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

作者：Shad B. Smith, Marc Parisien, Eric Bair, Inna Belfer, Anne‐Julie Chabot‐Doré, Pavel Gris, Samar Khoury, Shannon N. Tansley, Yelizaveta Torosyan, Dmitri V. Zaykin, Olaf Bernhardt, Priscila de Oliveira Serrano, Richard H. Gracely, Deepti Jain, Marjo‐Riitta Järvelin, Linda M. Kaste, Kathleen F. Kerr, Thomas Kocher, Raija Eliisa Lähdesmäki, Nadia Laniado, Cathy C. Laurie, Cecelia A. Laurie, Minna Männikkö, Carolina B. Meloto, Andrea G. Nackley, Sarah C. Nelson, Paula Pesonen, Margarete Ribeiro-Dasilva, Célia Marisa Rizzatti‐Barbosa, Anne E. Sanders, Christian Schwahn, Kirsi Sipilä, Tamar Sofer, Alexander Teumer, Jeffrey S. Mogil, Roger Benton Fillingim, Joel D. Greenspan, Richard K. Ohrbach, Gary Douglas Slade, William D. Maixner, Luda B. Diatchenko · 发表于：Pain · 年份：2018 · DOI：10.1097/j.pain.0000000000001438 · 被引用次数：50 · 研究领域：Pain Mechanisms and Treatments、Temporomandibular Joint Disorders、Botulinum Toxin and Related Neurological Disorders

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 × 10). 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 × 10). 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 × 10). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammator...