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



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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  1. Boberg KM . Prevalence and epidemiology of autoimmune hepatitis. Clin Liver Dis 2002; 6: 635–647.

    Article  Google Scholar 

  2. Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D et al. Diagnosis and management of autoimmune hepatitis. Hepatology 2010; 51: 2193–2213.

    Article  CAS  Google Scholar 

  3. Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999; 31: 929–938.

    Article  CAS  Google Scholar 

  4. Van Gerven NM, Verwer BJ, Witte BI, van Erpecum KJ, van Buuren HR, Maijers I et al. Epidemiology and clinical characteristics of autoimmune hepatitis in the Netherlands. Scand J Gastroenterol 2014; 49: 1245–1254.

    Article  CAS  Google Scholar 

  5. Boberg KM, Chapman RW, Hirschfield GM, Lohse AW, Manns MP, Schrumpf E . Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol 2011; 54: 374–385.

    Article  Google Scholar 

  6. Woodward J, Neuberger J . Autoimmune overlap syndromes. Hepatology 2001; 33: 994–1002.

    Article  CAS  Google Scholar 

  7. Hennes EM, Zeniya M, Czaja AJ, Pares A, Dalekos GN, Krawitt EL et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008; 48: 169–176.

    Article  Google Scholar 

  8. Czaja AJ, Strettell MD, Thomson LJ, Santrach PJ, Moore SB, Donaldson PT et al. Associations between alleles of the major histocompatibility complex and type 1 autoimmune hepatitis. Hepatology 1997; 25: 317–323.

    Article  CAS  Google Scholar 

  9. Doherty DG, Donaldson PT, Underhill JA, Farrant JM, Duthie A, Mieli-Vergani G et al. Allelic sequence variation in the HLA class II genes and proteins in patients with autoimmune hepatitis. Hepatology 1994; 19: 609–615.

    Article  CAS  Google Scholar 

  10. Donaldson PT, Doherty DG, Hayllar KM, McFarlane IG, Johnson PJ, Williams R . Susceptibility to autoimmune chronic active hepatitis: human leukocyte antigens DR4 and A1-B8-DR3 are independent risk factors. Hepatology 1991; 13: 701–706.

    Article  CAS  Google Scholar 

  11. Oliveira LC, Porta G, Marin ML, Bittencourt PL, Kalil J, Goldberg AC . Autoimmune hepatitis, HLA and extended haplotypes. Autoimmun Rev 2011; 10: 189–193.

    Article  CAS  Google Scholar 

  12. Seki T, Ota M, Furuta S, Fukushima H, Kondo T, Hino K et al. HLA class II molecules and autoimmune hepatitis susceptibility in Japanese patients. Gastroenterology 1992; 103: 1041–1047.

    Article  CAS  Google Scholar 

  13. van Gerven NM, de Boer YS, Zwiers A, van Hoek B, van Erpecum KJ, Beuers U et al. Cytotoxic T lymphocyte antigen-4 +49A/G polymorphism does not affect susceptibility to autoimmune hepatitis. Liver Int 2013; 33: 1039–1043.

    Article  CAS  Google Scholar 

  14. Schott E, Witt H, Pascu M, van Boemmel F, Weich V, Bergk A et al. Association of CTLA4 single nucleotide polymorphisms with viral but not autoimmune liver disease. Eur J Gastroenterol Hepatol 2007; 19: 947–951.

    Article  CAS  Google Scholar 

  15. Bittencourt PL, Palacios SA, Cancado EL, Porta G, Carrilho FJ, Laudanna AA et al. Cytotoxic T lymphocyte antigen-4 gene polymorphisms do not confer susceptibility to autoimmune hepatitis types 1 and 2 in Brazil. Am J Gastroenterol 2003; 98: 1616–1620.

    CAS  PubMed  Google Scholar 

  16. Czaja AJ . Genetic factors affecting the occurrence, clinical phenotype, and outcome of autoimmune hepatitis. Clin Gastroenterol Hepatol 2008; 6: 379–388.

    Article  CAS  Google Scholar 

  17. de Boer YS, van Gerven NM, Zwiers A, Verwer BJ, van Hoek B, van Erpecum KJ et al. Genome-wide association study identifies variants associated with autoimmune hepatitis type 1. Gastroenterology 2014; 147: 443–452 e5.

