Association between oxidative stress and chronic orofacial pain and potential druggable targets: Evidence from a Mendelian randomization study

Abstract Background Oxidative stress indicators affect chronic orofacial pain (COFP), but how to reduce these effects is uncertain. Objectives 11 oxidative stress biomarkers were collected as exposures, while four forms of COFP were chosen as outcomes for Mendelian randomization (MR) study. Methods The effect estimates between oxidative stress and COFP were calculated using inverse variance‐weighted MR (IVW‐MR). Then, functional mapping and annotation (FUMA) was utilized in order to carry out SNP‐based functional enrichment analyses. In addition, the IVW‐MR method was applied to combine effect estimates when using genetic variants associated with oxidative stress biomarkers as an instrument for exploring potential druggable targets. Results The results indicated that oxidative stress biomarkers (causal OR of uric acid (UA), 0.998 for myofascial pain, 95% CI 0.996–1.000, p < .05; and OR of glutathione transferase (GST), 1.002 for dentoalveolar pain, 95% CI 1.000–1.003, p < .05) were significantly linked with the probability of COFP. Functional analysis also demonstrated that UA and myofascial pain genes were prominent in nitrogen and uracil metabolism, while GST and dentoalveolar pain genes were enriched in glutathione metabolism. Also, the study provided evidence that solute carrier family 2 member 9 (SLC2A9) and glutathione S‐transferase alpha 2 (GSTA2) cause discomfort in the myofascial pain (OR = 1.003, 95% CI 1.000–1.006; p < .05) and dentoalveolar region (OR = 1.001, 95% CI 1.000–1.002; p < .05), respectively. Conclusions In conclusion, this MR study indicates that genetically predicted myofascial pain was significantly associated with decreased UA and dentoalveolar pain was significantly associated with increased GST level. SLC2A9 inhibitor and GSTA2 inhibitor were novel chronic orofacial pain therapies and biomarkers, but clinical trials are called to examine if these oxidative biomarkers have the protective effect against orofacial pain, and further research are needed to explore the underlying mechanisms.