Potential genetic risk factors for chronic TMD: genetic associations from the OPPERA case control study.

UNLABELLED Genetic factors play a role in the etiology of persistent pain conditions, putatively by modulating underlying processes such as nociceptive sensitivity, psychological well-being, inflammation, and autonomic response. However, to date, only a few genes have been associated with temporomandibular disorders (TMD). This study evaluated 358 genes involved in pain processes, comparing allelic frequencies between 166 cases with chronic TMD and 1,442 controls enrolled in the OPPERA (Orofacial Pain: Prospective Evaluation and Risk Assessment) study cooperative agreement. To enhance statistical power, 182 TMD cases and 170 controls from a similar study were included in the analysis. Genotyping was performed using the Pain Research Panel, an Affymetrix gene chip representing 3,295 single nucleotide polymorphisms, including ancestry-informative markers that were used to adjust for population stratification. Adjusted associations between genetic markers and TMD case status were evaluated using logistic regression. The OPPERA findings provided evidence supporting previously reported associations between TMD and 2 genes: HTR2A and COMT. Other genes were revealed as potential new genetic risk factors for TMD, including NR3C1, CAMK4, CHRM2, IFRD1, and GRK5. While these findings need to be replicated in independent cohorts, the genes potentially represent important markers of risk for TMD, and they identify potential targets for therapeutic intervention. PERSPECTIVE Genetic risk factors for TMD pain were explored in the case-control component of the OPPERA cooperative agreement, a large population-based prospective cohort study. Over 350 candidate pain genes were assessed using a candidate gene panel, with several genes displaying preliminary evidence for association with TMD status.

[1]  M. Zhuo,et al.  Calcium–calmodulin-dependent protein kinase IV is required for fear memory , 2002, Nature Neuroscience.

[2]  S. Dworkin,et al.  Research diagnostic criteria for temporomandibular disorders: review, criteria, examinations and specifications, critique. , 1992, Journal of craniomandibular disorders : facial & oral pain.

[3]  E. Kalso,et al.  Clustering of symptoms associated with fibromyalgia in a Finnish Twin Cohort , 2009, European journal of pain.

[4]  B. Michalowicz,et al.  No Heritability of Temporomandibular Joint Signs and Symptoms , 2000, Journal of dental research.

[5]  D. Papanicolaou,et al.  Responses of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis to interleukin-6: a pilot study in fibromyalgia. , 2000, Arthritis and rheumatism.

[6]  William Maixner,et al.  Genetic architecture of human pain perception. , 2007, Trends in genetics : TIG.

[7]  W. Maixner,et al.  Effect of catechol-O-methyltransferase polymorphism on response to propranolol therapy in chronic musculoskeletal pain: a randomized, double-blind, placebo-controlled, crossover pilot study , 2010, Pharmacogenetics and genomics.

[8]  A. Silman,et al.  Association of HTR2A polymorphisms with chronic widespread pain and the extent of musculoskeletal pain: results from two population-based cohorts. , 2011, Arthritis & Rheumatism.

[9]  W. Maixner,et al.  Three major haplotypes of the β2 adrenergic receptor define psychological profile, blood pressure, and the risk for development of a common musculoskeletal pain disorder , 2006, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[10]  Y. Kim,et al.  Association between estrogen receptor polymorphism and pain susceptibility in female temporomandibular joint osteoarthritis patients. , 2007, International journal of oral and maxillofacial surgery.

[11]  R. Dionne,et al.  Genetic contributions to clinical pain and analgesia: avoiding pitfalls in genetic research. , 2009, The journal of pain : official journal of the American Pain Society.

[12]  R. Ohrbach,et al.  Orthodontic Treatment, Genetic Factors and Risk of Temporomandibular Disorder. , 2008, Seminars in orthodontics.

[13]  A. Basbaum,et al.  Contribution of sensory afferents and sympathetic efferents to joint injury in experimental arthritis , 1986, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[14]  D. Zaykin,et al.  Haplotype associations with quantitative traits in the presence of complex multilocus and heterogeneous effects , 2009, Genetic epidemiology.

[15]  M. Max,et al.  Candidate Gene Studies of Human Pain Mechanisms: Methods for Optimizing Choice of Polymorphisms and Sample Size , 2004, Anesthesiology.

