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

N M F van Gerven, Y S de Boer, A Zwiers, B J Verwer, J P H 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 J Guichelaar, J M Vrolijk, M J Coenraad, G Kraal, C J J Mulder, C M J van Nieuwkerk, E BloemenaH W Verspaget, V Kumar, A Zhernakova, C Wijmenga, L Franke, G Bouma,

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)247-52
Number of pages6
JournalGenes and Immunity
Issue number4
Publication statusPublished - Jun 2015


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