Genome-wide association study identifies variants associated with autoimmune hepatitis type 1

doi:10.1053/j.gastro.2014.04.022

Multicenter Study

. 2014 Aug;147(2):443-52.e5.

doi: 10.1053/j.gastro.2014.04.022. Epub 2014 Apr 23.

Genome-wide association study identifies variants associated with autoimmune hepatitis type 1

Ynto S de Boer¹, Nicole M F van Gerven¹, Antonie Zwiers², Bart J Verwer¹, Bart van Hoek³, Karel J van Erpecum⁴, Ulrich Beuers⁵, Henk R van Buuren⁶, Joost P H Drenth⁷, Jannie W den Ouden⁸, Robert C Verdonk⁹, Ger H Koek¹⁰, Johannes T Brouwer¹¹, Maureen M J Guichelaar¹², Jan M Vrolijk¹³, Georg Kraal¹⁴, Chris J J Mulder¹, Carin M J van Nieuwkerk¹, Janett Fischer¹⁵, Thomas Berg¹⁵, Felix Stickel¹⁶, Christoph Sarrazin¹⁷, Christoph Schramm¹⁸, Ansgar W Lohse¹⁸, Christina Weiler-Normann¹⁸, Markus M Lerch¹⁹, Matthias Nauck²⁰, Henry Völzke²¹, Georg Homuth²², Elisabeth Bloemena²³, Hein W Verspaget³, Vinod Kumar²⁴, Alexandra Zhernakova²⁴, Cisca Wijmenga²⁴, Lude Franke²⁴, Gerd Bouma²⁵; Dutch Autoimmune Hepatitis Study Group; LifeLines Cohort Study; Study of Health in Pomerania

Collaborators, Affiliations

Collaborators

Affiliations

¹ Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
² 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.
³ Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
⁴ Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands.
⁵ Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
⁶ Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁷ Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
⁸ Department of Gastroenterology and Hepatology, Haga Hospital, The Hague, The Netherlands.
⁹ 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.
¹⁰ Department of Gastroenterology and Hepatology, University Medical Center Maastricht, Maastricht, The Netherlands.
¹¹ Department of Gastroenterology and Hepatology, Reinier de Graaf Hospital, Delft, The Netherlands.
¹² Department of Gastroenterology and Hepatology, Medisch Spectrum Twente, Enschede, The Netherlands.
¹³ Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, The Netherlands.
¹⁴ Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
¹⁵ Department of Internal Medicine, Neurology and Dermatology, Medical Clinic of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital Leipzig, Leipzig, Germany.
¹⁶ Department of Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland.
¹⁷ Department of Medicine I, University of Frankfurt/M, Frankfurt, Germany.
¹⁸ Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁹ Department of Internal Medicine A, University Medicine Greifswald, Greifswald, Germany.
²⁰ Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
²¹ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
²² Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
²³ Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
²⁴ University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
²⁵ 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.

PMID: 24768677
DOI: 10.1053/j.gastro.2014.04.022

Multicenter Study

Genome-wide association study identifies variants associated with autoimmune hepatitis type 1

Ynto S de Boer et al. Gastroenterology. 2014 Aug.

. 2014 Aug;147(2):443-52.e5.

doi: 10.1053/j.gastro.2014.04.022. Epub 2014 Apr 23.

Authors

Collaborators

Affiliations

¹ Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
² 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.
³ Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
⁴ Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands.
⁵ Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
⁶ Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁷ Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
⁸ Department of Gastroenterology and Hepatology, Haga Hospital, The Hague, The Netherlands.
⁹ 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.
¹⁰ Department of Gastroenterology and Hepatology, University Medical Center Maastricht, Maastricht, The Netherlands.
¹¹ Department of Gastroenterology and Hepatology, Reinier de Graaf Hospital, Delft, The Netherlands.
¹² Department of Gastroenterology and Hepatology, Medisch Spectrum Twente, Enschede, The Netherlands.
¹³ Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, The Netherlands.
¹⁴ Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
¹⁵ Department of Internal Medicine, Neurology and Dermatology, Medical Clinic of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital Leipzig, Leipzig, Germany.
¹⁶ Department of Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland.
¹⁷ Department of Medicine I, University of Frankfurt/M, Frankfurt, Germany.
¹⁸ Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁹ Department of Internal Medicine A, University Medicine Greifswald, Greifswald, Germany.
²⁰ Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
²¹ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
²² Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
²³ Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
²⁴ University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
²⁵ 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.

PMID: 24768677
DOI: 10.1053/j.gastro.2014.04.022

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 × 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.

Keywords: Autoimmunity; GWAS; Genetics; SH2B Adaptor Protein 3.

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Comment in

Genetic risks link autoimmune hepatitis to other autoimmune liver disease.
Hirschfield GM, Karlsen TH. Hirschfield GM, et al. Gastroenterology. 2014 Aug;147(2):270-3. doi: 10.1053/j.gastro.2014.06.020. Epub 2014 Jun 25. Gastroenterology. 2014. PMID: 24973678 No abstract available.

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Genome-wide association study identifies variants associated with autoimmune hepatitis type 1

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Genome-wide association study identifies variants associated with autoimmune hepatitis type 1

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