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

Author(s):Show less -

Smith, Shad B. ^[1] ; Parisien, Marc ^[2] ; Bair, Eric ^{[3, 4]} ; Belfer, Inna ^[5] ; Chabot-Dore, Anne-Julie ^[2] ; Gris, Pavel ^[2] ; Khoury, Samar ^[2] ; Tansley, Shannon ^{[2, 6]} ; Torosyan, Yelizaveta ^[7] ; Zaykin, Dmitri ^[8] ; Bernhardt, Olaf ^[9] ; Serrano, Priscila de Oliveira ^[10] ; Gracely, Richard ^[3] ; Jain, Deepti ^[11] ; Jaervelin, Marjo-Riitta ^{[12, 13, 14, 15, 16]} ; Kaste, Linda ^[17] ; Kerr, Kathleen ^[11] ; Kocher, Thomas ^[9] ; Lahdesmaki, Raija ^{[18, 19]} ; Laniado, Nadia ^[20] ; Laurie, Cathy ^[11] ; Laurie, Cecelia ^[11] ; Mannikko, Minna ^{[21, 13]} ; Meloto, Carolina ^[2] ; Nackley, Andrea ^[1] ; Nelson, Sarah ^[11] ; Pesonen, Paula ^[22] ; Ribeiro-Dasilva, Margarete ^[23] ; Rizzatti-Barbosa, Celia ^[10] ; Sanders, Anne ^{[3, 24]} ; Schwahn, Christian ^[25] ; Sipila, Kirsi ^{[18, 19, 26, 27]} ; Sofer, Tamar ^{[28, 29]} ; Teumer, Alexander ^[30] ; Mogil, Jeffrey ^{[2, 6]} ; Fillingim, Roger ^[31] ; Greenspan, Joel ^[32] ; Ohrbach, Richard ^[33] ; Slade, Gary ^{[3, 24, 34]} ; Maixner, William ^[1] ; Diatchenko, Luda ^[2]

Affiliation:Show less -

^[1] Duke Univ, Ctr Translat Pain Med, Dept Anesthesiol, Durham, NC - USA

^[2] McGill Univ, Alan Edwards Ctr Res Pain, Montreal, PQ - Canada

^[3] Univ North Carolina Chapel Hill, Ctr Pain Res & Innovat, Chapel Hill, NC - USA

^[4] Univ North Carolina Chapel Hill, Dept Biostat, Chapel Hill, NC - USA

^[5] NIH, Natl Ctr Complementary & Integrat Hlth, Bldg 10, Bethesda, MD 20892 - USA

^[6] McGill Univ, Dept Psychol, Montreal, PQ - Canada

^[7] US FDA, Div Epidemiol, Ctr Devices & Radiol Hlth, Silver Spring, MD - USA

^[8] NIEHS, Biostat & Computat Biol Branch, NIH, Durham, NC - USA

^[9] Univ Med Greifswald, Dept Restorat Dent Prevent Dent & Pediat Dent, Greifswald - Germany

^[10] Univ Estadual Campinas, Piracicaba Dent Sch, Dept Prosthesis & Periodontol, Piracicaba, SP - Brazil

^[11] Univ Washington, Dept Biostat, Seattle, WA 98195 - USA

^[12] Imperial Coll London, Publ Hlth England Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, Med Res Council, London - England

^[13] Univ Oulu, Fac Med, Ctr Life Course Hlth Res, Oulu - Finland

^[14] Univ Oulu, Bioctr Oulu, Oulu - Finland

^[15] Oulu Univ Hosp, Unit Primary Care, Oulu - Finland

^[16] Brunel Univ London, Coll Hlth & Life Sci, Dept Life Sci, London - England

^[17] Univ Illinois, Coll Dent, Dept Pediat Dent, Chicago, IL - USA

^[18] Univ Oulu, Fac Med, Res Unit Oral Hlth Sci, Oulu - Finland

^[19] Oulu Univ Hosp, Med Res CenterOdu, Oulu - Finland

^[20] Albert Einstein Coll Med, Jacobi Merkel Ctr, Dept Dent, Bronx, NY 10467 - USA

^[21] Univ Oulu, Fac Biochem & Mol Med, Oulu - Finland

^[22] Univ Oulu, Fac Med, Northern Finland Birth Cohorts, Oulu - Finland

^[23] Univ Florida, Coll Dent, Restorat Dent Sci Dept, Div Prosthodont, Gainesville, FL - USA

^[24] Univ North Carolina Chapel Hill, Dept Dent Ecol, Chapel Hill, NC - USA

^[25] Univ Med Greifswald, Dept Prosthet Dent Gerodontol & Biomatenals, Greifswald - Germany

^[26] Univ Eastern Finland, Inst Dent, Kuopio - Finland

^[27] Kuopio Univ Hosp, Oral & Maxillofacial Dept, Kuopio - Finland

^[28] Brigham & Womens Hosp, Div Sleep & Circadian Disorders, 75 Francis St, Boston, MA 02115 - USA

^[29] Harvard Med Sch, Dept Med, Boston, MA 02115 - USA

^[30] Univ Med Greifswald, Inst Community Med, Greifswald - Germany

^[31] Univ Florida, Dept Community Dent & Behav Sci, Gainesville, FL - USA

^[32] Univ Maryland, Sch Dent, Dept Neural & Pain Sci, Brotman Facial Pain Clin, Baltimore, MD 21201 - USA

^[33] Univ Buffalo, Dept Oral Diagnost Serv, Buffalo, NY - USA

^[34] Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC - USA

• Document type: Journal article
• Source: Pain; v. 160, n. 3, p. 579-591, MAR 2019.
• Web of Science Citations: 2

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. (AU)

• FAPESP's process: 09/02520-6 - IL-1B, IL-6, IL-10 and TNF-a gene polymorphisms analyses in patients with TMJ internal derangements and osteoarthritis
• Grantee: Celia Marisa Rizzatti Barbosa
• Support Opportunities: Regular Research Grants