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: 4.01). 11/2011; 12(11 Suppl):T92-101. DOI: 10.1016/j.jpain.2011.08.005
Source: PubMed


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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    • "Age in years, sex, race/ethnicity (white, African American, Hispanic, Asian, or other), and a binary indicator (yes, no) of lifetime US residence were included in multivariable models because of their association with TMD incidence in this cohort (Bair et al. 2013). In Cox models that used COMT diplotypes, adjustment was made for population stratification using the first 3 dimensions of variance (eigenvectors) from multidimensional scaling analysis of all genotyped SNPs (Smith et al. 2011). Study site was a covariate because of the multisite study design. "
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    ABSTRACT: When measured once, psychological stress predicts development of painful temporomandibular disorder (TMD). However, a single measurement fails to characterize the dynamic nature of stress over time. Moreover, effects of stress on pain likely vary according to biological susceptibility. We hypothesized that temporal escalation in stress exacerbates risk for TMD, and the effect is amplified by allelic variants in a gene, catechol-O-methyltransferase (COMT), regulating catechol neurotransmitter catabolism. We used data from the Orofacial Pain: Prospective Evaluation and Risk Assessment prospective cohort study of 2,707 community-dwelling adults with no lifetime history of TMD on enrollment. At baseline and quarterly periods thereafter, the Perceived Stress Scale (PSS) measured psychological stress. Genotyped DNA from blood samples determined COMT diplotypes. During follow-up of 0.25 to 5.2 y, 248 adults developed examiner-verified incident TMD. PSS scores at baseline were 20% greater (P < 0.001) in adults who developed incident TMD compared with TMD-free controls. Baseline PSS scores increased by 9% (P = 0.003) during follow-up in cases but remained stable in controls. This stress escalation was limited to incident cases with COMT diplotypes coding for low-activity COMT, signifying impaired catabolism of catecholamines. Cox regression models confirmed significant effects on TMD hazard of both baseline PSS (P < 0.001), modeled as a time-constant covariate, and change in PSS (P < 0.001), modeled as a time-varying covariate. Furthermore, a significant (P = 0.04) interaction of COMT diplotype and time-varying stress showed that a postbaseline increase of 1.0 standard deviation in PSS more than doubled risk of TMD incidence in subjects with low-activity COMT diplotypes (hazard ratio = 2.35; 95% confidence limits: 1.66, 3.32), an effect not found in subjects with high-activity COMT diplotypes (hazard ratio = 1.42; 95% confidence limits: 0.96, 2.09). Findings provide novel insights into dynamic effects of psychological stress on TMD pain, highlighting that effects are most pronounced in individuals whose genetic susceptibility increases responsiveness to catecholamine neurotransmitters. © International & American Associations for Dental Research 2015.
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    • "TMD sufferers were also more likely to have suffered previous trauma, and had more comorbid pain conditions, like OA patients with persistent pain91,96. The two most promising SNPs identified in the analysis of the OPPERA cohort are SNPs in COMT, as described above, and the serotonin receptor HTR2A97. Revealingly, SNPs in HTR2A are also associated with the risk of chronic widespread pain98. "
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    • "Initially, it was widely assumed that variations in COMT activity in humans were caused only by the non-synonymous valine (Val) to methionine (Met) substitution at codon 158 (rs4680), which results in reduced thermostability and reduced activity of the enzyme (Lotta et al. 1995). Numerous studies identified associations between the low-activity Met158 allele and several pain phenotypes [e.g., (Smith et al. 2011; Cohen et al. 2009; Barbosa et al. 2012; Jacobsen et al. 2012; van Meurs et al. 2009; Gursoy et al. 2003)]; however, the observed associations were often modest and occasionally inconsistent "
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    ABSTRACT: Catechol-O-methyltransferase, encoded by COMT gene, is the primary enzyme that metabolizes catecholamines. COMT haplotypes have been associated with vulnerability to persistent non-traumatic pain. In this prospective observational study, we investigated the influence of COMT on persistent pain and pain interference with life functions after motor vehicle collision (MVC) in 859 European American adults for whom overall pain (0–10 numeric rating scale) and pain interference (Brief Pain Inventory) were assessed at week 6 after MVC. Ten single nucleotide polymorphisms spanning the COMT gene were successfully genotyped, and nine were present in three haploblocks: block 1 (rs2020917, rs737865, rs1544325), block 2 (rs4633, rs4818, rs4680, rs165774), and block 3 (rs174697, rs165599). After adjustment for multiple comparisons, haplotype TCG from block 1 predicted decreased pain interference (p = 0.004). The pain-protective effect of the low pain sensitivity (CGGG) haplotype from block 2 was only observed if at least one TCG haplotype was present in block 1 (haplotype × haplotype interaction p = 0.002 and <0.0001 for pain and pain interference, respectively). Haplotype AG from block 3 was associated with pain and interference in males only (sex × haplotype interaction p = 0.005 and 0.0005, respectively). These results suggest that genetic variants in the distal promoter are important contributors to the development of persistent pain after MVC, directly and via the interaction with haplotypes in the coding region of the gene.
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