Ellie H. Jhun

Dopamine D3 receptor Ser9Gly and catechol-o-methyltransferase Val158Met polymorphisms and acute pain in sickle cell disease.

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.

Prevalence of pain-related single nucleotide polymorphisms in patients of African origin with sickle cell disease

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.

Genetic variants of GCH1 associate with chronic and acute crisis pain in African Americans with sickle cell disease

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.

(280) Interleukin 1alpha rs1800587 associates with chronic non-crisis pain in sickle cell disease.

results suggest that the induction of CD163 via mPEI nanoparticles can shift the phenotype to an anti-inflammatory profile in human macrophages under different inflammatory conditions. This translational approach could be useful to specifically target macrophages in chronic inflammatory conditions such as invasive surgeries to prevent the development of chronic pain. Supported by Rita Allen Foundation & American Pain Society 2011 Pain grant (AR-S); National Institutes of Health, NIGMS, R15GM109333 (AR-S). PRSI program 2014 and 2015, Presbyterian College School of Pharmacy (AA, LB and DF).

245) Vasopressin SNP is related to sickle cell acute care utilization for pain

Millions of Americans present to the emergency department (ED) annually after motor vehicle collision (MVC), and more than 90% are discharged to home after evaluation. To date, the association between prior exposure to stressful life events and acute pain reported at the time of presentation has not been examined. Data for this analysis were obtained from an ongoing, prospective cohort study of African Americans (current n = 898)

Single nucleotide polymorphisms associated with pain in sickle cell disease

18 and <65 years of age who presented to the ED within 24 hours of MVC. Exclusion criteria included hospital admission after evaluation and long bone fracture. Previous burden of adverse life events was assessed at 6-week follow-up using the Life Events Checklist for DSM-4 (LEC). Exposure to each event was defined to include the options ‘‘happened to me,’’ ‘‘witnessed it,’’ and ‘‘learned about it.’’ The association between previous life stress and acute pain outcomes in the ED was assessed via linear regression, adjusting for age, sex, study site, and experiences of discrimination. Greater exposure to stressful life events prior to MVC was associated with increased acute pain (evaluated via a 0-10 NRS) in the ED (b = 0.103, p = 0.023). Further studies are needed to understand the influence of past trauma on acute stress exposure. Supported by NIAMS R01AR060852.

Abstract 4408: Molecular mechanisms underlying cancer pain: Application of cellular models

Pain is a major concern of patients with sickle cell disease (SCD). SCD pain is characterized by episodes of acute pain that are responsible for the majority of acute care utilization by SCD patients and persistent chronic pain that affects the quality of life in these patients. Acute care utilization is associatedwith SCD severity and pain. Pain severity and frequency vary significantly in SCD patients and we hypothesized that genetic polymorphisms would account for some of these variations. In the study, we applied the candidate gene approach to examine the role of single nucleotide polymorphisms (SNPs) in SCD pain. Sickle cell subjects (N=76; mean age=35; 67% female; 80% SS type) were recruited during routine outpatient clinic visits and entered answers to a computerized pain questionnaire (PAINReportIt), from which composite pain index (CPI) scores were calculated. Blood or buccal swab samples were collected for DNA extraction and genotyping was completed using PCR-RFLP, Taqman, and the Sequenom MassArray System. Data were analyzed using Pearson’s chi-square or Fisher’s exact tests followed by Bonferroni for multiplicity. Several SNPs were significantly associated with CPI scores, acute care utilization or opioid equivalent doses. One such association showed a relationship between DRD3 rs6280 and acute care utilization. Patients who did not have any acute care utilizationwithin the year after providing the pain assessmentweremore likely to carry the heterozygote genotype. DRD3 rs6280 has been implicated in several pain models conferring its role in opioid therapy for pain in humans. These data suggest that genetic polymorphisms may account for some of the pain variations seen in SCD. The study was supported in part by grants from NIH (R01 HL078536, R01 HL098141) and the Illinois Department of Public Health (IDPH).

IL1A rs1800587 associates with chronic noncrisis pain in sickle cell disease.

Pain is a major complaint in cancer patients. Little is known about the mechanisms leading to or maintaining cancer pain. This study is aimed to develop novel cellular models to study cancer pain. Isolated primary afferent sensory neurons were employed as a model system in order to produce cancer pain microenvironment in the presence of chemotherapeutic agents and cancer cells. Ca2+ imaging in sensory neurons showed increased [Ca2+]i within cancer pain microenvironment, suggesting a direct activation of sensory neurons. As a critical step in the initiation and transmission of pain cascades, release of pain neurotransmitters such as substance P and calcitonin-gene related peptide from primary afferent sensory neurons was studied and found to be significantly enhanced. As a result of sensory neuron activation, intracellular signaling transduction involving several major protein kinases was activated. For example, sub-apoptotic concentrations of paclitaxel (≤ 10 nM) potently elicit [Ca2+]i spikes, leading to PKA and PKC activation, and substance P release from primary afferent neurons. Moreover, AKAP150 was identified as a molecular mechanism synchronizing and transducing the activation of PKA to PKC. Our results reveal the presence of a specific cellular signaling pathway involving Ca2+/PKA/AKAP150/PKC(e, βII, & Δ), independent of apoptosis, mediating pain neurotransmitter release and, ultimately, neuropathic pain induced by paclitaxel. Developing cellular models of cancer pain and identifying biomarkers/pathways may lead to novel diagnostic and therapeutic strategies for cancer pain. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4408. doi:10.1158/1538-7445.AM2011-4408