Genetically predicted associations between inflammatory cytokines and juvenile idiopathic arthritis: A Mendelian...

This study evaluates associations between genetically predicted circulating levels of 91 inflammatory cytokines and juvenile idiopathic arthritis (JIA) susceptibility. Summary statistics for 91 circulating inflammatory cytokines were obtained from a meta-analysis of 11 cohorts comprising 14,824 participants of European ancestry. JIA summary statistics were obtained from FinnGen Release 9 and included 788 cases and 172,834 controls of European ancestry. The primary estimator was the inverse-variance weighted (IVW) random-effects model. MR-Egger, weighted median, simple mode, and weighted mode analyses were used as complementary estimators. Sensitivity analyses included the MR-Egger intercept, Mendelian Randomization Pleiotropy RESidual Sum and Outlier, Cochran's Q, MR-Steiger, and leave-one-out tests. The C-C motif chemokine ligand 19 (CCL19) analysis used 19 independent single-nucleotide polymorphism instruments. At the nominal threshold of P < .05, IVW estimates indicated associations of CCL19 (odds ratio [OR], 2.48), fibroblast growth factor 19 (OR, 0.78), and monocyte chemotactic protein 3 (OR, 0.79) with JIA. After Bonferroni correction for 91 tests (threshold P < 5.49 × 10-4), only CCL19 remained significant (IVW P = 8.93 × 10-8; adjusted P = 8.12 × 10-6). The direction of the CCL19 estimate was consistent across Mendelian randomization methods, although significant heterogeneity and attenuation after outlier correction using Mendelian Randomization Pleiotropy RESidual Sum and Outlier indicated uncertainty in its magnitude. Higher genetically predicted CCL19 levels were associated with greater JIA susceptibility in participants of European ancestry. These findings reflect genetically predicted associations rather than established causal effects and do not support clinical prediction or intervention. Independent genetic, experimental, and clinical validation is required before CCL19 can be considered a biomarker or therapeutic target.