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

Center for Neurosensory Disorders, University of North Carolina at Chapel Hill, North Carolina 27514, USA.
The journal of pain: official journal of the American Pain Society (Impact Factor: 4.22). 11/2011; 12(11 Suppl):T92-101. DOI: 10.1016/j.jpain.2011.08.005
Source: PubMed

ABSTRACT 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.

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    ABSTRACT: Genetic risk factors are believed to combine with environmental exposures and contribute to the risk of developing temporomandibular disorder (TMD). In this prospective cohort study, 2,737 people without TMD were assessed for common genetic variation in 358 genes known to contribute to nociceptive pathways, inflammation, and affective distress. During a median follow-up period of 2.8 years, 260 people developed first-onset TMD. Hazard ratios were computed as measures of association between 2,924 single-nucleotide polymorphisms and TMD incidence. After correction for multiple testing, no single single-nucleotide polymorphism was significantly associated with risk of onset TMD. However, several single-nucleotide polymorphisms exceeded Bonferroni correction for multiple comparison or false discovery rate thresholds (.05, .1, or .2) for association with intermediate phenotypes shown to be predictive of TMD onset. Nonspecific orofacial symptoms were associated with voltage-gated sodium channel, type I, alpha subunit (SCN1A, rs6432860, P = 2.77 × 10−5) and angiotensin I–converting enzyme 2 (ACE2, rs1514280, P = 4.86 × 10−5); global psychological symptoms with prostaglandin-endoperoxide synthase 1 (PTGS1, rs3842803, P = 2.79 × 10−6); stress and negative affectivity with amyloid-β (A4) precursor protein (APP, rs466448, P = 4.29 × 10−5); and heat pain temporal summation with multiple PDZ domain protein (MPDZ, rs10809907, P = 3.05 × 10−5). The use of intermediate phenotypes for complex pain diseases revealed new genetic pathways influencing risk of TMD. Perspective This article reports the findings of a large candidate gene association study of first-onset TMD and related intermediate phenotypes in the OPPERA Study. Although no genetic markers predicted TMD onset, several genetic risk factors for clinical, psychological, and sensory phenotypes associated with TMD onset were observed.
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