Background Pain in sickle cell disease (SCD) is characterized by episodes of acute pain, primarily responsible for acute health care utilization, and persistent chronic pain. Pain severity and frequency vary significantly among SCD patients. In this study, we investigated the possible contribution of monoamine gene polymorphisms to pain variation. Methods Adult subjects with SCD completed PAINReportIt®, a computerized McGill Pain Questionnaire, from which we calculated the Composite Pain Index. Utilization data were obtained from the medical record and biweekly telephone calls for 12 months. Utilization is defined as admissions to the emergency department and/or the acute care center resulting from a sickle cell pain crisis. We performed genotyping for catechol-O-methyltransferase (COMT) Val158Met (rs4680) and dopamine D3 receptor(DRD3) Ser9Gly (rs6280) polymorphisms, which were analyzed for associations with pain phenotypes. Results Binary logistic models revealed that DRD3 Ser9Gly heterozygote patients were more likely not to have an acute pain crisis (odds ratio [OR] [95% confidence interval (CI)], 4.37 [1.39, 22.89]; p=0.020), which remained so when demographic variables were considered (OR [95% CI], 4.53 [1.41, 28.58]; p=0.016). COMT Val158Met Met allele showed lower probability for zero utilization (OR [95% CI], 0.32 [0.12, 0.83]; p=0.020) than the Val allele. In the negative binomial regression analysis, subjects with COMT Met/Met genotype had utilization incident rate ratio [95% CI] of 2.20 [1.21, 3.99] over those with Val/Val (p=0.010). Conclusions These exploratory findings suggest that DRD3 Ser9Gly and COMT Val158Met may contribute to pain heterogeneity in SCD, as suggested by the different rates of acute pain crisis. Specifically, SCD patients with the DRD3 homozygote genotypes, COMT 158 Met allele or Met/Met genotype are more likely to have acute care utilization, an indicator of acute pain. These results, however, will need to be further examined in future large prospective studies.
We identified that rs920829 (incident rate ratio = 1.44, p = 0.027 additive; IRR=1.68, p=0.008 recessive models of negative binomial regression) and the CGAGG haplotype of TRPA1 (odds ratio = 0.218, p = 0.009) were significantly associated with utilization rate, suggesting that TRPA1 gene polymorphisms may influence acute pain crisis in SCD.
The multidimensional nature of pain in sickle cell disease (SCD) has rendered its therapeutic management extremely challenging. In this study, we explored the role of five single nucleotide polymorphisms (SNPs) of candidate gene GCH1 in SCD pain. Composite pain index (CPI) scores and acute care utilization rates were used as phenotype markers. Rs8007267 was associated with chronic pain (additive model: B = -3.76, p = 0.037; dominant model: B = -5.61, p = 0.021) and rs3783641 (additive model: incident rate ratio [IRR] = 1.37, p = 0.024; recessive model: IRR = 1.81, p = 0.018) with utilization rate. These associations persisted when subjects with HbSS and HbSβ° genotype only were analyzed. We also identified two haploblocks (rs10483639[G>C]-rs752688[C>T]-rs4411417[T>C] and rs3783641[T>A]-rs8007267[T>C]) with SNPs in high linkage disequilibrium. Of these, haplotype T-C of haploblock rs3783641-rs8007267 showed significant association with rate of utilization (odds ratio [OR] = 0.31, p = 0.001). Our study indicates potential contribution of GCH1 polymorphisms to the variability of pain in African Americans with SCD.
Background Prospective pain genetics research is hindered by a lack of data on the prevalence of polymorphisms in pain-relevant genes for patients with sickle cell disease (SCD). For African–Americans in general, limited information is available in public databases. Methods We prioritized and examined the genotype and allele frequencies of 115 SNPs from 49 candidate pain genes in 199 adult African–Americans and pediatric patients of African origin with SCD. Analyses were performed and compared with available data from public databases. Results Genotype and allele frequencies of a number of SNPs were found to be different between our cohort and those from the databases and between adult and pediatric subjects. Conclusion As pain therapy is inadequate in a significant percentage of patients with SCD, candidate pain genetic studies may aid in designing precision pain medicine. We provide prevalence data as a reference for prospective genetic studies in this population.
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.
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