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Type: Artigo
Title: Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males
Author: Smith, Shad B.
Parisien, Marc
Bair, Eric
Belfer, Inna
Chabot-Dore, Anne-Julie
Gris, Pavel
Khoury, Samar
Tansley, Shannon
Torosyan, Yelizaveta
Zaykin, Dmitri
Bernhardt, Olaf
Serrano, Priscila de Oliveira
Gracely, Richard
Jain, Deepti
Jaervelin, Marjo-Riitta
Kaste, Linda
Kerr, Kathleen
Kocher, Thomas
Lahdesmaki, Raija
Laniado, Nadia
Laurie, Cathy
Laurie, Cecelia
Mannikko, Minna
Meloto, Carolina
Nackley, Andrea
Nelson, Sarah
Pesonen, Paula
Ribeiro-Dasilva, Margarete
Rizzatti-Barbosa, Celia
Sanders, Anne
Schwahn, Christian
Sipila, Kirsi
Sofer, Tamar
Teumer, Alexander
Mogil, Jeffrey
Fillingim, Roger
Greenspan, Joel
Ohrbach, Richard
Slade, Gary
Maixner, William
Diatchenko, Luda
Abstract: Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although 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 genome-wide association study 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 3 distinct loci that were significant in combined or sex-segregated analyses. A single-nucleotide polymorphism on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio = 2.9, 95% confidence interval: 2.02-4.27, P = 2.2 x 10(-8)). This association was nominally replicated in a meta-analysis of 7 independent orofacial pain cohorts including 160,194 participants (odds ratio - 1.16, 95% confidence interval: 1.0-1.35, P = 2.3 x 10(-2)). Functional analysis in human dorsal root ganglia and blood indicated this variant is an expression quantitative trait locus, with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta = -0.51, P = 2.43 x 10(-5)). 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
Subject: Dor crônica
Country: Estados Unidos
Editor: Lippincott Williams & Wilkins
Rights: Fechado
Identifier DOI: 10.1097/j.pain.0000000000001438
Date Issue: 2019
Appears in Collections:FOP - Artigos e Outros Documentos

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