Genome-Wide Association Analysis in Primary Sclerosing Cholangitis

doi:10.1053/j.gastro.2009.11.046

Gastroenterology

Volume 138, Issue 3, March 2010, Pages 1102-1111

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https://doi.org/10.1053/j.gastro.2009.11.046 Get rights and content

Background & Aims

We aimed to characterize the genetic susceptibility to primary sclerosing cholangitis (PSC) by means of a genome-wide association analysis of single nucleotide polymorphism (SNP) markers.

Methods

A total of 443,816 SNPs on the Affymetrix SNP Array 5.0 (Affymetrix, Santa Clara, CA) were genotyped in 285 Norwegian PSC patients and 298 healthy controls. Associations detected in this discovery panel were re-examined in independent case-control panels from Scandinavia (137 PSC cases and 368 controls), Belgium/The Netherlands (229 PSC cases and 735 controls), and Germany (400 cases and 1832 controls).

Results

The strongest associations were detected near HLA-B at chromosome 6p21 (rs3099844: odds ratio [OR], 4.8; 95% confidence interval [CI], 3.6–6.5; P = 2.6 × 10⁻²⁶; and rs2844559: OR, 4.7; 95% CI, 3.5–6.4; P = 4.2 × 10⁻²⁶ in the discovery panel). Outside the HLA complex, rs9524260 at chromosome 13q31 showed significant associations in 3 of 4 study panels. Lentiviral silencing of glypican 6, encoded at this locus, led to the up-regulation of proinflammatory markers in a cholangiocyte cell line. Of 15 established ulcerative colitis susceptibility loci, significant replication was obtained at chromosomes 2q35 and 3p21 (rs12612347: OR, 1.26; 95% CI, 1.06–1.50; and rs3197999: OR, 1.22; 95% CI, 1.02–1.47, respectively), with circumstantial evidence supporting the G-protein–coupled bile acid receptor 1 and macrophage-stimulating 1, respectively, as the likely disease genes.

Conclusions

Strong HLA associations and a subset of genes involved in bile homeostasis and other inflammatory conditions constitute key components of the genetic architecture of PSC.

Section snippets

Study Panels

The diagnosis of PSC was based on accepted criteria and typical findings on cholangiography.¹ In total, 285 PSC patients (74% male) and 298 healthy controls (59% male) from Norway (discovery panel), 137 PSC patients (67% male) and 368 healthy controls (70% male) from Norway and Sweden (verification panel 1), 229 PSC patients (63% male) and 735 healthy controls (54% male) from Belgium and The Netherlands (verification panel 2), and 400 PSC patients (69% male) and 1832 healthy controls (41% male)

Results

Population stratification in the discovery panel was found to be negligible with a genomic inflation factor of 1.03 (Supplementary Figure 2). A multidimensional scaling plot of genetic relatedness across ethnicities also showed that our samples segregated together with individuals of European origin in the HapMap samples (Supplementary Figure 3).

Discussion

By combining a genome-wide association study design with gene-centric investigations based on previous findings in UC, our study verified the importance of susceptibility variants within the HLA complex in PSC and provided novel evidence for the presence of at least 3 non-HLA susceptibility loci.

Given the genetic complexity of any HLA association, biological insight may be derived more easily from the 3 non-HLA PSC loci. However, similar for most susceptibility loci detected in genome-wide

Acknowledgments

The authors wish to thank all primary sclerosing cholangitis patients and healthy controls for their participation. The authors also thank Tanja Wesse, Tanja Henke, Rainer Vogler, Katja Cloppenborg-Schmidt, Eva Buchert, Hege Dahlen Sollid, and Bente Woldseth for expert technical help. Professor Dr Thomas Wienker and Dr Michael Steffens (IMBIE, University of Bonn) are acknowledged for performing the quality control of the genome-wide single nucleotide polymorphism data set. The authors are

