Genome-wide association study identifies variants associated with autoimmune hepatitis type 1.
OBJECTIVE
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.
Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
Ynto S
YS
de Boer
Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
Nicole M F
NM
van Gerven
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.
Antonie
A
Zwiers
Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
Bart J
BJ
Verwer
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
Bart
B
van Hoek
Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands.
Karel J
KJ
van Erpecum
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
Ulrich
U
Beuers
Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Henk R
HR
van Buuren
Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Joost P H
JP
Drenth
Department of Gastroenterology and Hepatology, Haga Hospital, The Hague, The Netherlands.
Jannie W
JW
den Ouden
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.
Robert C
RC
Verdonk
Department of Gastroenterology and Hepatology, University Medical Center Maastricht, Maastricht, The Netherlands.
Ger H
GH
Koek
Department of Gastroenterology and Hepatology, Reinier de Graaf Hospital, Delft, The Netherlands.
Johannes T
JT
Brouwer
Department of Gastroenterology and Hepatology, Medisch Spectrum Twente, Enschede, The Netherlands.
Maureen M J
MM
Guichelaar
Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, The Netherlands.
Jan M
JM
Vrolijk
Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
Georg
G
Kraal
Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
Chris J J
CJ
Mulder
Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
Carin M J
CM
van Nieuwkerk
Department of Internal Medicine, Neurology and Dermatology, Medical Clinic of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital Leipzig, Leipzig, Germany.
Janett
J
Fischer
Department of Internal Medicine, Neurology and Dermatology, Medical Clinic of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital Leipzig, Leipzig, Germany.
Thomas
T
Berg
Department of Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland.
Felix
F
Stickel
Department of Medicine I, University of Frankfurt/M, Frankfurt, Germany.
Christoph
C
Sarrazin
Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Christoph
C
Schramm
Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Ansgar W
AW
Lohse
Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Christina
C
Weiler-Normann
Department of Internal Medicine A, University Medicine Greifswald, Greifswald, Germany.
Markus M
MM
Lerch
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
Matthias
M
Nauck
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
Henry
H
Völzke
Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
Georg
G
Homuth
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
Elisabeth
E
Bloemena
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
Hein W
HW
Verspaget
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
Vinod
V
Kumar
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
Alexandra
A
Zhernakova
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
Cisca
C
Wijmenga
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
Lude
L
Franke
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.
Gerd
G
Bouma
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D015551:Autoimmunity / Q000235:genetics*; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005858:Germany; D059811:HLA-DRB1 Chains / Q000235:genetics; D019693:Hepatitis, Autoimmune / Q000235:genetics* / Q000276:immunology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D012307:Risk Factors
D048868:Adaptor Proteins, Signal Transducing; D053468:CARD Signaling Adaptor Proteins; C430880:CARD10 protein, human; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; C553505:HLA-DRB1*04:01 antigen; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C490778:SH2B3 protein, human
Autoimmunity; GWAS; Genetics; SH2B Adaptor Protein 3