Genetic study links autoimmune liver diseases and systemic autoimmunity to IL12 signaling

A study published in Hepatology examined genetic associations with IL12 signaling across 27 autoimmune diseases using data from approximately 1.5 million individuals in 24 cohorts. Researchers assessed variants in four IL12-pathway genes and used three large observational medical and insurance-claims datasets to evaluate co-prevalence of the implicated conditions.

A rare variant upstream of IL12A was associated with increased odds of autoimmune hepatitis (per-allele OR 2.98), primary biliary cholangitis (2.80), systemic sclerosis (2.64), Sjogren’s disease (1.94), systemic lupus erythematosus (1.83) and multiple sclerosis (1.79). A separate variant linked to lower IL12A expression was protective against five of these diseases, whereas an IL12RB2 variant linked to higher expression increased odds of all six. Heterozygous carriers of rare predicted loss-of-function or missense IL12RB2 variants had 18% lower odds of lupus (OR 0.82; p=2×10−5).

IL23 signaling, despite sharing ligand and receptor components with IL12, was not associated with these conditions. All implicated diseases except multiple sclerosis strongly co-occurred with one another in epidemiologic analyses.

The findings support a shared biological pathway and a rationale for investigating IL12-targeted interventions across these conditions. However, genetic associations and observational co-prevalence do not establish treatment efficacy or safety. The study involved genetic data curated by the Regeneron Genetics Center; no therapeutic intervention was tested.