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Autoimmune liver diseases (AILDs) are complex diseases with unknown causes and immune-mediated pathophysiology. In primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) disease modifying drugs are available which improve patient quality and quantity of life. In primary sclerosing cholangitis (PSC) no medical therapy is available and the only accepted treatment is liver transplantation (LT). PBC, PSC and AIH possess features that describe the archetype of patients within each disorder. On the other hand, the classical disorders are not homogeneous, and patients within each diagnosis may present with a range of clinical, biochemical, serological, and histological findings.
Singularly, they are considered rare diseases, but together, they account for approximately 20% of LTs in Europe and USA. Management of these patients is complex, as AILDs are relatively uncommon in clinical practice with challenges in developing expertise, disease presentation can be sneaky, clinical phenotypes and disease course are heterogeneous. Prognostic models are key tools for clinicians to assess patients’ risk and to provide personalized care to patients. Aim of this review is to discuss challenges of the management of AILDs and how the available prognostic models can help. We will discuss the prognostic models developed in AILDs, with a special focus on the prognostic models that can support the clinical management of patients with AILDs: in PBC models based on ursodeoxycholic acid (UDCA) response and markers of liver fibrosis; in PSC several markers including biochemistry, disease stage and radiological semiquantitative markers; and finally in AIH, markers of disease stage and disease activity.
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Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic liver disease of unclear cause. Until now, there are no effective therapies for patients with PSC. A number of studies have evaluated the effects of immune-modulating therapies on the treatment of PSC. However, clinical benefits of these treatments in PSC patients are controversial and inconclusive. We performed a systematic review and meta-analysis to assess the efficacy and adverse effects of immunomodulators in adult patients with PSC based on prognostic markers (alkaline phosphatase (ALP) and total bilirubin), liver function marker (aspartate aminotransferase (AST)) and adverse event (AE) rates. Twenty-one studies (seven randomized controlled trials (RCT) and fourteen observational studies) involving 737 patients were included in this analysis. Immune-modulating therapies significantly reduced ALP level in PSC patients, but not to normal level. AST level was non-significantly decreased, while no effect was observed on total bilirubin level after treatments in PSC patients. In 16 studies reporting AEs, an average of 16.1% patients had severe AEs, resulting in discontinuation of therapies. Importantly, subgroup analysis further indicated that immune-modulating therapy significantly reduced ALP or AST levels in PSC patients with high baseline levels of ALP (over 420 U/L, > three times the upper limit of normal (ULN)) or AST (over 80 U/L, > two times the ULN), but had no effect in patients with low baseline levels. Compared to other immune-modulating therapies, immunosuppressants had the most significant effect on reducing ALP and AST levels in PSC patients but was associated with the highest incidence of severe AEs of 24.9%. Glucocorticoids showed a positive effect by significantly reducing ALP levels with the minimal AE rate of 6.1%. In conclusion, immune-modulating therapies could improve the prognostic marker of cholestasis (ALP level) in patients with PSC, especially in those of worse liver function. These findings suggest patients with high baseline level of ALP (>420 U/L) and AST (>80 U/L) respond better to immune-modulating therapy compared to those with low level of ALP and AST. Future RCTs would be needed to include different dosing regimens, a longer treatment duration and follow-up period, and patients stratified by liver function to obtain solid conclusion.
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In children the most common SC is associated with strong autoimmune features, overlapping with those of autoimmune hepatitis (AIH); this form is known as autoimmune sclerosing cholangitis, ASC.
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Despite treatment, SC often progresses to biliary cirrhosis and end-stage liver disease requiring liver transplantation. The disease can recur after transplant.
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: Conflicts of interest The authors disclose no conflicts.

: Funding The study was supported by the German Ministry of Education and Research (BMBF) through the National Genome Research Network and the PopGen biobank (www.popgen.de). The project received infrastructure support through the DFG excellence cluster “Inflammation at Interfaces” (www.inflammation-at-interfaces.de) and the Norwegian PSC research center (www.rikshospitalet.no/nopsc).

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Basic—Liver, Pancreas, and Biliary TractGenome-Wide Association Analysis in Primary Sclerosing Cholangitis

Background & Aims

Methods

Results

Conclusions

Section snippets

Study Panels

Results

Discussion

Acknowledgments

Gastroenterology

Gastrointest Endosc

Clin Gastroenterol Hepatol

Am J Hum Genet

Gastroenterology

Mucosal Immunol

Biochem Biophys Res Commun

Biochem Biophys Res Commun

J Pediatr

J Biol Chem

J Hepatol

Primary sclerosing cholangitis: a review of its clinical features, cholangiography, and hepatic histology

Gut

Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population

Scand J Gastroenterol

HLA antigens and immunoregulatory T cells in ulcerative colitis associated with hepatobiliary disease

Scand J Gastroenterol

Genetic epidemiology of primary sclerosing cholangitis

World J Gastroenterol

Gene map of the extended human MHC

Nat Rev Genet

Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis

Nat Genet

Basic—Liver, Pancreas, and Biliary Tract
Genome-Wide Association Analysis in Primary Sclerosing Cholangitis