    Article  CAS  Google Scholar 

  18. Fujinami RS, Oldstone MB . Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science 1985; 230: 1043–1045.

    Article  CAS  Google Scholar 

  19. Enouz S, Carrie L, Merkler D, Bevan MJ, Zehn D . Autoreactive T cells bypass negative selection and respond to self-antigen stimulation during infection. J Exp Med 2012; 209: 1769–1779.

    Article  CAS  Google Scholar 

  20. Longhi MS, Ma Y, Mieli-Vergani G, Vergani D . Aetiopathogenesis of autoimmune hepatitis. J Autoimmun 2010; 34: 7–14.

    Article  CAS  Google Scholar 

  21. Czaja AJ, Carpenter HA, Santrach PJ, Moore SB . Significance of HLA DR4 in type 1 autoimmune hepatitis. Gastroenterology 1993; 105: 1502–1507.

    Article  CAS  Google Scholar 

  22. Naeim F, Keesey JC, Herrmann C Jr, Lindstrom J, Zeller E, Walford RL . Association of HLA-B8, DRw3, and anti-acetylcholine receptor antibodies in myasthenia gravis. Tissue Antigens 1978; 12: 381–386.

    Article  CAS  Google Scholar 

  23. Bossini-Castillo L, de Kovel C, Kallberg H, van 't Slot R, Italiaander A, Coenen M et al. A genome-wide association study of rheumatoid arthritis without antibodies against citrullinated peptides. Ann Rheum Dis (e-pub ahead of print 14 February 2014; doi:10.1136/annrheumdis-2013-204591).

    Article  Google Scholar 

  24. van Heemst J, van der Woude D, Huizinga TW, Toes RE . HLA and rheumatoid arthritis: How do they connect? Ann Med 2014; 46: 304–310.

    Article  CAS  Google Scholar 

  25. Ferucci ED, Choromanski TL, Hurlburt KJ, Livingston S, Plotnik J, Manns MP et al. Autoimmune hepatitis in the Alaska Native population: autoantibody profile and HLA associations. Liver Int 2013; 34: 1241–1249.

    Article  Google Scholar 

  26. Ma Y, Okamoto M, Thomas MG, Bogdanos DP, Lopes AR, Portmann B et al. Antibodies to conformational epitopes of soluble liver antigen define a severe form of autoimmune liver disease. Hepatology 2002; 35: 658–664.

    Article  CAS  Google Scholar 

  27. Al-Chalabi T, Boccato S, Portmann BC, McFarlane IG, Heneghan MA . Autoimmune hepatitis (AIH) in the elderly: a systematic retrospective analysis of a large group of consecutive patients with definite AIH followed at a tertiary referral centre. J Hepatol 2006; 45: 575–583.

    Article  Google Scholar 

  28. Czaja AJ, Donaldson PT . Gender effects and synergisms with histocompatibility leukocyte antigens in type 1 autoimmune hepatitis. Am J Gastroenterol 2002; 97: 2051–2057.

    Article  CAS  Google Scholar 

  29. Liu JZ, Almarri MA, Gaffney DJ, Mells GF, Jostins L, Cordell HJ et al. Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis. Nat Genet 2012; 44: 1137–1141.

    Article  CAS  Google Scholar 

  30. Wiencke K, Karlsen TH, Boberg KM, Thorsby E, Schrumpf E, Lie BA et al. Primary sclerosing cholangitis is associated with extende d HLA-DR3 and HLA-DR6 haplotypes. Tissue Antigens 2007; 69: 161–169.

    Article  CAS  Google Scholar 

  31. Anderson CA, Pettersson FH, Clarke GM, Cardon LR, Morris AP, Zondervan KT . Data quality control in genetic case-control association studies. Nat Protoc 2010; 5: 1564–1573.

    Article  CAS  Google Scholar 

  32. Jia X, Han B, Onengut-Gumuscu S, Chen WM, Concannon PJ, Rich SS et al. Imputing amino acid polymorphisms in human leukocyte antigens. PLoS One 2013; 8: e64683.

    Article  CAS  Google Scholar 

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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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Supplementary Information accompanies this paper on Genes and Immunity website

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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).

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