title: Polymorphisms in the steroid and xenobiotic receptor gene influence survival in primary sclerosing cholangitis.
abstract: OBJECTIVE
  The steroid and xenobiotic receptor (SXR) is a ligand-dependent transcription factor that mediates protection against bile acid-induced liver injury in cholestatic animal models. Ursodeoxycholic acid and rifampicin are known ligands. We investigated whether functional polymorphisms of the SXR gene influence disease susceptibility or disease progression in patients with primary sclerosing cholangitis (PSC).
  
  
  METHODS
  Polymorphisms at 8 loci across the SXR gene were genotyped in 327 Scandinavian PSC patients and 275 healthy controls. Kaplan-Meier survival analyses and Cox regressions were performed to estimate effects from genotypes on patient survival, defined as time from diagnostic cholangiography to death or liver transplantation.
  
  
  RESULTS
  Susceptibility to PSC was not associated with any of the SXR polymorphisms studied. Median survival was significantly reduced in patients homozygous for the minor allele as compared with patients carrying at least 1 major allele of the neighboring polymorphisms rs6785049 (10.8 vs 14.0 years, respectively, P = .01), rs1054190 (3.6 vs 13.6 years, respectively, P = .004), and rs3814058 (3.5 vs 13.3 years, respectively, P = .01). The increased risk of death or liver transplantation was confirmed in univariate Cox regressions (relative risk [RR](rs6785049) = 1.7, 95% CI: 1.1-2.6; RR(rs1054190) = 3.1, 95% CI: 1.4-7.1; and RR(rs3814058) = 2.2, 95% CI: 1.2-4.2 for the 3 polymorphisms, respectively). In multiple Cox regressions including age at PSC onset, rs1054190 remained an independent risk factor.
  
  
  CONCLUSIONS
  Functional SXR gene variants appear to modify disease course in PSC. Further investigations of polymorphisms in the SXR gene may provide insight into the prognostic importance of SXR-regulated pathways in this disease, perhaps even in a therapeutic perspective.
authors.affiliation: Medical Department, Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway. t.h.karlsen@klinmed.uio.no
authors.forename: Tom H
authors.initials: TH
authors.lastname: Karlsen
authors.forename: Benedicte A
authors.initials: BA
authors.lastname: Lie
authors.forename: Kathrine
authors.initials: K
authors.lastname: Frey Frøslie
authors.forename: Erik
authors.initials: E
authors.lastname: Thorsby
authors.forename: Ulrika
authors.initials: U
authors.lastname: Broomé
authors.forename: Erik
authors.initials: E
authors.lastname: Schrumpf
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Boberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D015209:Cholangitis, Sclerosing / Q000235:genetics* / Q000378:metabolism / Q000401:mortality*; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D000077297:Pregnane X Receptor; D011379:Prognosis; D016016:Proportional Hazards Models; D011987:Receptors, Steroid / Q000235:genetics*; D012307:Risk Factors; D015996:Survival Rate / Q000639:trends; D013997:Time Factors; D015262:Xenobiotics
chemical_list: D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D015262:Xenobiotics