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. 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.
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.
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.
Authors: Robert John Fontana; Elizabeth Theresa Cirulli; Jiezhun Gu; David Kleiner; David Ostrov; Elizabeth Phillips; Ryan Schutte; Huiman Barnhart; Naga Chalasani; Paul Brent Watkins; Jay H Hoofnagle Journal: J Hepatol Date: 2018-08-21 Impact factor: 25.083
Authors: David N Assis; Hiroki Takahashi; Lin Leng; Mikio Zeniya; James L Boyer; Richard Bucala Journal: Dig Dis Sci Date: 2016-10-01 Impact factor: 3.199