HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1

N.M. van Gerven, Y.S. de Boer, A. Zwiers, B.J. Verwer, J.P. Drenth, B. van Hoek, K.J. van Erpecum, U. Beuers, H.R. van Buuren, J. W. den Ouden, R. C. Verdonk, G.H. Koek, J. T. Brouwer, M. M. Guichelaar, J.M. Vrolijk, M. J. Coenraad, G. Kraal, C.J. Mulder, C. M. van Nieuwkerk, E. BloemenaH.W. Verspaget, V Kumar, A. Zhernakova, C. Wijmenga, L. Franke, G. Bouma

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P=0.2; HLA-DRB1*04:01; P=0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P=0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.Genes and Immunity advance online publication, 22 January 2015; doi:10.1038/gene.2014.82.
Original languageEnglish
Pages (from-to)247-252
Number of pages6
JournalGenes and Immunity
Volume16
Issue number4
DOIs
Publication statusPublished - Jun 2015

Keywords

  • LIVER-DISEASE
  • SUSCEPTIBILITY
  • HLA
  • ASSOCIATION
  • POLYMORPHISMS
  • HAPLOTYPES
  • ANTIBODIES
  • DIAGNOSIS

Cite this

van Gerven, N. M., de Boer, Y. S., Zwiers, A., Verwer, B. J., Drenth, J. P., van Hoek, B., van Erpecum, K. J., Beuers, U., van Buuren, H. R., den Ouden, J. W., Verdonk, R. C., Koek, G. H., Brouwer, J. T., Guichelaar, M. M., Vrolijk, J. M., Coenraad, M. J., Kraal, G., Mulder, C. J., van Nieuwkerk, C. M., ... Bouma, G. (2015). HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1. Genes and Immunity, 16(4), 247-252. https://doi.org/10.1038/gene.2014.82