Genetic Differences Contributing to TMJ Susceptibility in Males

Temporomandibular disorders (TMD) are the leading cause of chronic orofacial pain. They represent a type of “idiopathic” pain disorder, meaning that the cause or causes are unknown, but research over the decade suggests a genetic component contributing to susceptibility. There is also a well-known gender difference in frequency of TMD, with more women affected than men, especially in more severe and chronic cases. Further, evidence is accumulating that there are sex differences in the way men and women perceive and respond to pain.  

To shed light on the role of genes in susceptibility to TMD, investigators are analyzing data from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study, a multi-university project led by investigators at the University of North Carolina at Chapel Hill. Initiated in 2006, the investigators recruited a diverse group of over 3,000 American adults, collected data and tissue samples reflecting behavioral, environmental, and genetic factors that might be associated with TMD. Over time, some of these subjects developed TMD; others did not. DNA from the volunteers was analyzed using a “gene chip” that assessed the presence of over two million genetic markers, single places in the genetic code called single nucleotide polymorphisms (“SNPs”). The aim was to detect any SNPs that distinguished TMD cases from controls for over 20,000 genes. The investigators found groups of SNPs on three different chromosomes that were associated with TMD status in the OPPERA subjects, including a set of variants on chromosome 3 near a gene called MRAS. Interestingly, the correlation between the SNPs and TMD only existed in male TMD subjects; there was no effect in females. They then checked seven other oral/facial pain studies, representing over 160,000 participants in total, to see if the chromosome 3 SNPs affected pain in those cohorts as well.  It did. They saw that the same sex-specific effect was replicated in the other cohorts, confirming the OPPERA finding.  

To understand the relationship of the SNP markers to nearby genes, the researchers examined how they affected the expression of these genes. It turned out that the SNP variants that were associated with greater TMD risk were associated with lower production of the RNA signal transcript of MRAS, indicating lower expression of the protein coded for by the gene. They then tested the pain sensitivity of mice engineered to have either two, one, or zero functional copies of the analogous MRAS gene. Female mice that had an injection of a substance into their paw producing inflammation showed a typical period of hypersensitivity to pain followed by recovery within 7-14 days, regardless of how many copies of MRAS they had. Male mice with functional versions of MRAS also showed a typical pain recovery pattern, but male mice with no functioning MRAS remained hypersensitive to pain beyond two weeks. Evidence from both humans and mice therefore suggests that MRAS is part of an injury recovery pathway, and is needed for this pathway to function properly in males, but not females. This finding may lead to treatments that leverage MRAS function to recruit a person’s innate resiliency against pain, although this approach may only be effective in males.