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. / de Boer, Ynto S; van Gerven, Nicole M F; Zwiers, Antonie; Verwer, Bart J; van Hoek, Bart; van Erpecum, Karel J; Beuers, Ulrich; van Buuren, Henk R; Drenth, Joost P H; den Ouden, Jannie W; Verdonk, Robert C; Koek, Ger H; Brouwer, Johannes T; Guichelaar, Maureen M J; Vrolijk, Jan M; Kraal, Georg; Mulder, Chris J J; van Nieuwkerk, Carin M J; Fischer, Janett; Berg, Thomas; Stickel, Felix; Sarrazin, Christoph; Schramm, Christoph; Lohse, Ansgar W; Weiler-Normann, Christina; Lerch, Markus M; Nauck, Matthias; Völzke, Henry; Homuth, Georg; Bloemena, Elisabeth; Verspaget, Hein W; Kumar, Vinod; Zhernakova, Alexandra; Wijmenga, Cisca; Franke, Lude; Bouma, Gerd; Dutch Autoimmune Hepatitis Study Group.
in: GASTROENTEROLOGY, Jahrgang 147, Nr. 2, 01.08.2014, S. 443-452.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Genome-wide association study identifies variants associated with autoimmune hepatitis type 1
AU - de Boer, Ynto S
AU - van Gerven, Nicole M F
AU - Zwiers, Antonie
AU - Verwer, Bart J
AU - van Hoek, Bart
AU - van Erpecum, Karel J
AU - Beuers, Ulrich
AU - van Buuren, Henk R
AU - Drenth, Joost P H
AU - den Ouden, Jannie W
AU - Verdonk, Robert C
AU - Koek, Ger H
AU - Brouwer, Johannes T
AU - Guichelaar, Maureen M J
AU - Vrolijk, Jan M
AU - Kraal, Georg
AU - Mulder, Chris J J
AU - van Nieuwkerk, Carin M J
AU - Fischer, Janett
AU - Berg, Thomas
AU - Stickel, Felix
AU - Sarrazin, Christoph
AU - Schramm, Christoph
AU - Lohse, Ansgar W
AU - Weiler-Normann, Christina
AU - Lerch, Markus M
AU - Nauck, Matthias
AU - Völzke, Henry
AU - Homuth, Georg
AU - Bloemena, Elisabeth
AU - Verspaget, Hein W
AU - Kumar, Vinod
AU - Zhernakova, Alexandra
AU - Wijmenga, Cisca
AU - Franke, Lude
AU - Bouma, Gerd
AU - Dutch Autoimmune Hepatitis Study Group
N1 - Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.
PY - 2014/8/1
Y1 - 2014/8/1
N2 - 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.
AB - 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.
KW - Adult
KW - Autoimmunity
KW - CARD Signaling Adaptor Proteins
KW - Case-Control Studies
KW - Female
KW - Gene Frequency
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Germany
KW - HLA-DRB1 Chains
KW - Hepatitis, Autoimmune
KW - Humans
KW - Major Histocompatibility Complex
KW - Male
KW - Middle Aged
KW - Netherlands
KW - Phenotype
KW - Polymorphism, Single Nucleotide
KW - Proteins
KW - Risk Factors
U2 - 10.1053/j.gastro.2014.04.022
DO - 10.1053/j.gastro.2014.04.022
M3 - SCORING: Journal article
C2 - 24768677
VL - 147
SP - 443
EP - 452
JO - GASTROENTEROLOGY
JF - GASTROENTEROLOGY
SN - 0016-5085
IS - 2
ER -