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

Ynto S de Boer; Nicole M F van Gerven; Antonie Zwiers; Bart J Verwer; Bart van Hoek; Karel J.  van Erpecum; Ulrich Beuers; Henk R van Buuren; Joost P H Drenth; Jannie W den Ouden; Robert C Verdonk; Ger H Koek; Johannes T Brouwer; Maureen M J Guichelaar; Jan M Vrolijk; Georg Kraal; Chris J J Mulder; Carin M J van Nieuwkerk; Janett Fischer; Thomas Berg; Felix Stickel; Christoph Sarrazin; Christoph Schramm; Ansgar W Lohse; Christina Weiler-Normann; Markus M Lerch; Matthias Nauck; Henry Völzke; Georg Homuth; Elisabeth Bloemena; Hein W Verspaget; Vinod Kumar; Alexandra Zhernakova; Cisca Wijmenga; Lude Franke; Gerd Bouma

doi:10.1053/j.gastro.2014.04.022

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

Ynto S de Boer
, Nicole M F van Gerven
, Antonie Zwiers
, Bart J Verwer
, Bart van Hoek
, Karel J. van Erpecum
, Ulrich Beuers
, Henk R van Buuren
, Joost P H Drenth
, Jannie W den Ouden
, Robert C Verdonk
, Ger H Koek
, Johannes T Brouwer
, Maureen M J Guichelaar
, Jan M Vrolijk
, Georg Kraal
, Chris J J Mulder
, Carin M J van Nieuwkerk
, Janett Fischer
, Thomas Berg

Felix Stickel, Christoph Sarrazin, Christoph Schramm, Ansgar W Lohse, Christina Weiler-Normann, Markus M Lerch, Matthias Nauck, Henry Völzke, Georg Homuth, Elisabeth Bloemena, Hein W Verspaget, Vinod Kumar, Alexandra Zhernakova, Cisca Wijmenga, Lude Franke, Gerd Bouma,

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	443-52.e5
Journal	Gastroenterology
Volume	147
Issue number	2
DOIs	https://doi.org/10.1053/j.gastro.2014.04.022
Publication status	Published - Aug 2014

Keywords

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
Major Histocompatibility Complex
Male
Middle Aged
Netherlands
Phenotype
Polymorphism, Single Nucleotide
Proteins
Risk Factors

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10.1053/j.gastro.2014.04.022

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de Boer, Y. S., van Gerven, N. M. F., Zwiers, A., Verwer, B. J., van Hoek, B., van Erpecum, K. J., Beuers, U., van Buuren, H. R., Drenth, J. P. H., den Ouden, J. W., Verdonk, R. C., Koek, G. H., Brouwer, J. T., Guichelaar, M. M. J., Vrolijk, J. M., Kraal, G., Mulder, C. J. J., van Nieuwkerk, C. M. J., Fischer, J. (2014). Genome-wide association study identifies variants associated with autoimmune hepatitis type 1. Gastroenterology, 147(2), 443-52.e5. https://doi.org/10.1053/j.gastro.2014.04.022

@article{3aa431ab5e794a0187c64a5a87ae0458,

title = "Genome-wide association study identifies variants associated with autoimmune hepatitis type 1",

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 = "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, Major Histocompatibility Complex, Male, Middle Aged, Netherlands, Phenotype, Polymorphism, Single Nucleotide, Proteins, Risk Factors",

author = "\{de Boer\}, \{Ynto S\} and \{van Gerven\}, \{Nicole M F\} and Antonie Zwiers and Verwer, \{Bart J\} and \{van Hoek\}, Bart and \{van Erpecum\}, \{Karel J.\} and Ulrich Beuers and \{van Buuren\}, \{Henk R\} and Drenth, \{Joost P H\} and \{den Ouden\}, \{Jannie W\} and Verdonk, \{Robert C\} and Koek, \{Ger H\} and Brouwer, \{Johannes T\} and Guichelaar, \{Maureen M J\} and Vrolijk, \{Jan M\} and Georg Kraal and Mulder, \{Chris J J\} and \{van Nieuwkerk\}, \{Carin M J\} and Janett Fischer and Thomas Berg and Felix Stickel and Christoph Sarrazin and Christoph Schramm and Lohse, \{Ansgar W\} and Christina Weiler-Normann and Lerch, \{Markus M\} and Matthias Nauck and Henry V{\"o}lzke and Georg Homuth and Elisabeth Bloemena and Verspaget, \{Hein W\} and Vinod Kumar and Alexandra Zhernakova and Cisca Wijmenga and Lude Franke and Gerd Bouma",

year = "2014",

month = aug,

doi = "10.1053/j.gastro.2014.04.022",

language = "English",

volume = "147",

pages = "443--52.e5",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders",

number = "2",

}

de Boer, YS, van Gerven, NMF, Zwiers, A, Verwer, BJ, van Hoek, B, van Erpecum, KJ, Beuers, U, van Buuren, HR, Drenth, JPH, den Ouden, JW, Verdonk, RC, Koek, GH, Brouwer, JT, Guichelaar, MMJ, Vrolijk, JM, Kraal, G, Mulder, CJJ, van Nieuwkerk, CMJ, Fischer, J, Berg, T, Stickel, F, Sarrazin, C, Schramm, C, Lohse, AW, Weiler-Normann, C, Lerch, MM, Nauck, M, Völzke, H, Homuth, G, Bloemena, E, Verspaget, HW, Kumar, V, Zhernakova, A, Wijmenga, C, Franke, L, Bouma, G 2014, 'Genome-wide association study identifies variants associated with autoimmune hepatitis type 1', Gastroenterology, vol. 147, no. 2, pp. 443-52.e5. https://doi.org/10.1053/j.gastro.2014.04.022

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

PY - 2014/8

Y1 - 2014/8

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 - Article

C2 - 24768677

SN - 0016-5085

VL - 147

SP - 443-52.e5

JO - Gastroenterology

JF - Gastroenterology

IS - 2

ER -

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

Abstract

Keywords

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