title: Enrichment of Genetic Variants in the Glucocorticoid Receptor Signalling Pathway in Autoimmune Hepatitis with Failure of Standard Treatment.
abstract: The standard treatment for autoimmune hepatitis (AIH) is predniso(lo)ne for remission induction, tapered and followed by azathioprine, which effectively controls the disease in the majority of patients. However, some patients prove to be unresponsive or non-tolerant and require alternative immunosuppressive regimens for disease control. We aimed to investigate whether these AIH patients who experience failure of standard treatment have a genomic basis for their problem in the form of pharmacogenetic variants. Fifty-six consecutive patients with AIH [41 female and 15 male; median age 42 years (12-76)] were retrospectively stratified according to being responders to standard therapy (n = 33) or patients with failure of standard therapy (n = 23). Their blood DNA was exome-captured and sequenced. Genomic variants were filtered and compared between the groups using Ingenuity Variant Analysis (3.1.20150407). The exome sequencing and data processing revealed glucocorticoid receptor signalling to be the most prominently affected pathway among the patients with failure of standard therapy (highly significant). Standard treatment failure was not associated with thiopurine S-methyltransferase variants or the HLA-DRB1*03 genotype. In conclusion, enrichment of variants related to glucocorticoid receptor signalling was a particular genomic trait of the AIH patients in whom standard treatment failed and alternative immunosuppression was required. If confirmed, a future application of this finding may be to identify prospective cases of failure of standard treatment already at diagnosis.
authors.affiliation: Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus C, Denmark.
authors.forename: Peter Lykke
authors.initials: PL
authors.lastname: Eriksen
authors.affiliation: Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus C, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Kreutzfeldt
authors.affiliation: Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus C, Denmark.
authors.forename: Henning
authors.initials: H
authors.lastname: Grønbaek
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus C, Denmark.
authors.forename: Kasper
authors.initials: K
authors.lastname: Thorsen
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus C, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Vang
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus C, Denmark.|Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus C, Denmark.|Department of Research Laboratory for Biochemical Pathology, Aarhus University Hospital, Aarhus C, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Jessen
authors.affiliation: Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus C, Denmark.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Vilstrup
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000627:therapeutic use; D002648:Child; D015331:Cohort Studies; D003718:Denmark; D018432:Drug Resistance, Multiple; D005260:Female; D056726:Genetic Association Studies; D059811:HLA-DRB1 Chains / Q000235:genetics*; D019693:Hepatitis, Autoimmune / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D006785:Hospitals, University; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011239:Prednisolone / Q000627:therapeutic use; D012189:Retrospective Studies; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; D007166:Immunosuppressive Agents; D011239:Prednisolone; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine