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

Research output: Contribution to journalArticleAcademicpeer-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 languageEnglish
Pages (from-to)443-452-e5
Number of pages15
JournalGastroenterology
Volume147
Issue number2
DOIs
Publication statusPublished - 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

Cite this

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