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

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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.

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Acknowledgements

We would like to thank all the patients in the Dutch AIH Study for their participation in this project. The Dutch AIH Study Group is supported by the Netherlands Association for the Study of the Liver (NASL/NVH). YdB is supported by a grant of Dutch Digestive Diseases Foundation (MLDS WO11–58 to GB). AZ is supported by a grant from the Dutch Reumafonds (11–1–101) and from Rosalind Franklin Fellowship, University of Groningen, The Netherlands. Research in the Wijmenga group is supported by research grants from the Netherlands Organization for Scientific Research (NWO-VENI grant 916.10.135 to LF), the European Research Council Advanced Grant (ERC-322698 to CW) and the Dutch Digestive Diseases Foundation (MLDS WO11–30 to CW). This study was supported by unrestricted grants of Bayer BV, Mijdrecht, the Netherlands, Dr Falk Pharma Benelux BV, Breda, the Netherlands, Ferring Pharmaceuticals BV, Hoofddorp, the Netherlands, Gilead Sciences Netherlands BV, Amsterdam, the Netherlands, Janssen-Cilag BV, Tilburg, the Netherlands, MSD BV, Haarlem, the Netherlands, Roche Nederland BV, Woerden, The Netherlands, Tramedico BV, Weesp, the Netherlands and Zambon Nederland BV, Amersfoort, the Netherlands.

Author Contributions

CM and GB had the original idea. YdB performed analysis and wrote the manuscript. NvG coordinated and contributed to the characterization of individuals and collection of clinical data and samples. VK and LF performed the analysis. AZh performed the imputation and analysis of the MHC region. BV, BvH, KvE, UB, HvB, MC, JD, JdO, RV, GK, JB, MG, JV, CvN, WN, EB and HV characterized individuals and collected clinical data and samples. YdB, BV, AnZ and GK contributed to the design of the study. CW, LF and GB designed the study. YdB, NvG and GB wrote the manuscript. All authors reviewed and approved the final version of the manuscript.

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Correspondence to Y S de Boer or G Bouma.

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Appendix

Appendix

Appendix Contributors to the Dutch Autoimmune Hepatitis Study Group

LC Baak (Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands), AM Baven-Pronk (Leiden University Medical Center, Leiden, The Netherlands), M Klempt-Kropp (Medisch Centrum Alkmaar, Alkmaar, The Netherlands), JJM van Meyel (Sint Lucas Andreas Ziekenhuis, Amsterdam, The Netherlands), RK Linskens (St Anna ziekenhuis, Geldrop, The Netherlands), BW Spanier (Rijnstate Ziekenhuis, Arnhem, The Netherlands), JC Kneppelhout (St Anna ziekenhuis, Geldrop, The Netherlands), JPh Kuyvenhoven (Kennemer Gasthuis, Haarlem, The Netherlands), EJM van Geenen (Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands), MJ Wagtmans (Rode Kruis ziekenhuis, Beverwijk, The Netherlands), DL Cahen (ziekenhuis Amstelland, Amstelveen, The Netherlands), FHJ Wolfhagen (Tweesteden ziekenhuis, Tilburg, The Netherlands), PJ Kingma (Tergooiziekenhuizen, Hilversum, The Netherlands), JML de Vree (University of Groningen, University Medical Center Groningen, Groningen, The Netherlands), RJLF Loffeld (Zaans Medisch Centrum, Zaandam, The Netherlands), Rob A de Man (Erasmus University Medical Center, Rotterdam, The Netherlands), PW Friederich (Meander Medisch Centrum, Amersfoort, The Netherlands), TCMA Schreuder (Slingeland ziekenhuis, Doetichem, The Netherlands), AWM van Milligen de Wit (Amphia ziekenhuis, Breda, the Netherlands), MA Alleman (Isala, Zwolle, The Netherlands), A Bhalla (Hagaziekenhuis, Den Haag, The Netherlands), PHGM Stadhouders (St Antonius Hospital, Nieuwegein, The Netherlands), MAMT Verhagen (Diakonessenhuis, Utrecht, The Netherlands).

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van Gerven, N., de Boer, Y., Zwiers, A. et al. HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1. Genes Immun 16, 247–252 (2015). https://doi.org/10.1038/gene.2014.82

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