Background & Aims: Autoimmune hepatitis (AIH) is an uncommon autoimmune liver disease of unknown etiology. We used a genome-wide approach to identify genetic variants that predispose individuals to AIH.
Methods: We performed a genome-wide association study of 649 adults in The Netherlands with AIH type 1 and 13,436 controls. Initial associations were further analyzed in an independent replication panel comprising 451 patients with AIH type 1 in Germany and 4103 controls. We also performed an association analysis in the discovery cohort using imputed genotypes of the major histocompatibility complex region.
Results: We associated AIH with a variant in the major histocompatibility complex region at rs2187668 (P = 1.5 × 10-78). Analysis of this variant in the discovery cohort identified HLA-DRB10301 (P = 5.3 × 10-49) as a primary susceptibility genotype and HLA-DRB10401 (P = 2.8 × 10-18) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P = 7.7 × 10-8) and CARD10 (rs6000782, 22q13.1; P = 3.0 × 10 -6). In addition, strong inflation of association signal was found with single-nucleotide polymorphisms associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with single-nucleotide polymorphisms associated with other genetic traits.
Conclusions: In a genome-wide association study, we associated AIH type 1 with variants in the major histocompatibility complex region, and identified variants of SH2B3and CARD10 as likely risk factors. These findings support a complex genetic basis for AIH pathogenesis and indicate that part of the genetic susceptibility overlaps with that for other immune-mediated liver diseases.

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Department of Gastroenterology & Hepatology

de Boer, Y.S, van Gerven, N.M.F, Zwiers, A, Verwer, B.J, van Hoek, B, van Erpecum, K.J, … Bouma, G. (2014). Genome-wide association study identifies variants associated with autoimmune hepatitis type 1. Gastroenterology, 147(2). doi:10.1053/j.gastro.2014.04.022