Pain Pharmacogenetics in Sickle Cell Disease

Pain is the most conspicuous aspect of sickle cell disease (SCD) to those that are affected that even African tribes have been calling it onomatopoetic names describing its pain for at least hundreds of years. The acute pain crisis is the hallmark symptom of SCD and the leading cause of hospital admissions among patients. It is an unpredictable event that may have some triggers including stress, dehydration, weather, and infection, but occurrence is very heterogeneous. Chronic pain in sickle cell disease is typically caused by bone infarction, avascular necrosis, chronic leg ulcers, among others. Pain heterogeneity is seen in patients reporting baseline pain and this variability is also not completely understood in SCD. Race, gender, environment, socio-economic status, trauma, and stress contribute to the variability in pain seen between individuals, however, pain sensitivity and risk are complex traits that are up to 30-76% heritable and polygenic. Several studies have observed the genetic components that contribute to phenotypic diversity in SCD. Pain is a complex phenotype that has multiple contributions made by genes and the environment. In this study, candidate pain single nucleotide polymorphisms and pain genes are prioritized to further investigate the role multiple genes may play in pain variability. Particular focus is on the monoamine neurotransmitter system because of its high relevance and comorbidities seen in pain and other neurological disorders. Each candidate SNP is analyzed to ascertain individual contributions, and then a polygenic approach is taken to observe the contributions made to a complex phenotype

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

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.</p

Vasopressin SNP pain factors and stress in sickle cell disease.

PurposeFrequencies 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.MethodsIn 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.ResultsThe 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).ConclusionThis 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