Gastroenterology

Gastroenterology

Volume 131, Issue 3, September 2006, Pages 781-787
Gastroenterology

Clinical–liver, pancreas, and biliary tract
Polymorphisms in the Steroid and Xenobiotic Receptor Gene Influence Survival in Primary Sclerosing Cholangitis

https://doi.org/10.1053/j.gastro.2006.05.057Get rights and content

Background & Aims: 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; RRrs1054190 = 3.1, 95% CI: 1.4–7.1; and RRrs3814058 = 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.

Section snippets

Study Population

The study included 327 clinically well-characterized Scandinavian PSC patients (71.3% male) recruited successively on admission to the Medical Department, Rikshospitalet University Hospital, Oslo, Norway (n = 235), and the Department of Gastroenterology and Hepatology, Huddinge University Hospital, Stockholm, Sweden (n = 92). Both hospitals serve as tertiary referral centers. Diagnosis was based on accepted criteria and typical findings on cholangiography.1 IBD was diagnosed and classified

Results

Genotype distributions for all polymorphisms were in Hardy–Weinberg equilibrium for both patient and control populations. The minor allele at rs12721608 was not observed in our population, so this SNP was subsequently excluded from further analyses. The LD pattern of the investigated polymorphisms is shown in Figure 1. The promoter SNP rs3814055 displayed almost perfect LD with the 6-bp promoter deletion (D′ = 0.99 and r2 = 0.99) (LD block 1). Rs6785049, rs1054190, and rs3814058 were found to

Discussion

This is, to our knowledge, the first study to demonstrate that SXR gene polymorphisms may influence survival in human cholestatic liver disease. PSC susceptibility was not associated with any of the polymorphisms under study. Our findings thus indicate that genetically determined SXR properties are important only in the course of PSC and not during disease initiation.

In cholestasis, potentially toxic bile acids accumulate, resulting in hepatocellular and bile duct tissue damage. Together with

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      Besides ABCB4 representing a potential disease progression modifier, a similar role has been postulated for the steroid and xenobiotic receptor (SXR), alternatively pregnane X receptor (PXR) or nuclear receptor (NR) 1I2, which fine-tunes the function of multiple hepatobiliary transporters such as ABCC2 (MRP2) and ABCC3 (MRP3) (Halilbasic et al., 2013). In accordance with experimental cholestasis models showing protective effects, genetic SXR variation is not associated with PSC risk but with unfavourable disease progression in terms of fibrogenic acceleration (Karlsen et al., 2006; Wagner et al., 2005). There is an increased cancer risk in PSC driven by chronic inflammation and retention of carcinogenic bile acids mostly affecting the biliary system itself.

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