Clinical–liver, pancreas, and biliary tractPolymorphisms in the Steroid and Xenobiotic Receptor Gene Influence Survival in Primary Sclerosing Cholangitis
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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2014, Molecular Aspects of MedicineCitation Excerpt :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.
Supported by The Norwegian Foundation for Health and Rehabilitation (to T.H.K.).