title: HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1.
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.
authors.affiliation: Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: N M F
authors.initials: NM
authors.lastname: van Gerven
authors.affiliation: Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Y S
authors.initials: YS
authors.lastname: de Boer
authors.affiliation: 1] Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands [2] Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Zwiers
authors.affiliation: Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: B J
authors.initials: BJ
authors.lastname: Verwer
authors.affiliation: Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: J P H
authors.initials: JP
authors.lastname: Drenth
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: van Hoek
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: K J
authors.initials: KJ
authors.lastname: van Erpecum
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: U
authors.initials: U
authors.lastname: Beuers
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: H R
authors.initials: HR
authors.lastname: van Buuren
authors.affiliation: Department of Gastroenterology and Hepatology, Haga Hospital, The Hague, The Netherlands.
authors.forename: J W
authors.initials: JW
authors.lastname: den Ouden
authors.affiliation: 1] University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands [2] Department of Gastroenterology and Hepatology, St Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands.
authors.forename: R C
authors.initials: RC
authors.lastname: Verdonk
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Maastricht, Maastricht, The Netherlands.
authors.forename: G H
authors.initials: GH
authors.lastname: Koek
authors.affiliation: Department of Gastroenterology and Hepatology, Reinier de Graaf Hospital, Delft, The Netherlands.
authors.forename: J T
authors.initials: JT
authors.lastname: Brouwer
authors.affiliation: Department of Gastroenterology and Hepatology, Medisch Spectrum Twente, Enschede, The Netherlands.
authors.forename: M M J
authors.initials: MM
authors.lastname: Guichelaar
authors.affiliation: Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, The Netherlands.
authors.forename: J M
authors.initials: JM
authors.lastname: Vrolijk
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: Coenraad
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Kraal
authors.affiliation: Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: C J J
authors.initials: CJ
authors.lastname: Mulder
authors.affiliation: Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: C M J
authors.initials: CM
authors.lastname: van Nieuwkerk
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Bloemena
authors.affiliation: Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: H W
authors.initials: HW
authors.lastname: Verspaget
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: V
authors.initials: V
authors.lastname: Kumar
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Zhernakova
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Franke
authors.affiliation: 1] Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands [2] Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Bouma
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D059811:HLA-DRB1 Chains / Q000235:genetics* / Q000276:immunology; D019693:Hepatitis, Autoimmune / Q000175:diagnosis / Q000209:etiology / Q000235:genetics* / Q000628:therapy; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016896:Treatment Outcome
chemical_list: D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; C553505:HLA-DRB1*04:01 antigen; D007074:Immunoglobulin G