Association between interleukin-12 p40 subunit and risk of primary Sjögren’s syndrome: a Mendelian randomization study

Objectives:
Interleukin-12 (IL-12) signalling was proposed in the immunopathogenesis of primary Sjögren’s disease. The efficacy of therapies targeting this pathway is currently unclear. Herein, we investigated the associations between circulating proteins involved in the IL-12 and IL-23 signalling pathways on primary Sjögren’s disease using mendelian randomization.

Methods: We selected SNPs from protein quantitative trait loci of IL12A, IL12B, IL12Rβ1, IL12Rβ2, and IL23R to examine the association between alterations in their levels and risk of primary Sjögren’s disease. Genetic association data for proteins were taken from studies ranging from 3,301-54,306 in sample size, and from 3,232 cases of primary Sjögren’s disease and 17,481 controls. The Wald ratio or inverse variance weighted methods estimated causal effects. We applied colocalization and pleiotropy-robust methods as sensitivity analyses for confounding.

Results:
There was a negative association between genetically predicted IL-12p40 (encoded by IL12B) and primary Sjögren’s disease. In the two independent exposure datasets odds ratio (OR) 0.79 (95% confidence interval [CI] 0.68-0.93; P-value = 0.004) and OR 0.86 (95% CI 0.78-0.95; P-value = 0.003) per standard deviation decrease in genetically predicted IL-12p40. Neither IL-12Rβ2 and IL-23R met the threshold P-value after MR analyses (P-value < 0.01) for colocalization assessment. No variants for the IL12A gene met prerequisite thresholds for weak instrument bias.

Conclusion:
This study provides genetic evidence that IL-12p40 has a causal role in primary Sjögren’s disease pathogenesis. Our data suggest that decreasing levels of IL-12p40 may be deleterious. We would not suggest selecting this drug target as a therapeutic option.