Genome-Wide Association Study Identifies Variants Associated With Autoimmune Hepatitis Type 1

YS de Boer, NMF van Gerven, A Zwiers, BJ Verwer, B van Hoek, KJ van Erpecum, U Beuers, Henk Buuren, JPH Drenth, JW den Ouden, RC Verdonk, GH Koek, JT Brouwer, MMJ Guichelaar, JM (Jan) Vrolijk, G Kraal, CJJ Mulder, CMJ van Nieuwkerk, J Fischer, Tilja BergF Stickel, C Sarrazin, C Schramm, AW Lohse, C Weiler-Normann, MM Lerch, M Nauck, H Volzke, G Homuth, E Bloemena, HW Verspaget, V Kumar, A Zhernakova, C Wijmenga, L Franke, G Bouma

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Abstract

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 x 10(-78)). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3 x 10(-49)) as a primary susceptibility genotype and HLA-DRB1*0401 (P = 2.8 x 10(-18)) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P = 7.7 x 10(-8)) and CARD10 (rs6000782, 22q13.1; P = 3.0 x 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.
Original languageUndefined/Unknown
Pages (from-to)443-452
Number of pages10
JournalGastroenterology
Volume147
Issue number2
DOIs
Publication statusPublished - 2014

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