Are Epigenetic Factors Implicated in Chronic Widespread Pain?
BACKGROUND
Chronic widespread musculoskeletal pain (CWP) is the cardinal symptom of fibromyalgia and affects about 12% of the general population. Familial aggregation of CWP has been repeatedly demonstrated with estimated heritabilities of around 50%, indicating a genetic susceptibility. The objective of the study was to explore genome-wide disease-differentially methylated positions (DMPs) for chronic widespread pain (CWP) in a sample of unrelated individuals and a subsample of discordant monozygotic (MZ) twins.


RESULTS
A total of N = 281 twin individuals from the TwinsUK registry, including N = 33 MZ twins discordant for self-reported CWP, were part of the discovery sample. The replication sample included 729 men and 756 women from a subsample of the KORA S4 survey-an independent population-based cohort from Southern Germany. Epigenome-wide analysis of DNA methylation was conducted using the Illumina Infinium HumanMethylation 450 DNA BeadChip in both the discovery and replication sample. Of our 40 main loci that were carried forward for replication, three CPGs reached significant p-values in the replication sample, including malate dehydrogenase 2 (MDH2; p-value 0.017), tetranectin (CLEC3B; p-value 0.039), and heat shock protein beta-6 (HSPB6; p-value 0.016). The associations between the collagen type I, alpha 2 chain (COL1A2) and monoamine oxidase B (MAOB) observed in the discovery sample-both of which have been previously reported to be biological candidates for pain-could not be replicated.


CONCLUSIONS
Our results may serve as a starting point to encourage further investigation in large and independent population-based cohorts of DNA methylation and other epigenetic changes as possible disease mechanisms in CWP. Ultimately, understanding the key mechanisms underlying CWP may lead to new treatments and inform clinical practice.
Health and Rehabilitation Research Institute, Auckland University of Technology, Auckland, New Zealand.|Waitemata Pain Service, Department of Anaesthesia and Perioperative Medicine, North Shore Hospital, Auckland, New Zealand.|Department of Psychology, University of Zurich, Binzmühlestrasse 14, 8050 Zurich, Switzerland.
Andrea
A
Burri
Department of Psychosomatic Medicine, Clinic Barmelweid, Barmelweid 5017, Switzerland.
Zoya
Z
Marinova
SIB Swiss Institute of Bioinformatics, University of Zurich, 8057 Zurich, Switzerland.|Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
Mark D
MD
Robinson
Research Unit of Molecular Epidemiology and Institute of Epidemiology II, Helmholtz Zentrum München, Munich, Germany.
Brigitte
B
Kühnel
Research Unit of Molecular Epidemiology and Institute of Epidemiology II, Helmholtz Zentrum München, Munich, Germany.
Melanie
M
Waldenberger
Research Unit of Molecular Epidemiology and Institute of Epidemiology II, Helmholtz Zentrum München, Munich, Germany.
Simone
S
Wahl
Research Unit of Molecular Epidemiology and Institute of Epidemiology II, Helmholtz Zentrum München, Munich, Germany.
Sonja
S
Kunze
Research Unit of Molecular Epidemiology and Institute of Epidemiology II, Helmholtz Zentrum München, Munich, Germany.
Christian
C
Gieger
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Twin Research and Genetic Epidemiology, King's College London, St.Thomas´ Hospital, Westminster Bridge Road SE1 7EH, London, United Kingdom.
Gregory
G
Livshits
Department of Twin Research and Genetic Epidemiology, King's College London, St.Thomas´ Hospital, Westminster Bridge Road SE1 7EH, London, United Kingdom.
Frances
F
Williams
D000368:Aged; D059350:Chronic Pain / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005356:Fibromyalgia / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D050886:HSP20 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics; D008291:Malate Dehydrogenase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D059352:Musculoskeletal Pain / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D014430:Twins, Monozygotic
D050886:HSP20 Heat-Shock Proteins; C494382:HSPB6 protein, human; D037181:Lectins, C-Type; C048648:tetranectin; C000619306:MDH2 protein, human; D008291:Malate Dehydrogenase