From time to time, The TMJ Association has reported research findings indicating that one or another form of a gene is found more frequently in patients with Temporomandibular Disorders (TMD) than in non-patients, suggesting a role for genetic factors in causing TMD. One of the early studies involved a variant of the catechol-O -methytransferase (COMT) gene, which encodes an enzyme important in regulating levels of the neurotransmitters dopamine, epinephrine and norepinephrine. A “variant” here refers to a change in one of the four nucleotides (abbreviated A, C, G, and T) at a single site in the genetic code for the gene. Such changes are called “single nucleotide polymorphisms” (SNPs, pronounced SNIPS). The variant in the COMT gene found to be more prevalent in TMD patients increases their sensitivity to pain. The Orofacial Pain Prospective Evaluation and Risk Assessment (OPPERA) study researchers found higher levels of the pain-sensitive COMT variant in chronic TMD patients as compared to controls. Also, they explored SNPs found in the codes for other genes important in pain pathways, some involving the neurotransmitter serotonin.
As techniques for genetic analyses have become more efficient and less costly, studies of TMD genetics have increased. Now two researchers based in Amsterdam C.M. Visscher and E.F. Lobbezoo have undertaken a systematic review of the literature.1 Using databases of publications in English, they found 21 studies that met their criteria for inclusion. Five were familial studies which included four twin studies and one was a survey of TMD patients and close relatives. Sixteen were genetic association studies. In these cases, investigators looked at candidate genes (genes suspected of being responsible for a particular trait or illness) involved in pain pathways to see if there were particular SNPs, which are found throughout the genome, that were more common in TMD patients than non-patients.
Results. Only one of the familial studies found evidence for heritability of TMD. This was a large study of identical and non-identical twins in which the authors concluded that TMD pain was 27% heritable. Visscher and Lobbezoo attribute the lack of genetic findings in the other four studies to their small sample size and the potential that shared environmental factors in a family might be a contributing factor to the development of a trait like TMD pain, making it difficult to tease out genetic factors. They also noted that the investigators in the large twin study discovered that the genetic factors they found in association with TMD pain partially overlapped with factors associated with migraine. This raises a red flag in future studies since it becomes essential that control groups not include individuals with other non-TMD pain conditions that may share genetic risk factors and thus confound analysis.
The gene association studies were more positive in finding modest evidence for gene variants that were more common in TMD patients than in controls. In addition to the COMT gene studies, associations with genes in serotonergic and immune system pathways have been found. And there were interesting nuances. For example, in a 2008 report of orthodontic treatment in relation to COMT gene variants and the development of TMD, a team of OPPERA investigators studied several hundred female volunteers who were TMD-free at the start of a three-year period of study. The investigators used several SNPS in the COMT gene to classify the women into two groups: those with high or average pain sensitivity and those with low pain sensitivity, essentially pain-resistant. Among those with the pain-resistant COMT variants, the development of TMD pain over three years was relatively low, whether the women had or had not had orthodontic treatments (6.3% vs. 5.5%). In contrast, the risk of development of TMD was much higher in women with the pain-sensitive COMT variants who reported having orthodontic treatments, thus revealing how an environmental factor can interact with genes in increasing the risk for disease.
OPPERA group investigators are also credited with developing a more complex form of genetic analysis and applying it in studies that divided TMD patients into two groups according to whether the patient’s symptoms were localized to the jaw alone or included pain conditions elsewhere in the body. Their SNP analyses revealed differences between the two groups. The localized TMD patient group shared SNPS in a serotonergic pathway whereas those with widespread pain had SNPS relating to cells in the immune system.
What It All Means. The Dutch investigators concluded that there is mounting evidence that TMD is heritable in part, but the story is complex involving the actions of multiple genes, probably interacting with environmental factors. Further, not only are future studies needed to replicate current findings, but attention must be paid to the makeup of control groups lest they include individuals with conditions that might share risk factors with TMD. In that regard, investigators would do well to divide TMD study populations according to whether the patients’ symptoms are localized to the jaw alone or are accompanied by other pain conditions and treat these two groups separately in their analyses.
Reference:
- Visscher, C. M. and Lobbezoo, F. (2015), TMD pain is partly heritable. A systematic review of family studies and genetic association studies. Journal of Oral Rehabilitation, 42: 386–399. doi: 10.1111/joor.12263