Genome-wide association study identifies variants associated with autoimmune hepatitis type 1.
- de Boer YS Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
- van Gerven NM Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
- 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.
- Verwer BJ Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
- van Hoek B Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
- van Erpecum KJ Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands.
- Beuers U Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
- van Buuren HR Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
- Drenth JP Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
- den Ouden JW Department of Gastroenterology and Hepatology, Haga Hospital, The Hague, The Netherlands.
- 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.
- Koek GH Department of Gastroenterology and Hepatology, University Medical Center Maastricht, Maastricht, The Netherlands.
- Brouwer JT Department of Gastroenterology and Hepatology, Reinier de Graaf Hospital, Delft, The Netherlands.
- Guichelaar MM Department of Gastroenterology and Hepatology, Medisch Spectrum Twente, Enschede, The Netherlands.
- Vrolijk JM Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, The Netherlands.
- Kraal G Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
- Mulder CJ Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
- van Nieuwkerk CM Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
- Fischer J Department of Internal Medicine, Neurology and Dermatology, Medical Clinic of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital Leipzig, Leipzig, Germany.
- Berg T Department of Internal Medicine, Neurology and Dermatology, Medical Clinic of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital Leipzig, Leipzig, Germany.
- Stickel F Department of Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland.
- Sarrazin C Department of Medicine I, University of Frankfurt/M, Frankfurt, Germany.
- Schramm C Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Lohse AW Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Weiler-Normann C Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Lerch MM Department of Internal Medicine A, University Medicine Greifswald, Greifswald, Germany.
- Nauck M Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
- Völzke H Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
- Homuth G Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
- Bloemena E Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
- Verspaget HW Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
- Kumar V University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
- Zhernakova A University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
- Wijmenga C University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
- Franke L University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
- 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.
- 2014-04-29
Published in:
- Gastroenterology. - 2014
Autoimmunity
GWAS
Genetics
SH2B Adaptor Protein 3
Adult
Autoimmunity
CARD Signaling Adaptor Proteins
Case-Control Studies
Female
Gene Frequency
Genetic Predisposition to Disease
Genome-Wide Association Study
Germany
HLA-DRB1 Chains
Hepatitis, Autoimmune
Humans
Intracellular Signaling Peptides and Proteins
Major Histocompatibility Complex
Male
Middle Aged
Netherlands
Phenotype
Polymorphism, Single Nucleotide
Proteins
Risk Factors
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.
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.
- Language
-
- English
- Open access status
- green
- Identifiers
-
- DOI 10.1053/j.gastro.2014.04.022
- PMID 24768677
- Persistent URL
- https://sonar.ch/global/documents/172815
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