Endocrine Abstracts

Objectives: Graves’ ophthalmopathy is an immunological manifestation of the orbit associated with autoimmune thyroid disease. The immunopathology, although not completely understood, is driven by B lymphocytes and plasma cells with the production of autoantibodies that have a high affinity for the thyroid stimulating hormone receptor. Understanding the pathogenic architecture of Grave’s ophthalmopathy is important, particularly the role of T-lymphocytes. Two case reports demonstrated an association between Ustekinumab, a monoclonal antibody inhibiting IL-12 p40 subunit and IL-23 pathways (related to T helper 2 cell functioning and interferon pathways), and the development of thyrotoxicosis [1]. Herein we investigated the associations between circulating IL-12p40 on Grave’s ophthalmopathy using two-sample mendelian randomization.

Methods: We selected SNPs from protein quantitative trait loci of IL12B, the gene associated with encoding protein IL12-B, also referred to as IL-12 p40 to examine the association between alterations the levels of this protein and risk of incident Grave’s ophthalmopathy. Genetic association data for proteins were taken from 3,301 healthy participants and from 643 cases of Grave’s ophthalmopathy from the FinnGen studies. The Wald ratio or inverse variance weighted methods used to estimate causal effects. We applied colocalization and pleiotropy-robust methods as sensitivity analyses for confounding.

Results: There was a negative association between genetically predicted IL-12 p40 and Grave’s ophthalmopathy (odds ratio [OR] 2.65, 95% Confidence Interval [CI] 1.50 to 4.69), with conditional probability of 96% suggesting no genetic confounding.

Conclusion: This study provides genetic evidence that IL-12p40 has a causal role in Grave’s ophthalmopathy 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.

1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450299/