HUMAN STUDY COMT and DRD3 haplotype-associated pain intensity and acute care utilization in adult sickle cell disease.

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.

Appraisal and development of evidence-based clinical decision support to enable perioperative pharmacogenomic application.

Variable responses to medications complicates perioperative care. As a potential solution, we evaluated and synthesized pharmacogenomic evidence that may inform anesthesia and pain prescribing to identify clinically actionable drug/gene pairs. Clinical decision-support (CDS) summaries were developed and were evaluated using Appraisal of Guidelines for Research and Evaluation (AGREE) II. We found that 93/180 (51%) of commonly-used perioperative medications had some published pharmacogenomic information, with 18 having actionable evidence: celecoxib/diclofenac/flurbiprofen/ibuprofen/piroxicam/CYP2C9, codeine/oxycodone/tramadol CYP2D6, desflurane/enflurane/halothane/isoflurane/sevoflurane/succinylcholine/RYR1/CACNA1S, diazepam/CYP2C19, phenytoin/CYP2C9, succinylcholine/mivacurium/BCHE, and morphine/OPRM1. Novel CDS summaries were developed for these 18 medications. AGREE II mean ± standard deviation scores were high for Scope and Purpose (95.0 ± 2.8), Rigor of Development (93.2 ± 2.8), Clarity of Presentation (87.3 ± 3.0), and Applicability (86.5 ± 3.7) (maximum score = 100). Overall mean guideline quality score was 6.7 ± 0.2 (maximum score = 7). All summaries were recommended for clinical implementation. A critical mass of pharmacogenomic evidence exists for select medications commonly used in the perioperative setting, warranting prospective examination for clinical utility.

S100B single nucleotide polymorphisms exhibit sex-specific associations with chronic pain in sickle cell disease in a largely African-American cohort.

BACKGROUND: Pain in sickle cell disease (SCD) is severe and multifaceted resulting in significant differences in its frequency and intensity among individuals. In this study, we examined the influence of S100B gene single nucleotide polymorphisms (SNP) on acute and chronic pain variability in SCD. METHODS: Composite pain index (CPI) scores captured chronic pain. Painful crisis related emergency care utilization recorded acute pain incidence. Genotyping was performed using MassARRAY iPLEX platform. RESULTS: Regression analysis revealed associations of increased CPI with rs9722 A allele in additive (p = 0.005) and dominant (p = 0.005) models. Rs1051169 G allele on the other hand was associated with decreased CPI in additive (p = 0.001), and dominant (p = 0.005) models. Sex-specific analysis found that these associations were significant in females but not males in this cohort. Linkage analysis identified two haploblocks. Block 1 (rs9983698-rs9722) haplotype T-A was associated with increased CPI (p = 0.002) while block 2 (rs1051169-rs11911834) haplotype G-G was associated with decreased CPI (p = 0.001). Both haplotypic associations were only significant in females. No association of S100B SNPs with utilization reached statistical significance. CONCLUSIONS: S100B SNPs and haplotypes are associated with chronic pain in female, but not male, patients with SCD, implicating a potential role of S100B polymorphism in SCD pain heterogeneity in a sex-dependent manner.

Phenylethanolamine N-methyltransferase gene polymorphisms associate with crisis pain in sickle cell disease patients.

Aim: Phenylethanolamine N-methyltransferase (PNMT) catalyzes the conversion of sympathetic neurotransmitter norepinephrine to epinephrine. We examined the association of PNMT polymorphisms with acute and chronic pain in sickle cell disease (SCD). Methods: Utilization of emergency care owing to painful crisis was used as a marker for acute pain in 131 patients with SCD. Results: rs876493 A allele, rs2934965 T allele and rs2941523 G allele were significantly associated with decreased utilization (p ≤ 0.05). rs876493 A allele showed association with utilization in females (p = 0.003), not males (p = 0.803). rs2934965 T allele and rs2941523 G allele were predicted to cause loss of putative transcription factor binding sites. This is the first report of the association of PNMT polymorphisms with acute crisis pain in SCD. Together with our previous findings in catechol-o-methyltransferase, polymorphisms in catecholamine metabolizing enzymes appear to primarily influence acute pain in SCD.

Vasopressin SNP pain factors and stress in sickle cell disease.

