Jesse Brown Veteran's Administration Medical Center, Chicago, IL, United States.
Division of Hematology/Oncology, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States.


Pain in sickle cell disease (SCD) is severe, variable, and inadequately comprehended. The β2-adrenergic receptor (ADRB2) is critical in mediating neurotransmitter response in the sympathetic nervous system. In this association study, we examined 16 single nucleotide polymorphisms (SNPs) covering 5'-UTR and coding regions of ADRB2 for pain variability in SCD. Subjects recorded their non-crisis, baseline pain experience on a computerized tool from which we obtained chronic pain measurement score- composite pain index (CPI). Regression models yielded significant associations between chronic pain and seven SNPs. Non-synonymous SNP rs1042713 A allele (Arg16) caused a 5.73-fold decrease in CPI (p = 0.002). Allele A of rs12654778 and T of rs17778257 reduced CPI by a fold of 4.52 (p = 0.019), and 4.39 (p = 0.032), respectively. Whereas, in the 5' UTR, allele C of rs1042711, G of rs11168070, C of rs11959427, and C of rs1801704 increased CPI by a fold of 10.86 (p = 0.00049), 5.99 (p = 0.016), 5.69 (p = 0.023), and 5.26 (p = 0.031), respectively. Together, these SNPs accounted for 2-15% of CPI variance after adjusting for covariates. Moreover, these SNPs were in high linkage disequilibrium (LD) showing three LD blocks in our cohort. A 10-marker haplotype increased CPI by 11.5-fold (p = 0.000407). Thus, ADRB2 polymorphisms might contribute to chronic pain severity and heterogeneity in SCD.


beta2-adrenergic receptor; chronic pain; haplotype; sickle cell disease; single nucleotide polymorphism

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