[16]  N. Martin,et al.  Genetic and environmental influences on migraine: a twin study across six countries. , 2003, Twin research : the official journal of the International Society for Twin Studies.

[17]  William Maixner,et al.  Orofacial pain prospective evaluation and risk assessment study--the OPPERA study. , 2011, The journal of pain : official journal of the American Pain Society.

[18]  E. Bleecker,et al.  A polymorphism of G-protein coupled receptor kinase5 alters agonist-promoted desensitization of beta2-adrenergic receptors. , 2008, Pharmacogenetics and genomics.

[19]  M. Narita,et al.  Temporomandibular disorder is associated with a serotonin transporter gene polymorphism in the Japanese population , 2007, BioPsychoSocial medicine.

[20]  N. Pedersen,et al.  Genetic Influence in Headaches: A Swedish Twin Study , 1995, Headache.

[21]  J. Li,et al.  Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix , 2005, Heredity.

[22]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[23]  Michael Boehnke,et al.  Quantifying and correcting for the winner's curse in quantitative‐trait association studies , 2011, Genetic epidemiology.

[24]  W. Thomson,et al.  Genetic variation in neuroendocrine genes associates with somatic symptoms in the general population: Results from the EPIFUND study , 2010, Journal of psychosomatic research.

[25]  J. Hartvigsen,et al.  Heritability of neck pain: a population-based study of 33,794 Danish twins. , 2006, Rheumatology.

[26]  W. Maixner,et al.  Idiopathic pain disorders – Pathways of vulnerability , 2006, PAIN.

[27]  D. Nyholt.  A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. , 2004, American journal of human genetics.

[28]  David Goldman,et al.  Genetic influence on variability in human acute experimental pain sensitivity associated with gender, ethnicity and psychological temperament , 2004, Pain.

[29]  J. Mogil,et al.  Progress in genetic studies of pain and analgesia. , 2009, Annual review of pharmacology and toxicology.

[30]  J. Belknap,et al.  Genetic sensitivity to hot-plate nociception in DBA/2J and C57BL/6J inbred mouse strains: possible sex-specific mediation by δ 2-opioid receptors , 1997, Pain.

[31]  E. Young,et al.  Basal Circadian Cortisol Secretion in Women with Temporomandibular Disorders , 2002, Journal of dental research.

[32]  H. Herken,et al.  Possible association of temporomandibular joint pain and dysfunction with a polymorphism in the serotonin transporter gene. , 2001, American journal of orthodontics and dentofacial orthopedics : official publication of the American Association of Orthodontists, its constituent societies, and the American Board of Orthodontics.

[33]  P. Magnus,et al.  Myofascial pain dysfunction (MPD) syndrome in twins. , 1980, Community dentistry and oral epidemiology.

[34]  W. Maixner,et al.  Genetic basis for individual variations in pain perception and the development of a chronic pain condition. , 2005, Human molecular genetics.

[35]  J. Beckmann,et al.  A highly significant association between a COMT haplotype and schizophrenia. , 2002, American journal of human genetics.

[36]  W. Guo,et al.  Differential involvement of trigeminal transition zone and laminated subnucleus caudalis in orofacial deep and cutaneous hyperalgesia: the effects of interleukin-10 and glial inhibitors , 2009, Molecular pain.

[37]  A. Basbaum,et al.  Epinephrine exacerbates arthritis by an action at presynaptic b2-adrenoceptors , 1990, Neuroscience.

[38]  Y. Bayazıt,et al.  T102C polymorphism of the 5-HT2A receptor gene may be associated with temporomandibular dysfunction. , 2004, Oral diseases.

[39]  M. Zhuo,et al.  Evidence for a role of CaMKIV in the development of opioid analgesic tolerance , 2006, The European journal of neuroscience.

[40]  K. Roeder,et al.  Genomic Control for Association Studies , 1999, Biometrics.

[41]  J. Shendure,et al.  IFRD1 is a candidate gene for SMNA on chromosome 7q22-q23. , 2009, American journal of human genetics.

[42]  Rasmus Jorgensen,et al.  Phosphorylation of the beta2-adrenergic receptor in plasma membranes by intrinsic GRK5. , 2007, Biochemistry.

[43]  R. Fillingim,et al.  Estrogen receptor-alpha polymorphisms and predisposition to TMJ disorder. , 2009, The journal of pain : official journal of the American Pain Society.