Genome-wide association study identifies variants associated with autoimmune hepatitis type 1.
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de Boer YS
Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
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van Gerven NM
Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
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Zwiers A
Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands; Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
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Verwer BJ
Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
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van Hoek B
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
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van Erpecum KJ
Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands.
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Beuers U
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
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van Buuren HR
Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
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Drenth JP
Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
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den Ouden JW
Department of Gastroenterology and Hepatology, Haga Hospital, The Hague, The Netherlands.
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Verdonk RC
University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands; Department of Gastroenterology and Hepatology, St Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands.
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Koek GH
Department of Gastroenterology and Hepatology, University Medical Center Maastricht, Maastricht, The Netherlands.
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Brouwer JT
Department of Gastroenterology and Hepatology, Reinier de Graaf Hospital, Delft, The Netherlands.
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Guichelaar MM
Department of Gastroenterology and Hepatology, Medisch Spectrum Twente, Enschede, The Netherlands.
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Vrolijk JM
Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, The Netherlands.
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Kraal G
Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
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Mulder CJ
Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
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van Nieuwkerk CM
Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
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Fischer J
Department of Internal Medicine, Neurology and Dermatology, Medical Clinic of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital Leipzig, Leipzig, Germany.
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Berg T
Department of Internal Medicine, Neurology and Dermatology, Medical Clinic of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital Leipzig, Leipzig, Germany.
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Stickel F
Department of Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland.
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Sarrazin C
Department of Medicine I, University of Frankfurt/M, Frankfurt, Germany.
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Schramm C
Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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Lohse AW
Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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Weiler-Normann C
Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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Lerch MM
Department of Internal Medicine A, University Medicine Greifswald, Greifswald, Germany.
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Nauck M
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
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Völzke H
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
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Homuth G
Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
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Bloemena E
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
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Verspaget HW
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
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Kumar V
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
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Zhernakova A
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
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Wijmenga C
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
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Franke L
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
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Bouma G
Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands; Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: g.bouma@vumc.nl.
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English
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-DRB1*0301 (P = 5.3 × 10(-49)) as a primary susceptibility genotype and HLA-DRB1*0401 (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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Open access status
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green
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Persistent URL
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https://folia.unifr.ch/global/documents/172815
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