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Pain Genetics and Epigenetics

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Pain Genetics and Epigenetics 11/10/2017 Pain Genetics and Epigenetics Stephen McMahon King’s College London London Pain Consortium Disclosures Research support 1) Via EU-IMI support of ‘Europain’: Astra Zeneca, Lundbeck, Pfizer, Lilly, Boehringer Ingelheim, Esteve, SanofiAventis, Grünenthal, AbbVie, Astellas, Neuroscience Technologies 2) Nevro Corporation 3) Convergence Pharmaceuticals Ltd & Evotec. 4) GSK. Studentships 1) CASE studentship with Medimmune 2) PhD studentship with Pfizer Consultancies Pfizer Bayer healthcare Astra Zeneca Mundipharma Glenmark Pharmaceuticals Regeneron Lundbeck Afferent Pharma Why does tissue injury cause pain? Rene Descartes 1596-1640 1 11/10/2017 We have a good understanding of why injury cause pain TRANSDUCTION MODULATION Heat Cold Damage mediators Glutamate ATP TRPV1 TRPM8 P2X3 P2Y Neuropeptides BDNF TRPV2 TRPA1 Bradykinin B1/2 Inhibitory controls TRPV3 5-HT3 and other 5HT MOR CB1/2 GABA TRPV4 Mechanosensation Microglial Activation P2X3 TRPV4 ATP via P2X4,P2X7 TRPC/V/P? CSF1, CCL2, BDNF, Inflammatory mediators & targets Fractalkine Prostaglandins, NGF, IL-1, TNF etc. Ligand & Voltage-gated channels e.g. TRPV1,Nav1.9, Nav1.7, Nav1.8 TRANSMISSION Nav1.7, Nav1.8 Nav1.1, Nav1.2, Nav1.6 (Nav1.3) Threshold - Nav1.9 Why is the pain experience so variable? Experimental pain in healthy human subjects varies enormously 50 C) o 48 46 44 42 Mean +/- 2 x std dev Heat Pain Tolerance ( Tolerance Pain Heat 40 >2000 twins tested 35 40 45 50 Heat Pain Threshold ( oC) 2 11/10/2017 Pain and pathology are only weakly correlated Kellgren-Lawrence scores of radiographic damage Prevalence of pain 70 60 50 40 Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 30 Magnitude of pain 20 100 Arendt-Neilsen et al., 2014 %patients with pain 80 N=281 10 N=10,278 60 N 0 40 K/L 0/1 2 3/4 20 ♂carpal ♂wrist ♂hand 0 ♀cervical ♂lumbar ♂hip Pain in last in Pain 24hlast (VAS) 0 1 2 3 4 foot Lawrence et al., 1966 Kellgren/Lawrence score ♀ Pain can persist when pathology resolves * 10 50 Chronic Widespread pain 8 34% Chronic Regional pain 40 * * * * No chronic pain 6 30 46% mean VAS meanVAS Swollen joints 4 * 20 * 20% 2 10 24 60 Ent. 6 12 24 60 months Ent. 6 12 1,386 RA patients followed longitudinally Andersson et al., 2013 J Rheumatology What explains this variability? 3 11/10/2017 What explains pain variability? Genetic factors Single gene mutations can result in abnormal pain states, but are very rare Phenotypes are dramatic and don’t explain pain normal variability Loss of function Gain of function Courtesy Dave Bennett Normal HSN IV Sural nerve patient Known genes: NGF/TrkA; Na v1.7; Known genes: Na v1.7; Na v1.8; PRDM12 Na v1.9; TrpA1 Genetic influences on Pain – MONOZYGOTIC DIZYGOTIC Twin Studies • Heat Pain Threshold (HPT) • Pain during creation of 45 °C thermal burn • Primary & secondary hyperalgesia after burn symptom-based classification 30 • Pain during iontophoresis of Acid + ATP Flare 25 Static Allodynia • Itch after iontophoresis of Histamine Dynamic 20 Allodynia 15 Area (cm2) Area 10 n = 20 5 0 0 5 10 15 20 30 40 50 60 Time (mins) 45 oC for 330sec Tim Norbury Heritability of pain traits – twin studies Shared Monozygotes Modality Rmz Rdz Heritability Environment 52 Twin 2 HPT (°C) HPT 2 Twin 0.62 0.26 0.57 50 Pre-Burn HPT 0 48 (0.46-0.79) (0.01-0.52) (0.40-0.70) 0.45 46 Post-Burn HPT 0.49 0.28 0 (0.29-0.69) (0.03-0.54) (0.26-0.60) 44 Pain Rating during 0.30 0.08 0.30 42 0 n=110 burn creation (0.06-0.54) (0.00-0.35) (0.05-0.51) 40 R=0.6 Pain during ATP 0.27 0.00 0.24 38 2 0 38 40 42 44 46 48 50 52 iontophoresis (0.02-0.52) (0.00-0.29) (0.00-0.45) Pain during acid 0.28 0.13 0.27 Twin 1 HPT (°C) 0 iontophoresis (0.03-0.52) (0.00-0.41) (0.04-0.47) Dizygotes Itch after histamine 0.19 0.34 0.2 0 Twin 2 HPT (°C) HPT 2 Twin 52 iontophoresis (0.12-0.62) (0.00-0.35) (0.09-0.52) 50 2°pinprick 0.60 0.29 0.59 0 48 hyperalgesia area (0.43-0.77) (0.04-0.54) (0.41-0.73) 46 2°brush evoked 0.35 0.55 0.38 0 44 allodynia area (0.36-0.74) (0.19-0.57) (0.00-0.74) 42 n=102 0.76 0.56 0.69 2°skin flare area 0 40 R=0.26 (0.66-0.87) (0.38-.075) (0.57-0.78) 38 38 40 42 44 46 48 50 52 Twin 1 HPT (°C) Norbury et al., 2007 4 11/10/2017 Heritability of pain traits from twin studies Authors Subject details Cohort Heritability Phenotype examined MacGregor et al., Female twins Twins UK 0.52-0.68 Lower back pain 2004 (181 MZ, 351 DZ) 0.35-0.58 Neck pain Norbury et al., Female twins Twins UK 0.22-0.59 Quantitative sensory 2007 (51 MZ, 47 DZ) testing Battie et al., 2007 Male twins Finnish twin cohort 0.3-0.46 Lower back pain (147 MZ, 153 DZ) Nielsen et al., 2008 Mixed twins Norwegian twin 0.6 Cold-pressor pain (53 MZ, 39 DZ) registry 0.26 Heat contact pain Altman et al., 2011 Female twins Swedish twin 0.3 Bladder pain syndrome (1,867 MZ, 1,293 DZ) registry Williams et al., 2010 Mixed twins Twins UK 0.46 Pain at different body sites (991 MZ, 1,074 DZ) Markkula et al., Mixed twins Finnish twin cohort 0.51 fibromyalgia 2009 (12,500) Kato, Sullivan and Mixed twins Swedish twin ♂0.09 Chronic widespread pain Pedersen, 2010 (28,531 pairs) registry ♀0.13 Hocking et al., 2012 2,195 extended Scottish family 0.16 Any chronic pain families health study 0.3 Severe chronic pain Livshits et al., 2011 Female twins Twins UK 0.43-0.68 Lower back pain (371 MZ, 698 DZ) Hartvigsen et al., Mixed twins Danish twin registry 0.33-0.39 Back pain (lumbar, 2009 (6,700 MZ, 8,500 DZ) thoracic and neck) Polderman et al., Mixed twins Meta-analysis 0.42 Migraine 2015 (9,019) (0.36-0.47) Denk 2015 What genes contribute to pain heritability? GWAS – comparing the genomes of different individuals 1 2 3 SNP1 SNP2 Case Con Case Con Ask if a particular SNP is associated with a given trait. Significance Human genome ~ 3billion base pairs. SNPs on average every 300 nucleotides. Any 2 individuals likely to Test the statistical significance of the differ by <0.5%. association. Does not imply disease causing. GWAS in large numbers of migraineurs identifies 44 SNPs Gormley et al. 2016, Nat Genetics OR= 1.111.11 0.941.06 1.09 1.11 0.90 0.89 1.07 -log value P -log Chromosome 60,000 migraineurs, 316,000 controls Odds Ratio of individual loci typically 5-10% Only 2 loci close to neuronal channels Most SNPs are in regulatory regions 6 associated with NO signalling Together only explain 10-20% of the heritability 30% associated with vascular function 5 11/10/2017 Do rare variants explain a lot of the variability? 