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Genetics –Epigenetics- Who is more vulnerable?

Explore the factors influencing the transition from acute to chronic pain and the role of genetics and epigenetics. Discover how gene mutations and epistasis play a role in pain perception.

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Genetics –Epigenetics- Who is more vulnerable?

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  1. Genetics –Epigenetics- Who is more vulnerable? FPM Refresher Course Day 1 May 2015 Adelaide SESSION: The Faces of Pain: Acute to Chronic Andrew Somogyi Discipline of Pharmacology, Faculty of Health Sciences, University of Adelaide, Australia andrew.somogyi@adelaide.edu.au

  2. Overview • Factors influencing acute to chronic pain transition • Non-genetic • Genetics/Genomics (what is it) Factors • COMT: pain perception • GCH1, FKBP5 • Inflammation: TGFB1, IL8 • Haplotype-Epistasis • EpigeneticFactors • What is it?TRPA1 • Research problems

  3. Acute to Chronic Pain Transition • Epidemiology: Mostly postsurgical setting • S Shipton Trends Anaesth & Crit Care 4, 67, 2014 MacIntyre et al Acute Pain Management 2010 • Any injury can be the sensitizer: traumatic stress

  4. Acute to Chronic Pain Transition: Factors Psychosocial Shipton Trends Anaesth & Crit Care 4, 67, 2014 Phenotype: what is it?

  5. Acute to Chronic Pain Transition: Risk Factors MacIntyre et al Acute Pain Management 2010 Shipton Trends Anaesth & Crit Care 4, 67, 2014

  6. Genetic/Genomics! • Mutations in coding region • Mutations in noncoding region • Candidate Genes • Haplotypes • Epistasis • Epigenetic • Few studies in postsurgical transition

  7. What is ‘Omics? • “a coined phrase and refers to a field of study in biology that endsin the suffix - omics, such as genomics..” (Wikipedia) • Opposite to reductionism: understanding complex systems by reducing to simpler /more fundamental parts Extremeomics, facebookomics, nonsenseomics, balomics, omics-schmomics!

  8. What is Genomics? • Study of genes or gene products in a person or organism. • Coined by Dr Tom Roderick (geneticist- Jackson Lab (Maine)) in 1986 over a beer at meeting in Maryland on the mapping of the human genome

  9. Two types of Genetics: Somatic, Germline Somatic: Tumour Germline: Host • Germline • Inherited variations • Pharmacokinetics: CYP2D6 • Pharmacodynamic: mu receptor And then there is Epigenetics!! Hertz & Mcleod, J Hum Gen 2013

  10. Gene Mutations • Changes in base sequence of DNA • SNPs [single nucleotide polymorphisms] • Indels [Insertions/Deletions] • Coding SNPs: Changes in amino acid structure of protein (drug target) -> altered binding to drug • Transcriptional SNPs: /protein (drug target) expression or degradation • Loss of function alleles much more common than gain of function • Genetic Polymorphisms: frequency of >1% population

  11. Reading the Genetic Code • Genes consist of EXONS and introns iiiiiiiiTHE iiiiiiiiBAD AND iiiiiiiiiOLD HiiiiiiiiOG ATETiiiiiiiiiiHE FATiiiii iiiRAT ENDiiiii • Normal processed “gene” message is read in blocks of 3 bases (codons) • THE BAD AND OLD HOG ATE THE FAT RAT END • Think of this as: • the normal functioning enzyme/protein- system On time

  12. Missense Mutation:SNP Mutation changing H to L iiiiiiiiTHE iiiiiiBAD AND iiiiiiiiiOLD LiiiiiiiiOG ATETiiiiiiiiiiiiHE FATiiiii RAT ENDiiiiiiiii THE BAD AND OLD LOG ATE THE FAT RAT END • Readable but Makes no Sense. • Mutated enzyme with some (but not 100%) function

  13. Splice site mutation Mutated splice site leading to exon skipping iiiiiiiiTHE iiiiiiBAD AND iiiiiiOLD HiiiiiOG ATETiiiiiiiiiHE FATiiiii RAT ENDiiiiiiiii THE BAD AND OLDH OGA TET HEF ATR ATE NDi iii • Loss of genetic message • 100% loss of function enzyme

  14. COMT: Catechol-O-Methyltransferase • Metabolizes catecholamines in glial & postsynaptic neurons: CNS, other tissues • Noradrenaline, adrenaline, dopamine • Pain, Sympathetic tone, Mood, Inflammation • Descending inhibitory pathway

  15. COMT: Genetics • > 900 SNP variants of gene (COMT) • Val158Met:widely studied • Met/Met: 4-fold  in activity • MetMet[26%] individuals versus ValVal[25%] • higher sensory & affective pain ratings • Lower morphine doses • Increased risk of chronic pain with Met individuals ( fibromyalgia, TMD)

  16. COMT and Postoperative Persistent Pain J Clin Anaesth 23, 482, 2011 • Small numbers:n=42; Post Surgical Persistent Pain: 43% • Val158Met: 27% Val/Val; 39% Val/Met • Odd’s Ratio: 3.5 (0.6-22) P=0.17

  17. COMT: Chronic Pain Development BUT: Val158Met not the only variant Haplotypes: multiple SNPs in gene 200 females: risk of TMD (temporomandibular joint disorder)

  18. Val158Mett • From these haplotype combinations-> pain sensitivity phenotype Diatchenko et al Human Mol Gen 14, 135, 2005

  19. Haplotype Analysis: Differentiates less with more pain sensitivity • Pressure & thermal pain testing • Less pain sensitive: GCGG • High pain sensitive: ATCA/ACCG Diatchenko et al Human Mol Gen 14, 135, 2005

