title: HLA variants related to primary sclerosing cholangitis influence rejection after liver transplantation.
abstract: OBJECTIVE
  To investigate influence of human leukocyte antigen (HLA) and killer immunoglobuline-like receptor (KIR) genotypes on risks of acute rejection (AR) after liver transplantation (LTX).
  
  
  METHODS
  In this retrospective study we included 143 adult donor-recipient pairs with a minimum of 6 mo follow-up after LTX for whom DNA was available from both donor and recipients. Clinical data, all early complications including episodes and severity of AR and graft/patient survival were registered. The diagnosis of AR was based on clinical, biochemical and histological criteria. All suspected episodes of AR were biopsy confirmed. Key classical HLA loci (HLA-A, HLA-B, HLA-C and HLA-DRB1) were genotyped using Sanger sequencing. 16 KIR genes were genotyped using a novel real time PCR approach which allows for determination of the diploid copy number of each KIR gene. Immunohistochemical staining for T (CD3), B (CD20) and natural killer (NK) cells (CD56 and CD57) were performed on liver biopsies from 3 different patient groups [primary sclerosing cholangitis (PSC), primary biliary cirrhosis and non-autoimmune liver disease], 10 in each group, with similar grade of AR.
  
  
  RESULTS
  Fourty-four (31%) patients were transplanted on the basis of PSC, 40% of them had AR vs 24% in the non-PSC group (P = 0.04). No significant impact of donor-recipient matching for HLA and KIR genotypes was detected. In the overall recipient population an increased risk of AR was detected for HLA-B*08 (P = 0.002, OR = 2.5; 95%CI: 1.4-4.6), HLA-C*07 (P = 0.001, OR = 2.4; 95%CI: 1.4-4.0) and HLA-DRB1*03 (P = 0.03, OR = 1.9; 95%CI: 1.0-3.3) and a decreased risk for HLA-DRB1*04 (P = 0.001, OR = 0.2; 95%CI: 0.1-0.5). For HLA-B*08, HLA-C*07 and DRB1*04 the associations remained evident in a subgroup analysis of non-PSC recipients (P = 0.04, P = 0.003 and P = 0.02, respectively). In PSC recipients corresponding P values were 0.002, 0.17 and 0.01 for HLA-B*08, HLA-C*07 and DRB1*04, respectively. A dosage effect of AR prevalence according to the PSC associated HLA alleles was also notable in the total recipient population. For HLA-B*08 the frequency of AR was 56% in HLA-B*08 homozygous recipients, 39% in heterozygous recipients and 21% in recipients lacking HLA-B*08 (P = 0.02). The same was observed for the HLA-C*07 allele with AR in 57%, 27% and 18% in recipients being homozygous, heterozygous and lacking HLA-C*07 respectively (P = 0.003). Immunohistochemical analysis showed similar infiltration of T, B and NK cells in biopsies with AR in all three groups.
  
  
  CONCLUSIONS
  We found significant associations between the PSC-associated HLA-B*08, HLA-C*07, HLA-DRB1*03 and HLA-DRB1*04 alleles and risk of AR in liver transplant recipients.
authors.affiliation: Bjarte Fosby, Sigrid Næss, Johannes R Hov, Kirsten M Boberg, Espen Melum, Tom H Karlsen, Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, N-0424 Oslo, Norway.
authors.forename: Bjarte
authors.initials: B
authors.lastname: Fosby
authors.affiliation: Bjarte Fosby, Sigrid Næss, Johannes R Hov, Kirsten M Boberg, Espen Melum, Tom H Karlsen, Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, N-0424 Oslo, Norway.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Næss
authors.affiliation: Bjarte Fosby, Sigrid Næss, Johannes R Hov, Kirsten M Boberg, Espen Melum, Tom H Karlsen, Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, N-0424 Oslo, Norway.
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Hov
authors.affiliation: Bjarte Fosby, Sigrid Næss, Johannes R Hov, Kirsten M Boberg, Espen Melum, Tom H Karlsen, Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, N-0424 Oslo, Norway.
authors.forename: James
authors.initials: J
authors.lastname: Traherne
authors.affiliation: Bjarte Fosby, Sigrid Næss, Johannes R Hov, Kirsten M Boberg, Espen Melum, Tom H Karlsen, Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, N-0424 Oslo, Norway.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Boberg
authors.affiliation: Bjarte Fosby, Sigrid Næss, Johannes R Hov, Kirsten M Boberg, Espen Melum, Tom H Karlsen, Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, N-0424 Oslo, Norway.
authors.forename: John
authors.initials: J
authors.lastname: Trowsdale
authors.affiliation: Bjarte Fosby, Sigrid Næss, Johannes R Hov, Kirsten M Boberg, Espen Melum, Tom H Karlsen, Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, N-0424 Oslo, Norway.
authors.forename: Aksel
authors.initials: A
authors.lastname: Foss
authors.affiliation: Bjarte Fosby, Sigrid Næss, Johannes R Hov, Kirsten M Boberg, Espen Melum, Tom H Karlsen, Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, N-0424 Oslo, Norway.
authors.forename: Pål-Dag
authors.initials: PD
authors.lastname: Line
authors.affiliation: Bjarte Fosby, Sigrid Næss, Johannes R Hov, Kirsten M Boberg, Espen Melum, Tom H Karlsen, Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, N-0424 Oslo, Norway.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Bjarte Fosby, Sigrid Næss, Johannes R Hov, Kirsten M Boberg, Espen Melum, Tom H Karlsen, Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, N-0424 Oslo, Norway.
authors.forename: Espen
authors.initials: E
authors.lastname: Melum
authors.affiliation: Bjarte Fosby, Sigrid Næss, Johannes R Hov, Kirsten M Boberg, Espen Melum, Tom H Karlsen, Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, N-0424 Oslo, Norway.
authors.forename: Helge
authors.initials: H
authors.lastname: Scott
authors.affiliation: Bjarte Fosby, Sigrid Næss, Johannes R Hov, Kirsten M Boberg, Espen Melum, Tom H Karlsen, Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, N-0424 Oslo, Norway.
authors.forename: Tom H
authors.initials: TH
authors.lastname: Karlsen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D015209:Cholangitis, Sclerosing / Q000235:genetics* / Q000276:immunology; D058625:End Stage Liver Disease / Q000276:immunology / Q000601:surgery*; D005260:Female; D005838:Genotype; D006084:Graft Rejection; D006085:Graft Survival; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D054340:Receptors, KIR / Q000235:genetics; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D006680:HLA Antigens; D054340:Receptors, KIR
keywords: Acute rejection; Human leukocyte antigen; Killer immunoglobulin-like receptor; Liver transplantation; Primary sclerosing cholangitis
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