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. 2011 Nov;12(11 Suppl):T92-101.
doi: 10.1016/j.jpain.2011.08.005.

Potential Genetic Risk Factors for Chronic TMD: Genetic Associations From the OPPERA Case Control Study

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Free PMC article

Potential Genetic Risk Factors for Chronic TMD: Genetic Associations From the OPPERA Case Control Study

Shad B Smith et al. J Pain. .
Free PMC article

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.

Figures

Figure 1
Figure 1
Genetic Association Test for 358 candidate genes from 166 TMD cases and 1442 controls in the OPPERA study Q-Q plot of case-control association test within OPPERA cohort only. Each blue dot represents a single SNP. The observed −log10(p-values) on the y-axis are ranked and plotted against the expected −log10(p-values) under the null hypothesis on the x-axis; the null distribution is represented by the red line. Since no SNP elevated significantly above the expected line, we were not able to reject the null hypothesis for SNPs with −log10(p-values).
Figure 2
Figure 2
Genetic Association Test for 358 candidate genes from 348 TMD cases and 1612 controls in the combined OPPERA and UNC studies Q-Q plot of case-control association test within combined OPPERA and UNC cohorts. Each blue dot represents a single SNP. The observed −log10(p-values) on the y-axis are ranked and plotted against the expected −log10(p-values) under the null hypothesis on the x-axis; the null distribution is represented by the red line. Eleven SNPs showed elevation above the expected line, thus rejecting the null hypothesis for SNPs with −log10(p-values).
Figure 3
Figure 3
Manhattan Plot of Genetic Association Test for 358 candidate genes from 348 TMD cases and 1612 controls in the combined OPPERA and UNC studies Each dot represents a single SNP, mapped by genomic location on the x-axis and the observed −log10(p-values) on the y-axis. Each chromosome is colored differently.
Figure 4
Figure 4
Genetic Association Test for Tier 1 SNPs in 23 candidate genes from 348 TMD cases and 1612 controls in the combined OPPERA and UNC studies Q-Q plot of case-control association test within combined OPPERA and UNC cohorts for Tier 1 genes. Each blue dot represents a single SNP. The observed −log10(p-values) on the y-axis are ranked and plotted against the expected −log10(p-values) under the null hypothesis on the x-axis; the null distribution is represented by the red line. Eight SNP showed elevation above the expected line, thus rejecting the null hypothesis for SNPs with −log10(p-values).

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