  20. Incidence of TMD was higher in High Pain sensitivity haplotype group (65%) than in Low pain sensitivity haplotype group (28%) Diatchenko et al Human Mol Gen 14, 135, 2005

  21. More than 1 gene in COMT Pathway: Epistasis GCH1: guanosine-5-triphosphate cyclohydrolase 1; ESR1: oestrogen receptor 1 GCH1: cofactor for catecholamine synthesis; ESR1: regulates COMT gene expression Met individuals :  musculoskeletal pain Met individuals + GCH1 variant: increased pain threshold ( pain) Val individuals + ESR1 Variant:  pain TMD cases vs Controls

  22. Tegeder et al Nat Med 12, 1269, 2006 • GTP cyclohydrolase – tetrahydrobiopterin (BH4) formation • BH4: modulates peripheral neuropathic and inflammatory pain • BH4: cofactor in serotonin, catecholamine & NO production • BH4 inhibition -> neuropathic pain /inflammatory pain in rats 0= 0 copy X = 1 copy X=- 2 copies 168 patients- surgical diskectomy Assessed at 1 year post surgery Genetics: 15 SNPs tested: Haplotype analysis 1 haplotype: 15% patients associated with low pain scores (0.44 vs 0.84 Z-score) 2 copies of low pain haplotype = minimal pain at leg rest 0,1 copy = pain at leg rest common

  23. Bortsov et al Pain 154, 1419, 2013 • Traumatic events: potent stressors activate neurobiological stress response systems • HPA contributes to developing persistent posttraumatic pain • FK506 protein 1: interacts with HSP90 which binds to glucocorticoid receptor and regulates its sensitivity; receptor co-chaperone • Discovery cohort: n= 949 Experienced MVA • Replication: women experiencing sexual assault (n=54) • Exclusion: oral morphine (< 30 mg/day); beta antagonists • 6 weeks: overall pain & neck pain (MVA) • Genotyping: 33 FKBP5 SNPS

  24. Bortsov et al Pain 154, 1419, 2013 MVA: 6 SNPS associated with overall pain (OR ~4) & neck pain (OR~3) Sexual Assault: 4 assoc with overall pain & 3 neck pain MVA: Haplotype: h2 & h3 associated: low overall and neck pain but no statistics! Problems: no haplotype analysis but mechanistic basis is sound

  25. Same Study: Different Gene- OPRM1 (A118G) Linnstaedt et al J Pain 2015

  26. Inflammation Biomarkers • Cytokines contribute to pathophysiol TMD & widespread pain • Acute Setting: MCP-1 & IL-8 confer survival • immune response; limit tissue damage; initiate remodeling • Persistent  MCP-1 & IL8: tissue pathology & nociceptor function changes • Proinflammatory cytokines concs correlate with  pain sensitivity

  27. Case Control: 355 females • TMP-WPT: without widespread palpation tenderness • TMT+ WPT: with widespread palpation tenderness • 22 cytokine gene SNPS: MCP-1, IL-1Ra, IL-8, TGFB1

  28. Inflammation Biomarkers No SNP (22) associated with Odd’s of TMP-WPT or TMT+ WPT cf control BUT Significant gene-gene interaction (epistasis): IL-8 SNP (proinflammatory chemokine) and TGFB1 SNP (regulates gene expression (incl IL8)

  29. Inflammation Biomarkers: Epistasis 1 copy T variant (minor) TGFB1 + 0 copy IL-8 variant = OR 2.6 + 1 copy IL-8 variant = OR 0.56 + 2 copy IL-8 variant = OR 0.11 TMD + WPT (wide spread pain palpation) Slade et al 2011 Pain 152, 2802

  30. Problems • Replication studies- numbers • Phenotype of persistent pain • Post surgical: acute to chronic: not been adequately studied • Trauma: stress only • TMD • Statistics: many other factors often not considered • Candidate Gene approach • Acts as a pointer only • Magnitude of effect: unlikely to be major • GWAS or NGS: who will fund? Big numbers • Epigenetics

  31. On Epigenetics • Tissue specific: • CNS a problem • Environmental- stress

  32. Epigenetic Phenomena: Phenotypic changes not involving DNA sequence alterations Ageing Ingelman-Sundberg 2009

  33. Twins same epigenome at birth- Environmental factors through development alter epigenome -> phenotype differences (No pain/ pain)

  34. Acute to Chronic Pain Transition: Epigenetics • Inflammatory cytokine expression • Glucocorticoid receptor expression • Glutamic acid decarboxylase (pain regulatory enzyme) • Mu opioid receptor expression • ALL GENES

  35. 2014 • 50 monozygotic twins- 50 controls • Heat pain: low vs high sensitivity • Methylation rate TRPA1 related to pain sensitivity TRPA1: ligand gated cation channel- sensor for pain, cold, stretch; chemicals: mustard, wasabi, horse radish

  36. Genetic and environment interactions contribute to pain development and response to treatment • Germline mutations • Epigenetics Diatchenko et al; Nat Rev Rheumatol 9, 340, 2013

  37. Take Home Message • Transiting from acute to chronic pain • Highly complex biochemical & biosocial process • Many factors: • Genetics: germline and epigenetics • We need postsurgery studies • We need replication studies

  38. What am I doing? • Predictors of persistent post surgical pain following total knee joint arthroplasty • Michal Kluger (Auckland) • 973 patients undergoing scheduled total hysterectomy under general anesthesia. • Alex Sia (Singapore) • ~ 25% persistent postsurgical pain

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