Smith, S., Parisien, M., Bair, E., Belfer, I., Chabot-Doré, A., Gris, P., Khoury, S., Tansley, S., Torosyan, Y., Zaykin, D., Bernhardt, O., de Oliveira Serrano, P., Gracely, R., Jain, D., Järvelin, M., Kaste, L., Kerr, K., Kocher, T., Lähdesmäki, R., Laniado, N., Laurie, C., Laurie, C., Männikkö, M., Meloto, C., Nackley, A., Nelson, S., Pesonen, P., Ribeiro-Dasilva, M., Rizzatti-Barbosa, C., Sanders, A., Schwahn, C., Sipilä, K., Sofer, T., Teumer, A., Mogil, J., Fillingim, R., Greenspan, J., Ohrbach, R., Slade, G., Maixner, W., Diatchenko, L. (2018) Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males. PAIN, 160(3), 579–591. https://doi.org/10.1097/j.pain.0000000000001438
Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males
|Author:||Smith, Shad B.1; Parisien, Marc2; Bair, Eric3,4;|
1Duke Univ, Ctr Translat Pain Med, Dept Anesthesiol, Durham, NC USA.
2McGill Univ, Alan Edwards Ctr Res Pain, Montreal, PQ, Canada.
3Univ North Carolina Chapel Hill, Ctr Pain Res & Innovat, Chapel Hill, NC USA.
4Univ North Carolina Chapel Hill, Dept Biostat, Chapel Hill, NC USA.
5NIH, Natl Ctr Complementary & Integrat Hlth, Bldg 10, Bethesda, MD 20892 USA.
6McGill Univ, Dept Psychol, Montreal, PQ, Canada.
7US FDA, Div Epidemiol, Ctr Devices & Radiol Hlth, Silver Spring, MD USA.
8NIEHS, Biostat & Computat Biol Branch, NIH, Durham, NC USA.
9Univ Med Greifswald, Dept Restorat Dent Prevent Dent & Pediat Dent, Greifswald, Germany.
10Univ Estadual Campinas, Piracicaba Dent Sch, Dept Prosthesis & Periodontol, Piracicaba, SP, Brazil.
11Univ Washington, Dept Biostat, Seattle, WA 98195 USA.
12Imperial Coll London, Publ Hlth England Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat,Med Res Council, London, England.
13Univ Oulu, Fac Med, Ctr Life Course Hlth Res, Oulu, Finland.
14Univ Oulu, Bioctr Oulu, Oulu, Finland.
15Oulu Univ Hosp, Unit Primary Care, Oulu, Finland.
16Brunel Univ London, Coll Hlth & Life Sci, Dept Life Sci, London, England.
17Univ Illinois, Coll Dent, Dept Pediat Dent, Chicago, IL USA.
18Univ Oulu, Fac Med, Res Unit Oral Hlth Sci, Oulu, Finland.
19Oulu Univ Hosp, Med Res CenterOdu, Oulu, Finland.
20Albert Einstein Coll Med, Jacobi Merkel Ctr, Dept Dent, Bronx, NY 10467 USA.
21Univ Oulu, Fac Biochem & Mol Med, Oulu, Finland.
22Univ Oulu, Fac Med, Northern Finland Birth Cohorts, Oulu, Finland.
23Univ Florida, Coll Dent, Restorat Dent Sci Dept, Div Prosthodont, Gainesville, FL USA.
24Univ North Carolina Chapel Hill, Dept Dent Ecol, Chapel Hill, NC USA.
25Univ Med Greifswald, Dept Prosthet Dent Gerodontol & Biomatenals, Greifswald, Germany.
26Univ Eastern Finland, Inst Dent, Kuopio, Finland.
27Kuopio Univ Hosp, Oral & Maxillofacial Dept, Kuopio, Finland.
28Harvard Med Sch, Dept Med, Boston, MA 02115 USA.
29Brigham & Womens Hosp, Div Sleep & Circadian Disorders, 75 Francis St, Boston, MA 02115 USA.
30Univ Med Greifswald, Inst Community Med, Greifswald, Germany.
31Univ Florida, Dept Community Dent & Behav Sci, Gainesville, FL USA.
32Univ Maryland, Sch Dent, Dept Neural & Pain Sci, Brotman Facial Pain Clin, Baltimore, MD 21201 USA.
33Univ Buffalo, Dept Oral Diagnost Serv, Buffalo, NY USA.
34Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC USA.
|Online Access:||PDF Full Text (PDF, 3.7 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2019041512261
|Publish Date:|| 2020-03-03
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 × 10⁻⁸). 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 × 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 × 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.
|Pages:||579 - 591|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
OPPERA was supported by the National Institute of Dental and Craniofacial Research (NIDCR; https://www.nidcr.nih.gov/): grant number U01DE017018. S.B. Smith was supported by K12DE022793. The OPPERA program also acknowledges resources specifically provided for this project by the respective host universities: University at Buffalo, University of Florida, University of Maryland–Baltimore, and University of North Carolina–Chapel Hill. Funding for genotyping was provided by NIDCR through a contract to the Center for Inherited Disease Research at Johns Hopkins University (HHSN268201200008I). Data from the OPPERA study are available through the NIH dbGaP: phs000796.v1.p1 and phs000761.v1.p1.
