Genome-Wide Association Study Identifies Variants Associated With Autoimmune Hepatitis Type 1

Y.S. de Boer; N.M. van Gerven; A. Zwiers; B.J. Verwer; B. van Hoek; K.J. van Erpecum; U. Beuers; H.R. van Buuren; J.P. Drenth; J. W. den Ouden; R. C. Verdonk; G.H. Koek; J. T. Brouwer; M. M. Guichelaar; J.M. Vrolijk; G. Kraal; C.J. Mulder; C. M. van Nieuwkerk; J. Fischer; T. Berg; F. Stickel; C. Sarrazin; C. Schramm; A.W. Lohse; C. Weiler-Normann; M.M. Lerch; M. Nauck; H. Volzke; G. Homuth; E. Bloemena; H.W. Verspaget; V Kumar; A. Zhernakova; C. Wijmenga; L. Franke; G. Bouma

doi:10.1053/j.gastro.2014.04.022

Genome-Wide Association Study Identifies Variants Associated With Autoimmune Hepatitis Type 1

Y.S. de Boer, N.M. van Gerven, A. Zwiers, B.J. Verwer, B. van Hoek, K.J. van Erpecum, U. Beuers, H.R. van Buuren, J.P. Drenth, J. W. den Ouden, R. C. Verdonk, G.H. Koek, J. T. Brouwer, M. M. Guichelaar, J.M. Vrolijk, G. Kraal, C.J. Mulder, C. M. van Nieuwkerk, J. Fischer, T. BergF. Stickel, C. Sarrazin, C. Schramm, A.W. Lohse, C. Weiler-Normann, M.M. Lerch, M. Nauck, H. Volzke, G. Homuth, E. Bloemena, H.W. Verspaget, V Kumar, A. Zhernakova, C. Wijmenga, L. Franke, G. Bouma^*

^*Corresponding author for this work

Interne Geneeskunde

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 MHC region. RESULTS: We associated AIH with a variant in the MHC region, at rs2187668 (P=1.5x10-78). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3x10-49) as a primary susceptibility genotype and HLA-DRB1*0401 (P=2.8x10-18) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P=7.7x10-8) and CARD10 (rs6000782, 22q13.1; P=3.0x10-6). Furthermore, strong inflation of association signal was found with single-nucleotide polymorphisms (SNPs) associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with SNPs associated with other genetic traits. CONCLUSIONS: In a genome-wide association study, we associated AIH type-1with variants in the MHC 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)	443-452-e5
Number of pages	15
Journal	Gastroenterology
Volume	147
Issue number	2
DOIs	https://doi.org/10.1053/j.gastro.2014.04.022
Publication status	Published - Aug 2014

Keywords

Autoimmunity
Genetics
GWAS
SH2B Adaptor Protein 3
PRIMARY BILIARY-CIRRHOSIS
NF-KAPPA-B
PRIMARY SCLEROSING CHOLANGITIS
ANTIGEN-4 GENE POLYMORPHISMS
SUSCEPTIBILITY LOCI
RISK LOCI
CONFER SUSCEPTIBILITY
JAPANESE PATIENTS
ADAPTER PROTEIN
DISEASE

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10.1053/j.gastro.2014.04.022

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de Boer, Y. S., van Gerven, N. M., Zwiers, A., Verwer, B. J., van Hoek, B., van Erpecum, K. J., Beuers, U., van Buuren, H. R., Drenth, J. P., den Ouden, J. W., Verdonk, R. C., Koek, G. H., Brouwer, J. T., Guichelaar, M. M., Vrolijk, J. M., Kraal, G., Mulder, C. J., van Nieuwkerk, C. M., Fischer, J., ... Bouma, G. (2014). Genome-Wide Association Study Identifies Variants Associated With Autoimmune Hepatitis Type 1. Gastroenterology, 147(2), 443-452-e5. https://doi.org/10.1053/j.gastro.2014.04.022

@article{f235c3f626e2466aa6d1e84be212de45,

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 MHC region. RESULTS: We associated AIH with a variant in the MHC region, at rs2187668 (P=1.5x10-78). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3x10-49) as a primary susceptibility genotype and HLA-DRB1*0401 (P=2.8x10-18) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P=7.7x10-8) and CARD10 (rs6000782, 22q13.1; P=3.0x10-6). Furthermore, strong inflation of association signal was found with single-nucleotide polymorphisms (SNPs) associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with SNPs associated with other genetic traits. CONCLUSIONS: In a genome-wide association study, we associated AIH type-1with variants in the MHC 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 = "Autoimmunity, Genetics, GWAS, SH2B Adaptor Protein 3, PRIMARY BILIARY-CIRRHOSIS, NF-KAPPA-B, PRIMARY SCLEROSING CHOLANGITIS, ANTIGEN-4 GENE POLYMORPHISMS, SUSCEPTIBILITY LOCI, RISK LOCI, CONFER SUSCEPTIBILITY, JAPANESE PATIENTS, ADAPTER PROTEIN, DISEASE",

