ENPP1 and ESR1 genotypes associated with subclassifications of craniofacial asymmetry and severity of temporomandibular disorders

Abstract

Introduction We investigated if ACTN3, ENPP1, ESR1, PITX1 and PITX2 genes which contribute to sagittal and vertical malocclusion also contribute to facial asymmetries and TMD before and after orthodontic and orthognathic surgery treatment. Methods One hundred seventy four dentofacial deformity patients were diagnosed as symmetric or subdivided into four asymmetric groups according to PA cephalometric measurements. TMD exam diagnosis and Jaw Pain and Function-(JPF) questionnaires assessed presence and severity of TMD. Results Fifty two % of patients were symmetric and forty eight % asymmetric. The asymmetry classification demonstrated significant cephalometric differences between symmetric and asymmetric groups, and across the four asymmetric subtypes: Group 1 - mandibular body asymmetry, Group 2 - ramus asymmetry, Group 3 - atypical asymmetry and Group 4 - “C-shaped” asymmetry. ENPP1 SNP-rs6569759 associated with asymmetry Group 1(p=0.004), and rs858339 with asymmetry Group 3 (p=0.002). ESR1 SNP-rs164321 associated with asymmetry Group 4 (p=0.019). These results are confirmed by Principal Component Analysis (PCA) that showed three principal components explaining almost 80% of the variation seen in the studied group. PC1 and PC2 were associated with ESR1 SNP-rs3020318 (p<0.05). Diagnoses of disc displacement with reduction, masticatory muscle myalgia and arthralgia were highly prevalent in the asymmetry groups and all had strong statistical association to ENPP1 rs858339. The average JPF scores for asymmetric subjects before surgery (JPF=7), were significantly higher than symmetric subjects (JPF=2). Patients with asymmetry Group 3 reported the highest preoperative JPF scores and Group 2 and 3 were most likely to be cured of TMD one year after treatment. Conclusions PA cephalometrics can classify asymmetry into distinct groups; identify probability of TMD and genotype associations. Orthodontic and orthognathic treatment of facial asymmetry is very effective at eliminating TMD in most patients.

Mechanobehavior and mandibular ramus length in different facial phenotypes

“…13 If polymorphisms for mechanosensitive genes augment or diminish signal transduction, thereby modifying responsiveness of the TMJ secondary cartilages to mechanical stimuli, that is unknown. Also unknown is whether asymmetric differences in mechanosensitive genes, like those seen in asymmetric craniofacial anomalies, 22,23 affect unilateral differences in mechanosensitive genes in response to symmetric mechanobehavior.…”

The many faces of genetic contributions to temporomandibular joint disorder: An updated review

“…Genes involved in structural functions, such as ACTN3 (alpha‐actinin‐3), GSTM1 (glutathione S ‐transferase mu 1), MTHFD (C‐1‐tetrahydrofolate synthase, cytoplasmic) and MTRR (methionine synthase reductase), may influence the risk of temporomandibular dysfunction . We can speculate that these genes possibly respond differently to oxidative stress, which leads to the production of nitrous oxide and peroxynitrite, reacts to excessive mechanical overload, and is harmful to DNA, which could promote greater susceptibility to TMD.…”

Condyle modeling stability, craniofacial asymmetry and ACTN3 genotypes: Contribution to TMD prevalence in a cohort of dentofacial deformities

“…When craniofacial asymmetry was present, these patients reported a significantly elevated level of pain and jaw dysfunction. [ 14 ] This coincided with significantly elevated clinical diagnosis of disc displacement with reduction, myalgia, arthralgia and TMD related headache. In discriminating between different patterns of asymmetry, we developed a new posterior anterior cephalometric analysis which distinguishes four anatomic subclassifications (group one—four), each with a different rate of TMD symptoms.…”

“…This unusual subclassification of asymmetry is very common and results in the highest rate of patient reported TMD symptoms. [ 14 ] Genetic analysis revealed that an additional variant in ENPP1 (rs858339) associated with this asymmetry pattern. Group two and three had the highest rates of reported TMD symptoms, and four had the lowest—even though skeletal imbalance was the most pronounced in this group.…”

“…To further understand variation in presentation of TMD signs and symptoms, we evaluated how different patterns of craniofacial asymmetry, asymmetric condyle geometry variation and ENPP1 or ACTN3 genotypes might interact, in a cohort of dentofacial deformities subjects already included in previous studies. [ 13 , 14 , 22 , 23 ] These findings may be of diagnostic predictive value in counseling patients for their potential risk for developing or aggravation of TMD.…”