Novel Methods to Identify Pain Targets : Genomic/Genetic Approaches Luda Diatchenko, MD, PhD Canada Excellence Research Chair in Human Pain Genetics Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada The National Academies of SCIENCE ENGINEERING MEDICINE Advancing Therapeutic Development for Pain and Opioid Use Disorders through Public-Private Partnerships: A Workshop Washington, DC, October 11 12, 217
Translation of Genetic Information into Clinical Practice Zemunik and Boraska book edited by David Wagner, ISBN
How are genomes of individuals different? SNP Nature 49, 822-823 (21) DNA contains 99.9% of identical sequence in all the individuals with only.1% difference. Out of this.1% variation, over 8% are single nucleotide polymorphisms (SNPs).
Genes Responsible for Monogenic Pain Disorders HSN Type I SPTLC1 sphingolipid synthesis HSN Type II HSN2 (function unknown) HSN Type IID SCN9A sodium (Na v 1.7) channel HSN Type III IKBKAP transcription factor HSN Type IV NTRK1 neurotrophin receptor HSN Type V NGFB neurotrophin HSN Type? SCN11A sodium (Nav1.9) channel The Human Pincushion (congenital insensitivity to pain with anhidrosis; HSN Type IV) FEPS TRPA1 cation (TRPA1) channel PE SCN9A sodium (Na v 1.7) channel PEPD SCN9A sodium (Na v 1.7) channel FHM Type I CACNA1A1 calcium channel subunit FHM Type II ATP1A2 ion pump subunit FHM Type III SCN1A sodium (Na v 1.1) channel FEPS: familial episodic pain syndrome; HSN: hereditary sensory neuropathy; PE: primary erythromelalgia; PEPD: paroxysmal extreme pain disorder; FHM: familial hereditary migraine Courtesy from Dr. Mogil
Drug Development Based on Monogenic Pan Disorders - Mantyh et al, Anesthesiology, 211
Drug Development Based on Monogenic Pan Disorders Sodium Channel blockers
ENVIRONMENTAL CONTRIBUTION Mood Common Persistent Pain Conditions Anxiety High Psychological Distress Depression Stress Response Somatization Tissue Injury High State of Pain Amplification Blood Pressure Impaired Pain Regulatory Systems Proinflammatory State GAD65 Serotonin MAO receptor Cannabinoid receptors NMDA CREB1 Dopamine receptors GR Adrenergic receptors Serotonin transporter CACNA1A NET DREAM POMC Opioid receptors Na+, K+- ATPase BDNF NGF IKK COMT Prodynorphin Interleukins Xp11.23 12q11.2 9q34.3 11q23 5q31-q32 5q31-32 6q24-q25 1p13.1 22q11.21 Diatchenko et al, Pain 123: 226-3, 26
Development of Pain Genetics Field Questioning genetic component of human pain Single gene association studies COMT OPRM1 Genomewide analysis????????? Needs for integration of multiple genome-wide datasets 2 217 years We are here
HPGdb: DEVELOPMENT OF A COMPREHENSIVE REPOSITORY FOR HUMAN PAIN GENETICS To create a database that aggregates relevant and up-to-date human pain genetics data and complementary resources in one centralized location to be used as a resource for clinicians and pain researchers Meloto et in revvision
Genetic Loci Associated With Quantified By The Number Of Genetic Association Studies Migraine Musculoskeletal Pain Disorders MTHFR ACE PRDM16 TNF ESR1 AJAP1 C7orf1 DBH FHL5 LRP1 LTA MMP16 TRPM8 Other COMT HTR2A ESR1 ADRB2 Il1A Zorina-Lichtenwalter et al, Neuroscience, 216
The Translational Research Clock closing the circle 4 3 2 1 Association study results, HMG, 25 (942 citations) Clinical trial Pharmacogenet Genomics, 21 (83 citations) Molecular genetics of functional variants, Science, 26 (67 citations) The animal behavior study target identification, Pain 27 (198 citations)
Control Chronic Pain Risk EGFR KD
HPGdb: DEVELOPMENT OF A COMPREHENSIVE REPOSITORY FOR HUMAN PAIN GENETICS Phenotypes categories included in the HPGdb Meloto et al, Pain, Submitted
Multiple Roads to Migraine Freilinger et al Nature Genetics 212
Heterogeneity of patient population patients subgroup 1 patients subgroup 2
HPGdb: DEVELOPMENT OF A COMPREHENSIVE REPOSITORY FOR HUMAN PAIN GENETICS 6 Pain Index 82 / 36 14 / 38 15 / 49 16 / 89 3 Neuropathic Pain 4 / 36 / 38 / 49 / 89 6 49 / 36 9 / 38 12 / 49 12 / 89 Back (3571) 2 Facial (467) 5 General (2956) 2 / 36 4 / 38 9 / 49 6 / 89 2.5 2.5 2.5 / 36 / 38 / 49 / 89 2.5 2.5 Neck/Shoulder (344) 4 Observed -log 1 ( P ) 17 / 36 3 / 38 5 / 49 4 / 89 3 Abdominal (3741) 5 / 36 / 38 / 49 2 / 89 15 Headaches (3799) 22 / 36 1 / 38 / 49 3 / 89 3 / 36 1 / 38 / 49 / 89 4 Hip (3414) 49 / 36 1 / 38 11 / 49 165 / 89 Knee (3773) 2.5 Clinical Pain Nociception Analgesia FDR 5% 1% 2% null 2.5 GWAS 2.5 2.5 2.5 QQ plots for SNPs replication in the UK BioBank. Ratios are number of SNPs better than 2% FDR to the total number of SNPs in respective SNP groups (SNPs from GWAS in orange). Meloto et al, Pain, Submitted
Non-organ specific approach to treatment cancer PIK3CA target Colon Cancer patients Breast Cancer patients HER2 target FGFR target EGFR target Brain Cancer patients KRAS target
Non-organ specific approach to treatment pain Personalized pain treatment PP NGFR target ADRB2 target Neuropathic pain patients Low back pain patients Osteoarthritis patients Ca++ channels target NE target 5TH target
SUMMARY OF STEPS IN GLOBAL GENETIC PAIN TARGETS DEVELOPMENT PROGRAM
DEVELOPMENTS Welcome to themain Human Pain Genetics Lab
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