Autoimmune hepatitis and primary biliary cholangitis are among a subset of autoimmune diseases defined by profound co-prevalence and genetic risk association with the IL12 pathway

Background and Aims: Distinct autoimmune diseases can share symptoms and autoantibodies, but the molecular pathways underlying this shared etiology remain poorly understood. We assessed genetic support for IL12 signaling across 27 diseases. Approach and Results: We identified a rare variant upstream of IL12A with large risk-increasing effects on autoimmune hepatitis [AIH; per-allele odds ratio (OR)=2.98, p =3×10 −9 ], primary biliary cholangitis (PBC; OR=2.80, p =2×10 −8 ), systemic sclerosis (SSc; OR=2.64, p =2×10 −11 ), Sjogren's disease (SjD; OR=1.94, p =10 −11 ), systemic lupus erythematosus (SLE; OR=1.83, p =5×10 −10 ) and multiple sclerosis (OR=1.79, p =10 −11 ). Lifetime risk for developing at least one of these conditions increased 6-fold in homozygote carriers (OR=5.73, p =0.003). We then evaluated genetic support for all 4 IL12 signaling genes and found that: (i) a non-coding variant downstream of IL12A (linked to lower gene expression) protected against 5 of the 6 diseases; (ii) an intronic variant in IL12RB2 (linked to higher gene expression) increased risk of all 6 diseases; and (iii) heterozygote carriers of rare predicted loss-of-function or missense variants in IL12RB2 had 18% lower odds of SLE (OR=0.82, p =2×10 −5 ). IL23 signaling, which shares ligand and receptor subunits with IL12, was not associated with these conditions. In epidemiologic analyses of co-prevalence, 5 of the 6 diseases strongly co-occurred with each other: AIH, PBC, SSc, SjD and SLE. Conclusions: AIH, PBC, SSc, SjD and SLE represent a distinct subset of autoimmune diseases that share genetic associations with the IL12 pathway, as well as profound co-prevalence, suggesting they may have a shared etiology and may respond to the same targeted therapeutic intervention(s).