Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease

Ji, Sun Gou; Juran, Brian D.; Mucha, Sören; Folseraas, Trine; Jostins, Luke; Melum, Espen; Kumasaka, Natsuhiko; Atkinson, Elizabeth J.; Schlicht, Erik M.; Liu, Yushi; Shah, Tejas; Gutiérrez-Achury, Javier; Boberg, Kirsten Muri; Bergquist, Annika; Vermeire, Séverine; Eksteen, Bertus; Durie, Peter R.; Färkkilä, M.; Müller, Tobias; Schramm, Christoph; Sterneck, Martina; Weismüller, Tobias J.; Gotthardt, Daniel; Ellinghaus, David; Braun, Felix; Teufel, Andreas; Laudes, Mattias; Lieb, Wolfgang; Jacobs, Gunnar; Beuers, Ulrich; Weersma, Rinse K.; Wijmenga, Cisca; Marschall, Hanns‐Ulrich; Milkiewicz, Piotr; Pares, A.; Kontula, Kimmo; Chazouillères, Olivier; Invernizzi, Pietro; Goode, Elizabeth; Spiess, Kelly; Moore, Carmel; Sambrook, Jennifer; Ouwehand, Willem H.; Roberts, David J.; Danesh, John; Floreani, Annarosa; Gulamhusein, Aliya; Eaton, John E.; Schreiber, Stefan; Coltescu, Catalina; Bowlus, Christopher L.; Luketic, Velimir A.; Odin, Joseph A.; Chopra, Kapil; Kowdley, Kris V.; Chalasani, Naga; Manns, Michael P.; Srivastava, Brijesh; Mells, George; Sandford, Richard; Alexander, Graeme; Gaffney, Daniel J; Chapman, Roger W.; Hirschfield, Gideon M.; Andrade, Mariza de; Rushbrook, Simon; Franke, André; Karlsen, Tom H.; Lazaridis, Konstantinos N.; Anderson, Carl A.

doi:10.1038/ng.3745

Cited by 270 publications

(210 citation statements)

References 51 publications

(72 reference statements)

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“…14,16 Of note, the IPSCSG has recently demonstrated genetic distinctions between patients with PSC and IBD vs those with IBD alone. 26–28 Notwithstanding efforts to better understand clinical outcomes, our study further supports the need to improve IBD classification in PSC, particularly as the intestinal phenotype is often distinct compared with classical colitis descriptors, 15 and more so given that genetic signals in PSC/CD may be disparate to those with PSC/UC. 28,29 Of note, our study does not capture details pertaining to the precise distribution of intestinal inflammation; however, prior evidence suggests that CD in PSC is invariably localized to the colon, with isolated ileal disease being a seldom-reported finding.…”

Section: Discussionsupporting

confidence: 62%

Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis

et al. 2017

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BACKGROUND & AIMS Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. METHODS We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates. RESULTS Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21–30 years old, 9.0 per 100 patient-years for patients 31–40 years old, 14.0 per 100 patient-years for patients 41–50 years old, 15.2 per 100 patient-years for patients 51–60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn’s disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P =.001 and HR, 0.90; P = .03, respectively) and malignancy (HR, 0.68; P = .008 and HR, 0.77; P = .004, respectively). Small-duct PSC was associated with a lower risk of LTD or malignancy compared with classic PSC (HR, 0.30 and HR, 0.15, respectively; both P < .001). Female sex was also associated with a lower risk of LTD or malignancy (HR, 0.88; P = .002 and HR, 0.68; P < .001, respectively). In multivariable analyses assessing the primary endpoint, small-duct PSC characterized a low-risk phenotype in both sexes (adjusted HR for men, 0.23; P < .001 and adjusted HR for women, 0.48; P = .003). Conversely, patients with ulcerative colitis had an increased risk of liver disease progression compared with patients with Crohn’s disease (HR, 1.56; P < .001) or no IBD (HR, 1.15; P = .002). CONCLUSIONS In an analysis of data from individual patients with PSC worldwide, we found significant variation in clinical course associated with age at diagnosis, sex, and ductal and IBD subtypes. The survival estimates provided might be used to estimate risk levels for patients wi...

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Section: Discussionsupporting

confidence: 62%

Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis

et al. 2017

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“…To conclude, germ-line genetic variants of DCDC2 do not feature prominently among patients with PSC, consistent with recent genome-wide association studies 3 and lack of severe biliary disease in the heterozygous carriers of the NSC-causative DCDC2 alleles. However, a potential role for severe (but not complete) DCDC2 haploinsufficiency, due possibly to unobserved protein-damaging or expression-altering alleles, cannot be dismissed by our present study.…”

Section: To the Editorsupporting

confidence: 87%

Doublecortin domain containing protein 2 (DCDC2) genetic variants in primary sclerosing cholangitis

Cheung

Juran

Moore

et al. 2017

Journal of Hepatology

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“…Genome‐wide association studies (GWAS) have identified approximately 20 PSC risk loci, including a strong association with the human leukocyte antigen (HLA) complex. However, these studies have not yet been able to explain the heterogeneity of the disease, nor have they significantly advanced the ability to treat these patients …”

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confidence: 99%

Bile‐Derived Organoids From Patients With Primary Sclerosing Cholangitis Recapitulate Their Inflammatory Immune Profile

et al. 2019

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Primary sclerosing cholangitis (PSC) is a heterogeneous and progressive fibroinflammatory cholangiopathy with no known etiology or effective treatment. Studies of PSC are limited due to difficulty in accessing the cholangiocyte, the small percentage of these cells in the liver, instability of in vitro culture systems, and reliance on samples from end‐stage disease. Here, we demonstrate that stem cells can be isolated from the bile of PSC patients undergoing endoscopic retrograde cholangiopancreatography earlier in their clinical course and maintained long term in vitro as three‐dimensional (3D) organoids that express a biliary genetic phenotype. Additionally, bile‐derived organoids (BDOs) can be biobanked and samples obtained longitudinally over the course of the disease. These BDOs express known cholangiocyte markers including gamma glutamyl transferase, cytokeratin 19, epithelial cellular adhesion molecule, cystic fibrosis transmembrane conductance regulator, and anion exchanger 2. RNA sequence analysis identified 39 genes whose expression differed in organoids from PSC patients compared to non‐PSC controls, including human leukocyte antigen DM alpha chain and chemokine (C‐C motif) ligand 20 (CCL20), immune‐related genes previously described in genome‐wide association studies of PSC. Incubation of these BDOs with interleukin 17A or tumor necrosis factor alpha led to an immune‐reactive phenotype with a significant increase in secretion of proinflammatory mediators, including CCL20, a T‐cell chemoattractant. Conclusion: This study demonstrates that bile can be used as a source of biliary‐like cells that can be maintained long term in vitro as 3D organoids; these BDOs retain features of cholangiopathies, including the ability to react to inflammatory stimuli by secreting chemokines and propagating an immune‐reactive phenotype reflective of the pathogenesis of these diseases; thus, BDOs represent a platform for the study of the pathogenesis and therapy of cholangiopathies, particularly PSC.

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Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease

Cited by 270 publications

References 51 publications

Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis

Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis

Doublecortin domain containing protein 2 (DCDC2) genetic variants in primary sclerosing cholangitis

Bile‐Derived Organoids From Patients With Primary Sclerosing Cholangitis Recapitulate Their Inflammatory Immune Profile

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