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Pain in sickle cell disease (SCD) is complex and heterogeneous. In this study, we examine the influence of single nucleotide polymorphisms (SNP) in the S100B gene on acute and chronic pain variation in SCD. 136 subjects with SCD recorded their baseline, non-crisis pain experience on a digital version of the McGill Pain Questionnaire, from which we obtained composite pain index (CPI) scores as a measurement for chronic pain. Utilization of emergency or urgent care owing to painful crisis was recorded as a marker for acute pain. Blood/buccal swab samples were collected and genotyped using MassARRAY iPLEX platform. Multiple linear regression analyses revealed association with higher CPI scores for rs9983698 T allele (additive: B= 4.91, p= 0.014; dominant: B= 6.43, p= 0.009), rs9722 A allele (additive: B= 4.81, p= 0.005; dominant: B= 7.80, p= 0.003), and rs11911834 T allele (additive: B= 4.75, p= 0.016; dominant: B= 6.13, p= 0.011). On the other hand, the G allele of rs1051169 associated with decreased CPI (additive: B= -6.14, p= 0.001; dominant: B= -6.56, p= 0.009; recessive: B= -9.78, p= 0.005). Further, ordinal logistic regression of utilization groups showed that the G allele of rs1051169 also associated with lower utilization (additive: B= -1.02, p= 0.0003; dominant: B= -1.20, p= 0.002; recessive: B= -1.26, p= 0.015). Employing linkage disequilibrium plot, we identified two haploblocks for these 4 SNPs. In block 1 (rs9983698-rs9722), haplotypes T-A and C-G significantly associated with CPI (B= 5.63, -4.81; p= 0.007, 0.005, respectively). In block 2 (rs1051169-rs11911834), C-T and G-G haplotypes showed significant association with CPI (B= 4.52, -6.02; p= 0.024, 0.001, respectively). S100B SNPs and haplotypes were found to associate with acute and chronic pain in SCD indicating the potential role of S100B in sickle cell pain heterogeneity. Supported by grants from the NIH (R01HL124945, R01HL098141, T32DE018381) and IDPH. [ABSTRACT FROM AUTHOR]

A previous exploratory analysis of a COMT gene single-nucleotide polymorphism (SNP) and a DRD3 SNP by our group suggested possible contributions to pain-related acute care utilization in people with sickle cell disease (SCD). Our aim was to extend the analysis to gene-spanning haplotypes of COMT SNPs and DRD3 SNPs to investigate possible associations with pain intensity and pain-related acute care utilization in an SCD cohort. Genotyping was conducted, and clinical data were collected, including self-reported pain intensity using PAINReportIt ® (average of current pain and least and worst in past 24 hours, average pain intensity [API]) and medical record-extracted, pain-related acute care utilization data of 130 adults with SCD. Haplotype blocks were identified based on linkage disequilibria (COMT = 7 haploblocks; DRD3 = 8 haploblocks). Regression analyses were tested for association between haplotypes and API and utilization, yielding several significant findings. For COMT block 1 (rs2075507, rs4646310, rs737865), the A-G-G haplotype was associated with higher API compared to the reference A-G-A ( p = 0.02), whereas the A-A-A haplotype was associated with higher utilization ( p = 0.02). For DRD3 block 2 (rs9817063, rs2134655, rs963468, and rs3773679), relative to reference T-C-G-C, the T-T-G-C haplotype was associated with higher utilization ( p = 0.01). For DRD3 block 4 (rs167770, rs324029, and rs324023), the A-G-T haplotype was associated with higher API ( p = 0.04) and utilization ( p < 0.001) relative to reference G-A-T, whereas the A-A-T haplotype was associated with higher utilization ( p = 0.01). We found COMT and DRD3 haplotypes associated with pain-related SCD features, suggesting that in future studies more emphasis be placed on cis effects of SNP alleles in evaluating genetic contributions to SCD pain and acute care utilization for pain.

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 patients with SCD. 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.

The 12 transmembrane alpha helices (TMHs) of human erythrocyte glucose transporter were individually cut by pepsin digestion as membrane-bound 2.5-3.5-kDa peptide fragments. Radiation-induced chemical degradation of these fragments showed an average target size of 34 kDa. This is 10-12 x larger than the average size of an individual TMH, demonstrating that a significant energy transfer occurs among these TMHs in the absence of covalent linkage. Heating this TMH preparation at 100 degrees C for 15 min reduced the target size to 5 kDa or less, suggesting that the noncovalent energy transfer requires specific helix-helix interactions. Purified phospholamban, a small (6-kDa) integral membrane protein containing a single TMH, formed a pentameric assembly in sodium dodecyl sulfate. The chemical degradation target size of this phospholamban pentamer was 5-6 kDa, illustrating that not all integral membrane protein assemblies permit intersubunit energy transfer. These findings together with other published observations suggest strongly that significant noncovalent energy transfer can occur within the tertiary and quaternary structure of membrane proteins and that as yet undefined proper molecular interactions are required for such covalent energy transfer. Our results with pepsin-digested glucose transporter also illustrate the importance of the interhelical interaction as a predominating force in maintaining the tertiary structure of a transmembrane protein.