Beta2-adrenergic receptor gene polymorphisms and haplotypes associate with chronic pain in sickle cell disease

Pain in sickle cell disease (SCD) is a heterogeneous and severe phenotype that requires thorough characterization for precision therapy. The beta 2 adrenergic receptor (ADRB2) is an intronless gene in the monoamine neurotransmitter system that plays an important role in pain perception and modulation; however, its contribution to SCD pain has not been previously examined. In this study, we investigated 16 ADRB2 candidate SNPs that are located in 5’-intergenic/UTR and coding regions on chronic non-crisis pain variability in SCD. Subjects provided informed consent and recorded their pain experience on the tablet-based PAINReportIt system, from which we obtained comprehensive pain phenotypes. The Composite Pain Index (CPI) was used as a measurement for chronic pain. Using the additive multiple linear regression model adjusted for covariates, a single rs17778257 T allele was found to shift CPI by -4.39 (p=0.032). The A allele of rs12654778 caused a 4.52 decrease in the CPI (p=0.019), whereas rs11168070 G allele led to a 5.99 increase in CPI (p=0.016). Rs11959427 C allele caused a 5.69 increase in CPI (p=0.023), and 5’UTR rs1042711 C allele and rs1801704 C allele caused a 10.86 (p=0.000494) and 5.26 (p=0.031) increase, respectively. The coding SNP rs1042713 A allele (Arg16) caused a 5.73 decrease in CPI (p=0.002). Collectively, these SNPs accounted for 2-15% of the variance in CPI. Moreover, we found these SNPs are in linkage disequilibrium showing 3 LD blocks in our cohort. Haplotype analyses reveal association of CPI with a 10-marker haplotype from block 1 leading to a 10.60 increase in CPI (p=0.000341). A 2-marker haplotype from block 2 was associated with a 5.94 decrease in CPI (p=0.001). Data from this study strongly implicated significant influences of ADRB2 polymorphisms and haplotypes on chronic pain in SCD. Abstract source