Causal interplay between trigeminal neuralgia and systemic inflammatory markers: A bidirectional Mendelian...

Trigeminal neuralgia (TN) is a debilitating neuropathic pain disorder with profound impacts on quality of life. Although alterations in circulating inflammatory proteins have been reported, observational findings remain inconsistent and are vulnerable to confounding and reverse causation. Whether these immune changes are causal or merely downstream consequences of TN remains uncertain, underscoring the need for robust causal inference methods. We conducted a bidirectional 2-sample Mendelian randomization (MR) analysis to investigate the causal relationships between circulating inflammatory proteins and TN. Genetic instruments for 91 proteins and TN were obtained from large-scale publicly available genome-wide association studies. Five complementary MR estimators were applied - inverse-variance weighting (IVW), MR-Egger, weighted median, weighted mode, and simple mode - and sensitivity analyses were performed to evaluate heterogeneity, pleiotropy, and robustness. Forward MR identified 5 proteins significantly associated with TN risk: eotaxin (IVW odds ratio [OR] = 0.834, 95% CI = 0.711-0.977, P = .025); C-X-C motif chemokine ligand 5 [CXCL5]; IVW OR = 0.841, 95% CI = 0.726-0.974, P = .021); IL-20RA (IVW OR = 1.317, 95% CI = 1.032-1.679, P = .027); interleukin-6 (IVW OR = 1.343, 95% CI = 1.059-1.704, P = .015); and neurturin (IVW OR = 1.190, 95% CI = 1.004-1.410, P = .044). Reverse MR indicated that TN causally influenced 5 immune traits: eotaxin (OR = 0.39, 95% CI = 0.19-0.80, P = .010); CXCL5 (OR = 0.32, 95% CI = 0.11-0.91, P = .032); IL-20RA (OR = 2.07, 95% CI = 1.11-3.84, P = .022); interleukin-15 receptor α (OR = 0.28, 95% CI = 0.08-0.99, P = .048); and transforming growth factor-α (OR = 0.44, 95% CI = 0.23-0.83, P = .011). Notably, eotaxin, CXCL5, and IL-20RA showed bidirectional associations with TN. All signals were consistent across complementary estimators and sensitivity analyses, with no evidence of heterogeneity or horizontal pleiotropy (all P > .05). Our genetic evidence demonstrates a close coupling between the circulating inflammatory network and TN, providing testable leads for biomarker development and immunomodulatory strategies in TN.