L. Diatchenko and the analytical team at McGill University were supported by the Canadian Excellence Research Chairs (CERC) Program grant (http://www.cerc.gc.ca/home-accueil-eng.aspx, CERC09). CERC09 also funded genotyping and cDNA array assays for DRG and blood expression studies.
Funding for DRG cohort collection was kindly provided by the US Cancer Pain Relief Committee (Career Development Award “Neurochemistry and Physiology of Human Pain-Processing Nuclei” to I.B.). They gratefully acknowledge all the donor families who agreed to donate tissue samples to pain research, without whose participation and cooperation this work would not have been possible.
SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, by the Federal Ministry of Education and Research (https://www.bmbf.de; grant numbers 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg–West Pomerania and the network “Greifswald Approach to Individualized Medicine (GANI_MED),” funded by the Federal Ministry of Education and Research (grant number 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant number 03ZIK012) and a joint grant from Siemens Healthcare (Erlangen, Germany) and the Federal State of Mecklenburg–West Pomerania. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH.
The Northern Finland Birth Cohort 1966 has received financial support from the Academy of Finland (http://www.aka.fi; project grants 104781, 120315, 129269, 1114194, 24300796, Center of Excellence in Complex Disease Genetics and SALVE), University Hospital Oulu, Biocenter, University of Oulu (75617), NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), NIH/National Institute of Mental Health (NIMH) (5R01MH63706:02), ENGAGE project and grant agreement HEALTH-F4-2007-201413, EU FP7 EurHEALTH Ageing-277849, the Medical Research Council (G0500539, G0600705, G1002319, PrevMetSyn/SALVE), and the MRC, Centenary Early Career Award. The program is currently being funded by the H2020-633595 DynaHEALTH action and Academy of Finland EGEAproject (285547). The DNA extractions, sample quality controls, biobank upkeeping, and aliquoting were performed in the National Public Health Institute, Biomedicum Helsinki, and supported financially by the Academy of Finland and Biocentrum Helsinki. They thank the late Professor Paula Rantakallio (launch of NFBCs) and Ms Outi Tornwall and Ms Minttu Jussila (DNA biobanking). They would like to acknowledge the contribution of the late Academian of Science Leena Peltonen. The study has been financially supported by the Academy of Finland, the European Commission (EURO-BLCS, https://ec.europa.eu/commission; Framework 5 award QLG1-CT-2000-01643), the Sigrid Jusélius Foundation (http://sigridjuselius.fi), and US National Institute of Mental Health (https://www.nimh.nih.gov; 5R01 MH 63706:02).
The Brazilian cohort has been funded by the São Paulo Research Foundation (http://www.fapesp.br; grant numbers 2006/56019-8R and 2009/02520-6), and genotyping was funded by the Canadian Excellence Research Chairs (CERC) Program (grant CERC09).
The Complex Persistent Pain Conditions: Unique and Shared Pathways of Vulnerability Program Project were supported by NIH/National Institute of Neurological Disorders and Stroke (NINDS; https://www.ninds.nih.gov) grant NS045685 to the University of North Carolina at Chapel Hill, and genotyping was funded by the Canadian Excellence Research Chairs (CERC) Program (grant CERC09).
The OPPERA II study was supported by the NIDCR under Award Number U01DE017018, and genotyping was funded by the Canadian Excellence Research Chairs (CERC) Program (grant CERC09).
The Hispanic Community Health Study/Study of Latinos is a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI; https://www.nhlbi.nih.gov) to the University of North Carolina (HHSN268201300001I/N01-HC-65233), University of Miami (HHSN268201300004I/N01-HC-65234), Albert Einstein College of Medicine (HHSN268201300002I/N01-HC-65235), University of Illinois at Chicago (HHSN268201300003I/N01-HC-65236 Northwestern Univ), and San Diego State University (HHSN268201300005I/N01-HC-65237). The following Institutes/Centers/Offices have contributed to the HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, NIH Institution-Office of Dietary Supplements. Data from HCHS/SOL are available through the NIH database of Genotypes and Phenotypes (dbGaP): phs000810. v1.p1.
|EU Grant Number:||
(633595) DYNAHEALTH - Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging
(277849) EURHEALTHAGEING - European ResearcH on DevElopmentAL, BirtH and Genetic Determinants of Ageing
|Academy of Finland Grant Number:||
129269 (Academy of Finland Funding decision)
© 2019 International Association for the Study of Pain. This is the peer reviewed version of the following article: Smith, S., Parisien, M., Bair, E., Belfer, I., Chabot-Doré, A., Gris, P., Khoury, S., Tansley, S., Torosyan, Y., Zaykin, D., Bernhardt, O., de Oliveira Serrano, P., Gracely, R., Jain, D., Järvelin, M., Kaste, L., Kerr, K., Kocher, T., Lähdesmäki, R., Laniado, N., Laurie, C., Laurie, C., Männikkö, M., Meloto, C., Nackley, A., Nelson, S., Pesonen, P., Ribeiro-Dasilva, M., Rizzatti-Barbosa, C., Sanders, A., Schwahn, C., Sipilä, K., Sofer, T., Teumer, A., Mogil, J., Fillingim, R., Greenspan, J., Ohrbach, R., Slade, G., Maixner, W., Diatchenko, L. (2018) Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males. PAIN, 160(3), 579–591., which has been published in final form at https://doi.org/10.1097/j.pain.0000000000001438.