PURPOSE: Frequencies of single nucleotide polymorphisms (SNPs) from pain related candidate genes are available for individuals with sickle cell disease (SCD). One of those genes, the arginine vasopressin receptor 1A gene (AVPR1A) and one of its SNPs, rs10877969, has been associated with pain and disability in other pain populations. In patients with SCD, clinical factors such as pain and stress have been associated with increased health care utilization, but it is not known if the presence of the AVPR1A SNP plays a role in this observation. The study purpose was to explore the relationships between rs10877969 and self-reported pain, stress, and acute care utilization events among individuals with SCD. METHODS: In a cross-sectional investigation of outpatients with SCD, participants completed PAINReportIt®, a computerized pain measure, to describe their pain experience and contributed blood or saliva samples for genetic analysis. We extracted emergency department and acute care utilization from medical records. RESULTS: The SNP genotype frequencies (%) for this sample were CC 30 (28%), CT 44 (41%), TT 33 (31%). Acute care utilization and stress as an aggravator of pain were significantly associated with the rs10877969 genotype (p = .02 and p = .002, respectively). The CT genotype had the highest mean utilization and CC genotype was associated with not citing stress as a pain aggravator. Chronic pain was not associated with rs10877969 (p = .41). CONCLUSION: This study shows that rs10877969 is related to indicators of stress and acute pain. Further research is recommended with other measures of stress and acute pain.

Pharmacogenomic considerations for medications in the perioperative setting.

Several high-profile examples of adverse outcomes from medications used in the perioperative setting are well known (e.g., malignant hyperthermia, prolonged apnea, respiratory depression, inadequate analgesia), leading to an increased understanding of genetic susceptibilities underlying these risks. Pharmacogenomic information is increasingly being utilized in certain areas of medicine. Despite this, routine preoperative genetic screening to inform medication risk is not yet standard practice. In this review, we assess the current readiness of pharmacogenomic information for clinical consideration for several common perioperative medications, including description of key pharmacogenes, pharmacokinetic implications and potential clinical outcomes. The goal is to highlight medications for which emerging or considerable pharmacogenomic information exists and identify areas for future potential research.

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

Pain in sickle cell disease (SCD) is severe, variable, and inadequately comprehended. The ß2-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.

Glucocorticoid receptor single nucleotide polymorphisms are associated with acute crisis pain in sickle cell disease.

AIM: Pain in sickle cell disease patients is heterogeneous and genetic polymorphisms may predispose an individual to varied vulnerability to painful events. We studied the association of SNPs in the glucocorticoid receptor gene (NR3C1) with pain in sickle cell disease. METHOD: Acute pain was scored as the number of utilizations due to crisis pain in a 12-month period. Chronic pain was calculated as the Composite Pain Index score. RESULTS & CONCLUSION: rs33389 T allele (IRR = 1.53, p = 0.014 additive; IRR = 1.64, p = 0.011 recessive), rs2963155 G allele (IRR = 1.80, p < 0.001 additive; IRR = 2.25, p = 0.021 dominant; IRR = 2.07, p < 0.001 recessive) and rs9324918 C allele (IRR = 1.43, p = 0.021 additive) were associated with higher utilization rates, indicating the potential contribution of NR3C1 polymorphisms to acute pain heterogeneity in sickle cell disease.

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 HbS߰ 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.

Transient receptor potential polymorphism and haplotype associate with crisis pain in sickle cell disease.

AIM: Episodes of acute pain crisis contribute to considerable morbidity and mortality in sickle cell disease (SCD). Incomprehensive understanding of the underlying pain heterogeneity results in inadequate pain management. The transient receptor potential (TRP) family of voltage-gated ion channels acts as sensory transducers of diverse noxious stimuli. We performed an association study of polymorphisms in candidate genes TRPV1 and TRPA1 with pain in SCD patients. METHODS: Utilization rate, in other words, number of emergency department/acute care center admissions over 12 months as a result of pain crisis, served as a marker for acute pain. RESULTS & CONCLUSION: 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.

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

AIM: Pain is prevalent in sickle cell disease (SCD) patients who display great heterogeneity in pain severity and frequency. Hypothesizing that inflammatory factors are involved in the pathogenesis of SCD pain, we focused on the IL1A C/T polymorphism rs1800587 that is an SNP located in a cis-transcriptional regulatory region. METHODS: We genotyped IL1A rs1800587 and performed association studies with phenotype data obtained by a multidimensional pain assessment tool using the PAINReportIt® Questionnaire. RESULTS: Each T allele was associated with a 3.9 increase in composite pain index score (p = 0.04) as determined by multiple linear regression. CONCLUSION: IL1A rs1800587 may influence chronic pain in SCD.

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.

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.