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.
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Nakka Priyanka, Hobbs Brian D, Sidore Carlo, Palmer William H, Murdock Dana, Gurski Lauren, Glatman Zaretsky Arielle, Moll Keran, Campos Adrian I, Joshi Amit, Gaynor Sheila M, Guerreiro Rita, Kosmicki Jack A, Tang Jing, Marcketta Anthony, Baldassari Antoine, Joseph Tyler, Watanabe Kyoko, Yu Sean, Bai Xiaodong, Gillies Christopher E, Mbatchou Joelle, Sun Kathie, Ganel Liron, Casullo Veronica Mas, DiMartino Stephen, Geba Gregory P, Zhang Lili, Zhu Wen, Xia Zongqi, Melander Olle, Chalasani Naga, Hemmer Bernhard, Gasperi Christiane, Held Friederike, Uibel Paula, Jones Marcus, Shuldiner Alan R, Balasubramanian Suganthi, Ghoussani Maya, Ge Wenzhen, Reid Jeffrey G, Overton John D, Salerno William J, Marchini Jonathan, Kessler Michael D, Yancopoulos George D, Orengo Jamie M, Baras Aris, Lotta Luca A, Abecasis Gonçalo R, Siminovitch Katherine, Ferreira Manuel A R, Regeneron Genetics Center, Houston Scleroderma Family Registry and DNA Repository, Consejo Superior de Investigaciones Científicas Study, University of California Los Angeles ATLAS Collaboration, Mayo Clinic Project Generation, GHS-RGC DiscovEHR Collaboration, Colorado Center for Personalized Medicine, Penn Medicine Biobank, Aurora Healthcare System, Mount Sinai Million Health Discoveries Program, Indiana Biobank, Malmö Diet and Cancer Study, University of Tennessee Health Science Center BIG Initiative, Mayo Clinic PBC Cohort, Australia and New Zealand MS Genetics Consortium, Northwestern Scleroderma Patient Registry, Accelerated Cure Project Repository, Technical University of Munich MS Study, University of Pittsburgh PROMOTE Cohort, Oxford Million Women Study, University of Alabama at Birmingham Autoimmune Disease Biorepository, Discover Me South Africa Study
Аннотация
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).