Enrichment of genomic pathways based on differential DNA methylation associated with chronic postsurgical pain and anxiety in children – a prospective, pilot study

Autor: Kristie Geisler, Xue Zhang, Bobbie Stubbeman, Hong Ji, Vidya Chidambaran, Matthew T. Weirauch, Xiaoting Chen, Jarek Meller
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Oncology
Male
Pilot Projects
Anxiety
Medical and Health Sciences
Cohort Studies
chemistry.chemical_compound
0302 clinical medicine
Anesthesiology
030202 anesthesiology
2.1 Biological and endogenous factors
Prospective Studies
Aetiology
Child
Pain
Postoperative

DNA methylation
Pain Research
Neurology
Scoliosis
Female
medicine.symptom
Chronic Pain
functional genomics
Functional genomics
Biotechnology
medicine.medical_specialty
chronic postsurgical pain
Adolescent
Bioinformatics
Pain
Article
03 medical and health sciences
Internal medicine
Behavioral and Social Science
Genetics
medicine
Humans
Cyclic adenosine monophosphate
Epigenetics
Postoperative
Gene
epigenetics
business.industry
Human Genome
Psychology and Cognitive Sciences
Neurosciences
Postsurgical pain
DNA Methylation
Good Health and Well Being
Anesthesiology and Pain Medicine
Spinal Fusion
chemistry
Anxiety sensitivity
Gene-Environment Interaction
Neurology (clinical)
business
030217 neurology & neurosurgery
Zdroj: J Pain
The journal of pain, vol 20, iss 7
Popis: We have reported child anxiety sensitivity (Child Anxiety Sensitivity Index [CASI]) predicts chronic postsurgical pain (CPSP). Herein, we evaluated DNA methylation profiles to understand the gene-environment interactions underlying CPSP and CASI, to identify shared, enriched, genomic pathways. In 73 prospectively recruited adolescents undergoing spine fusion, preoperative CASI and pain data over 12 months after surgery were collected. DNA from the peripheral blood of evaluable subjects with (n = 16) and without CPSP (n = 40) were analyzed using MethylationEPIC arrays. We identified 637 and 2,445 differentially DNA methylated positions (DMPs) associated with CPSP and CASI, respectively (P ≤ .05). Ingenuity pathway analysis of 39 genes with DMPs for both CPSP and CASI revealed enrichment of several canonical pathways, including GABA receptor (P = .00016 for CPSP; P =.0008 for CASI) and dopamine-DARPP32 feedback in cyclic adenosine monophosphate (P = .004 for CPSP and P =.00003 for CASI) signaling. Gene-gene interaction network enrichment analysis revealed participation of pathways in cell signaling, molecular transport, metabolism, and neurologic diseases (P < 10-8). Bioinformatic approaches to identify histone marks and transcription factor (TF) binding events underlying DMPs, showed their location in active regulatory regions in pain pathway relevant brain cells. Using Enrichr/Pinet enrichment and Library of Integrated Network-Based Cellular Signatures knockdown signatures, we identified TFs regulating genes with DMPs in association with CPSP and CASI. In conclusion, we identified epigenetically enriched pathways associated with CPSP and anxiety sensitivity in children undergoing surgery. Our findings support GABA hypofunction and the roles of the dopamine-DARPP32 pathway in emotion/reward and pain. This pilot study provides new epigenetic insights into the pathophysiology of CPSP and a basis for future studies in biomarker development and targetable interventions. PERSPECTIVE: Differential DNA methylation in regulatory genomic regions enriching shared neural pathways were associated with CPSP and CASI in adolescents undergoing spine surgery. Our findings support GABA hypofunction and the roles of the dopamine-DARPP32 pathway in emotion/reward contributing to behavioral maintenance of pain 10 to 12 months after surgery.
Databáze: OpenAIRE