The −308 G/A TNF-α polymorphism showed a protective effect against HATMD.

The -174G/C IL-6 polymorphism was not associated with HATMD.

Patients with the C677T MTHFR polymorphism are less likely to have HATMD.

The aim of this study was to examine the relationship between three single nucleotide polymorphisms (SNPs): −308 G/A TNF-α, −174 G/C IL-6, and C677T MTHFR and the presence of headache attributed to temporomandibular disorder (HATMD).

This case-control study included a total of 68 patients with HATMD and 200 controls, aged 18 years and older. Both sets of participants included both genders. The diagnosis followed the diagnostic criteria for temporomandibular disorders (DC/TMD). The temporomandibular disorder pain screen was also applied. The −308 G/A TNF-α and 677 C/T MTHFR SNPs were genotyped using polymerase chain reaction-restriction fragment polymorphism (PCR-RFLP), and −174 G/C IL-6 SNP was performed by PCR. Allele frequencies and logistic regression analysis were used to assess the association between HATMD and genotypes.

The results revealed that the AA genotype of −308 G/A TNF-α SNP (ORGG/AA= 0.20, 95 % CI: 0.0568–0.7724,p = 0.0290) and the CT genotype of C677T MTHFR SNP (ORCC/CT = 0.40, 95 % CI: 0.2224–0.7350, p = 0.0042) were protective factors for HATMD risk. No significant association was found between -174G/C IL-6 SNP and the risk of HATMD (ORGG/CC = 0.58, 95 % CI: 0.2122–1.6367, p = 0.45).

The −308 G/A TNF-α and C677T MTHFR SNPs were identified as protective factors against the development of HATMD.

Headache

Temporomandibular joint disorders

Genetic polymorphism

Tumor necrosis factor-alpha

Interleukin-6

Human MTHFR protein

© 2026 The Author(s). Published by Elsevier Ltd.