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).

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Journal
Hepatology
Published
2026-10-13
DOI
https://doi.org/10.1097/hep.0000000000001819
Primary Topic
Liver Diseases and Immunity
Type
article
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article

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

Friederike Held, William J. Salerno, Alan R. Shuldiner, Brian D. Hobbs et al.
Hepatology
Liver Diseases and Immunity
article

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

Friederike Held, William J. Salerno, Alan R. Shuldiner, Brian D. Hobbs, Jamie Marie Orengo, Kyoko Watanabe, Carlo Sidore, Liron Ganel, Anthony Marcketta, Michael D. Kessler, Arielle Glatman Zaretsky, Jeffrey G. Reid, Suganthi Balasubramanian, Gregory P. Geba, Sheila M. Gaynor, Zongqi Xia, Manuel A. R. Ferreira, Wenzhen Ge, Christiane Gasperi, Gonçalo R. Abecasis, Jack A. Kosmicki, Keran Moll, William Hunt Palmer, Priyanka Nakka, George D. Yancopoulos, Christopher E. Gillies, Jing Tang, Katherine Siminovitch, Wen Zhu, Sean Yu, Rita Guerreiro, Malmö Diet and Cancer Study, Aris Baras, Amit Joshi, Naga Chalasani, Kathie Sun, Mount Sinai Million Health Discoveries Program, Jonathan Marchini, Tyler Joseph, Olle Melander, Houston Scleroderma Family Registry and DNA Repository, John D. Overton, Indiana Biobank, Lili Zhang, Paula Uibel, Bernhard Hemmer, Joelle Mbatchou, Dana Murdock, Xiaodong Bai, Penn Medicine Biobank, Luca A. Lotta, Maya Ghoussani, Accelerated Cure Project Repository, Aurora Healthcare System, Discover Me South Africa Study, Adrian I. Campos, Lauren Gurski, Veronica Mas Casullo, Stephen DiMartino, Antoine Baldassari, Consejo Superior de Investigaciones Científicas Study, Northwestern Scleroderma Patient Registry, Marcus Jones, Oxford Million Women Study
article en

Abstract

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).

Hepatology
University of Pittsburgh (US), Regeneron (United States) (US), Lund University (SE), TUM Klinikum (DE), Munich Cluster for Systems Neurology (DE), Skåne University Hospital (SE), Indiana University School of Medicine
Openalex Percentile: Top 15%
Liver Diseases and Immunity
DOIOpen Access PDFOpenAlex
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