author = "{de Boer}, Y.S. and {van Gerven}, N.M. and A. Zwiers and B.J. Verwer and {van Hoek}, B. and {van Erpecum}, K.J. and U. Beuers and {van Buuren}, H.R. and J.P. Drenth and {den Ouden}, {J. W.} and Verdonk, {R. C.} and G.H. Koek and Brouwer, {J. T.} and Guichelaar, {M. M.} and J.M. Vrolijk and G. Kraal and C.J. Mulder and {van Nieuwkerk}, {C. M.} and J. Fischer and T. Berg and F. Stickel and C. Sarrazin and C. Schramm and A.W. Lohse and C. Weiler-Normann and M.M. Lerch and M. Nauck and H. Volzke and G. Homuth and E. Bloemena and H.W. Verspaget and V Kumar and A. Zhernakova and C. Wijmenga and L. Franke and G. Bouma",

year = "2014",

month = aug,

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

language = "English",

volume = "147",

pages = "443--452--e5",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "Elsevier Saunders",

number = "2",

}

de Boer, YS, van Gerven, NM, Zwiers, A, Verwer, BJ, van Hoek, B, van Erpecum, KJ, Beuers, U, van Buuren, HR, Drenth, JP, den Ouden, JW, Verdonk, RC, Koek, GH, Brouwer, JT, Guichelaar, MM, Vrolijk, JM, Kraal, G, Mulder, CJ, van Nieuwkerk, CM, Fischer, J, Berg, T, Stickel, F, Sarrazin, C, Schramm, C, Lohse, AW, Weiler-Normann, C, Lerch, MM, Nauck, M, Volzke, 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. 443-452-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, Y.S.

AU - van Gerven, N.M.

AU - Zwiers, A.

AU - Verwer, B.J.

AU - van Hoek, B.

AU - van Erpecum, K.J.

AU - Beuers, U.

AU - van Buuren, H.R.

AU - Drenth, J.P.

AU - den Ouden, J. W.

AU - Verdonk, R. C.

AU - Koek, G.H.

AU - Brouwer, J. T.

AU - Guichelaar, M. M.

AU - Vrolijk, J.M.

AU - Kraal, G.

AU - Mulder, C.J.

AU - van Nieuwkerk, C. M.

AU - Fischer, J.

AU - Berg, T.

AU - Stickel, F.

AU - Sarrazin, C.

AU - Schramm, C.

AU - Lohse, A.W.

AU - Weiler-Normann, C.

AU - Lerch, M.M.

AU - Nauck, M.

AU - Volzke, H.

AU - Homuth, G.

AU - Bloemena, E.

AU - Verspaget, H.W.

AU - Kumar, V

AU - Zhernakova, A.

AU - Wijmenga, C.

AU - Franke, L.

AU - Bouma, G.

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 MHC region. RESULTS: We associated AIH with a variant in the MHC region, at rs2187668 (P=1.5x10-78). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3x10-49) as a primary susceptibility genotype and HLA-DRB1*0401 (P=2.8x10-18) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P=7.7x10-8) and CARD10 (rs6000782, 22q13.1; P=3.0x10-6). Furthermore, strong inflation of association signal was found with single-nucleotide polymorphisms (SNPs) associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with SNPs associated with other genetic traits. CONCLUSIONS: In a genome-wide association study, we associated AIH type-1with variants in the MHC 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 MHC region. RESULTS: We associated AIH with a variant in the MHC region, at rs2187668 (P=1.5x10-78). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3x10-49) as a primary susceptibility genotype and HLA-DRB1*0401 (P=2.8x10-18) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P=7.7x10-8) and CARD10 (rs6000782, 22q13.1; P=3.0x10-6). Furthermore, strong inflation of association signal was found with single-nucleotide polymorphisms (SNPs) associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with SNPs associated with other genetic traits. CONCLUSIONS: In a genome-wide association study, we associated AIH type-1with variants in the MHC 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 - Autoimmunity

KW - Genetics

KW - GWAS

KW - SH2B Adaptor Protein 3

KW - PRIMARY BILIARY-CIRRHOSIS

KW - NF-KAPPA-B

KW - PRIMARY SCLEROSING CHOLANGITIS

KW - ANTIGEN-4 GENE POLYMORPHISMS

KW - SUSCEPTIBILITY LOCI

KW - RISK LOCI

KW - CONFER SUSCEPTIBILITY

KW - JAPANESE PATIENTS

KW - ADAPTER PROTEIN

KW - DISEASE

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 - 443-452-e5

JO - Gastroenterology

JF - Gastroenterology

IS - 2

ER -