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Pain. 2018 Nov 13. doi: 10.1097/j.pain.0000000000001438. [Epub ahead of print]

Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males.

Author information

1
Center for Translational Pain Medicine, Department of Anesthesiology, Duke University, Durham, North Carolina, United States Of America.
2
Alan Edwards Centre for Research on Pain, McGill University, Montre[Combining Acute Accent]al, Que[Combining Acute Accent]bec, Canada.
3
Center for Pain Research and Innovation, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States Of America.
4
Division of Epidemiology, Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, Maryland, United States Of America.
5
National Institute of Environmental Health Sciences, National Institutes of Health, Durham, North Carolina, United States Of America.
6
Department of Restorative Dentistry, Periodontology, Endodontology, Preventive Dentistry and Pediatric Dentistry, University Medicine Greifswald, Greifswald, Germany.
7
Department of Prosthesis and Periodontology, Piracicaba Dental School, State University of Campinas, Piracicaba, São Paulo, Brazil.
8
Department of Biostatistics, University of Washington, Seattle, Washington, United States Of America.
9
Department of Epidemiology and Biostatistics, Medical Research Council-Public Health England Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
10
Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
11
Biocenter Oulu, University of Oulu, Oulu, Finland.
12
Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
13
Department of Pediatric Dentistry, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois, United States Of America.
14
Department of Restorative Dentistry, Periodontology, Endodontology, Preventive Dentistry and 26 Pediatric Dentistry, University Medicine Greifswald, Greifswald, Germany.
15
Oral Development and Orthodontics, Research Unit of Oral Health Sciences, Faculty of Medicine, University of Oulu, Oulu, Finland.
16
Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland.
17
Department of Dentistry, Jacobi Medical Center/Albert Einstein College of Medicine, Bronx, New York, United States Of America.
18
Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
19
Restorative Dental Science Department, Division of Prosthodontics, College of Dentistry, University of Florida, Gainesville, Florida, United States Of America.
20
Department of Dental Ecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States Of America.
21
Department of Prosthetic Dentistry, Gerodontology and Biomaterials, University Medicine Greifswald, Greifswald, Germany.
22
Institute of Dentistry, University of Eastern Finland, Kuopio, Finland.
23
Oral and Maxillofacial Department, Kuopio University Hospital, Kuopio, Finland.
24
Oral and Maxillofacial Department, Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland.
25
Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States Of America.
26
Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, Massachusetts, United States Of America.
27
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
28
Department of Community Dentistry and Behavioral Science, University of Florida, Gainesville, Florida, United States Of America.
29
Department of Neural and Pain Sciences, and Brotman Facial Pain Clinic, University of Maryland, School of Dentistry, Baltimore, Maryland, United States Of America.
30
Department of Oral Diagnostic Services, University at Buffalo, Buffalo, New York, United States Of America.
31
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States Of America.

Abstract

Painful temporomandibular disorders (TMD) is the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. While many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a GWAS assuming an additive genetic model of TMD in a discovery cohort of 999 cases and 2031 TMD-free controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Using logistic models adjusted for sex, age, enrollment site, and race, we identified three distinct loci that were significant in combined or sex-segregated analyses. A single nucleotide polymorphism (SNP) on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio [OR]=2.9, 95% CI: 2.02-4.27, P=2.2x10). This association was nominally replicated in a meta-analysis of seven independent orofacial pain cohorts including 160,194 participants (OR=1.16, 95% CI: 1.0-1.35, P = 2.3x10). Functional analysis in human dorsal root ganglia (DRG) and blood indicated this variant is an expression quantitative trait locus (eQTL), with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta = -0.51, P = 2.43x10). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammatory pain. Genetic and behavioral evidence support a novel mechanism by which genetically-determined MRAS expression moderates the resiliency to chronic pain. This effect is male-specific and may contribute to the lower rates of painful TMD in men.Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a "work of the United States Government" for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.

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