Objectives 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 single nucleotide polymorphisms 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 3301 to 54 306 in sample size, and from 3232 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% CI 0.68–0.93; P-value = 0.004) and OR 0.86 (95% CI 0.78–0.95; P-value = 0.003) per S.D. decrease in genetically predicted IL-12p40. Neither IL-12Rβ2 nor IL-23R met the threshold P-value after Mendelian randomization 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.

中文翻译：

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白细胞介素 12 p40 亚基与原发性干燥综合征风险之间的关联：一项孟德尔随机化研究


目的 IL-12 信号在原发性干燥症的免疫发病机制中被提出。目前尚不清楚针对该通路的疗法的疗效。在此，我们使用孟德尔随机化研究了原发性干燥综合征中 IL-12 和 IL-23 信号通路中涉及的循环蛋白之间的关联。方法 我们从 IL12A 、 IL12B 、 IL12Rβ1 、 IL12Rβ2 和 IL23R 的蛋白数量性状位点中选择单核苷酸多态性，以检验其水平改变与原发性干燥症风险之间的关联。蛋白质的遗传关联数据取自样本量从 3301 到 54 306 例的研究，以及 3232 例原发性干燥病病例和 17 481 例对照病例。Wald 比率或逆方差加权方法估计因果效应。我们应用共定位和多效性稳健方法作为混杂的敏感性分析。结果 遗传预测的 IL-12p40 （由 IL12B 编码） 与原发性干燥综合征呈负相关。在两个独立的暴露数据集中，比值比 （OR） 为 0.79 （95% CI 0.68–0.93;P 值 = 0.004）和 OR 0.86 （95% CI 0.78-0.95;P 值 = 0.003） 遗传预测的 IL-12p40 每 SD 减少。在孟德尔随机化分析后，IL-12Rβ2 和 IL-23R 均未达到共定位评估的阈值 P 值 （P 值 < 0.01）。IL12A 基因的变异均未达到弱仪器偏倚的先决条件阈值。结论 本研究提供了遗传学证据，证明 IL-12p40 在原发性干燥综合征的发病机制中起因果作用。我们的数据表明，降低 IL-12p40 的水平可能是有害的。我们不建议选择该药物靶点作为治疗选择。