50 C) o 48 46 44 42 Heat Pain Tolerance ( Tolerance Pain Heat 40 35 40 45 50 Heat Pain Threshold ( oC) Williams et al., PLoS genet, 2012 Rare variants in painful diabetic peripheral neuropathy: candidate gene approach (Nav1.7) Iulia Blesneac/Dave Bennett lab 190 Diabetic Peripheral Neuropathy Nav1.7 published variants (5) Nav1.7 unpublished variants (6) 11 0 WT M1852T T1596I PAINLESS 79 PAINFUL 111 S802G T1596I I II III IV K655R K1043N M1852T I564T Pain sensitivity varies enormously in health and disease Monogenic Monogenic NGF/TrkA Nav 1.7 Nav 1.7 Nav 1.8 (N av 1.9) Nav 1.9 PRDM12 TrpA1 Frequency Insensitive Normal Hypersensitive Polygenic/epigenetic Pain sensitivity 6 11/10/2017 Beyond genetics: Meta-analysis of Post-operative pain . Gerbershagen et al., 2014 Pre-op Pain Age Sex ♀ Environmental risk factors Knee Hernia Gastr. Hyster. Pain ‘history’ Append. Shoulder Hip (experimental pain Hyster. Chole. thresholds, prior pain) Spine Nasal Lamin. Psychosocial factors Hernia Thyroid (expectation, catastrophising, Hernia Fistula depression, anxiety) Mast. Hernia Hernia Age Sinus BCT BCT Gender Sling Veins Early life stressors Prostate Bladder Total ~23,000 0.9 1.40.4 1.2 0.5 3.0 Odds ratio to develop pain Mechanisms of acquired vulnerability: altered brain connectivity Mechanisms of acquired vulnerability: Epigenetics Cells have the same genes. Different genes are switched on or off in different types of cell. These regulatory patterns traditionally considered stable in maturity. 7 11/10/2017 Genetics Epigenetics PTMs Histone Variants Mutations DNA methylation Permanent Phenotypic inheritance Plastic Stable Species maintenance Memory of transitional change Somatic variability and development Response to environmental cues DNA methylation DNMTs guanin e CH 3 cytosineTet CpG island Transcriptional start site Methylated CpG Unmethylated CpG Typical Gene http://www.roadmapepigenomics.org/overview Histone modifications. 8 11/10/2017 Multiple proteins participate in chromatin modifications. Epigenetics: relevance to pain 1. Potential for novel therapeutic targets 2. Pain chronification & vulnerability Many genes are dysregulated in chronic pain states L4 DRG, 14 day spinal nerve injury Down Up 1012 1198 adjvalue P 10 Log HDAC1 HDAC4 Log 2 Fold Change Ana Antunes-Martin 9 11/10/2017 HDAC4 cKO mice have normal acute pain responses Von Frey Hargreaves Tail Flick 0.8 9 18 8 16 0.6 7 wt Nav1.8 cKO 14 6 fl/fl 12 5 Hdac4 0.4 10 4 Hdac4 Nav1.8 HDAC4 8 3 6 0.2 2 4 α-tubulin 1 2 0 50% threshold (g) 50% threshold 0 0 Withdrawal latencyWithdrawal (s) 49°C 52°C Withdrawal latency (s) latency Withdrawal 0.6 Adv 20 cKO fl/fl wt 0.5 18 9 Hdac4 16 8 Hdac4 Adv HDAC4 0.4 14 7 12 6 0.3 10 5 4 α-tubulin 8 0.2 6 3 4 2 0.1 2 1 50% threshold (g) threshold50% Withdrawl latency (s) 0 0 0 Wtihdrawal (s) latency 49C 52C Crow et al., FASEB 2015 HDAC4 cKO mice have reduced inflammatory pain fl/fl cKO HDAC4Nav1.8 CFA ipsi HDAC4Adv CFA ipsi 12 7 Baseline 10 Baseline 6 8 5 4 6 3 4 HDAC4 fl/fl 2 HDAC4 fl/fl Withdrawal Withdrawal (s) latency Withdrawal Withdrawal (s) latency 2 1 HDAC4 Nav1.8 cKO HDAC4 Adv cKO 0 0 Day 3 Day 7Day 10Day 14 Day 3 Day 7 Day 10Day 14 Crow et al., FASEB, 2015 Epigenetics: relevance to pain 1.
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