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Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis.

ABSTRACT: OBJECTIVE:Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. DESIGN:We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130?422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. RESULTS:We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10-9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. CONCLUSION:We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.

SUBMITTER: Alberts R

PROVIDER: S-EPMC5797498 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis.

Alberts Rudi R de Vries Elisabeth M G EMG Goode Elizabeth C EC Jiang Xiaojun X Sampaziotis Fotis F Rombouts Krista K Böttcher Katrin K Folseraas Trine T Weismüller Tobias J TJ Mason Andrew L AL Wang Weiwei W Alexander Graeme G Alvaro Domenico D Bergquist Annika A Björkström Niklas K NK Beuers Ulrich U Björnsson Einar E Boberg Kirsten Muri KM Bowlus Christopher L CL Bragazzi Maria C MC Carbone Marco M Chazouillères Olivier O Cheung Angela A Dalekos Georgios G Eaton John J Eksteen Bertus B Ellinghaus David D Färkkilä Martti M Festen Eleonora A M EAM Floreani Annarosa A Franceschet Irene I Gotthardt Daniel Nils DN Hirschfield Gideon M GM Hoek B van BV Holm Kristian K Hohenester Simon S Hov Johannes Roksund JR Imhann Floris F Invernizzi Pietro P Juran Brian D BD Lenzen Henrike H Lieb Wolfgang W Liu Jimmy Z JZ Marschall Hanns-Ulrich HU Marzioni Marco M Melum Espen E Milkiewicz Piotr P Müller Tobias T Pares Albert A Rupp Christian C Rust Christian C Sandford Richard N RN Schramm Christoph C Schreiber Stefan S Schrumpf Erik E Silverberg Mark S MS Srivastava Brijesh B Sterneck Martina M Teufel Andreas A Vallier Ludovic L Verheij Joanne J Vila Arnau Vich AV Vries Boudewijn de B Zachou Kalliopi K Chapman Roger W RW Manns Michael P MP Pinzani Massimo M Rushbrook Simon M SM Lazaridis Konstantinos N KN Franke Andre A Anderson Carl A CA Karlsen Tom H TH Ponsioen Cyriel Y CY Weersma Rinse K RK

Gut 20170804 8

<h4>Objective</h4>Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications.<h4>Design</h4>We collected standardised PSC subphenotypes in a large cohort of 3402 patients wi ...[more]

PMID: 28779025

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Project description:Background and aimsPrimary sclerosing cholangitis (PSC) is a heterogeneous cholangiopathy characterized by progressive biliary fibrosis. RNA sequencing of liver tissue from patients with PSC (n = 74) enrolled in a 96-week clinical trial was performed to identify associations between biological pathways that were independent of fibrosis and clinical events.Approach and resultsThe effect of fibrosis was subtracted from gene expression using a computational approach. The fibrosis-adjusted gene expression patterns were associated with time to first PSC-related clinical event (e.g., cholangitis, hepatic decompensation), and differential expression based on risk groups and Ingenuity Pathway Analysis were performed. Baseline demographic data were representative of PSC: median age 48 years, 71% male, 49% with inflammatory bowel disease, and 44% with bridging fibrosis or cirrhosis. The first principle component (PC1) of RNA-sequencing data accounted for 18% of variance and correlated with fibrosis stage (ρ = -0.80; P < 0.001). After removing the effect of fibrosis-related genes, the first principle component was not associated with fibrosis (ρ = -0.19; P = 0.11), and a semisupervised clustering approach identified two distinct patient clusters with differential risk of time to first PSC-related event (P < 0.0001). The two groups had similar fibrosis stage, hepatic collagen content, and α-smooth muscle actin expression by morphometry, Enhanced Liver Fibrosis score, and serum liver biochemistry, bile acids, and IL-8 (all P > 0.05). The top pathways identified by Ingenuity Pathway Analysis were eukaryotic translation inhibition factor 2 (eIF2) signaling and regulation of eIF4/p70S6K signaling. Genes involved in the unfolded protein response, activating transcription factor 6 (ATF6) and eIF2, were differentially expressed between the PSC clusters (down-regulated in the high-risk group by log-fold changes of -0.18 [P = 0.02] and -0.16 [P = 0.02], respectively). Clinical events were enriched in the high-risk versus low-risk group (38% [12/32] vs. 2.4% [1/42], P < 0.0001).ConclusionsRemoving the contribution of fibrosis-related pathways uncovered alterations in the unfolded protein response, which were associated with liver-related complications in PSC.

Project description:Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are forms of hepatic autoimmunity, and risk for both diseases has a strong genetic component. This study aimed to define the genetic architecture of PBC and PSC within the Polish population.Subjects were 443 women with PBC, 120 patients with PSC, and 934 healthy controls recruited from Gastroenterology Departments in various Polish hospitals. Allelotyping employed a pooled-DNA sample-based genome-wide association study (GWAS) approach, using Illumina Human Omni2.5-Exome BeadChips and the following novel selection criteria for risk loci: blocks of at least 10 single nucleotide polymorphisms (SNPs) in strong linkage disequilibrium, where the distance between each adjacent SNP pair in the block was less than 30 kb, and each SNP was associated with disease at a significance level of P < 0.005. A selected index SNP from each block was validated using TaqMan SNP genotyping assays.Nineteen and twenty-one SNPs were verified as associated with PBC and PSC, respectively, by individual genotyping; 19 (10/9, PBC/PSC) SNPs reached a stringent (corrected) significance threshold and a further 21 (9/12, PBC/PSC) reached a nominal level of significance (P < 0.05 with odds ratio (OR) > 1.2 or < 0.83), providing suggestive evidence of association. The SNPs mapped to seven (1p31.3, 3q13, 6p21, 7q32.1, 11q23.3, 17q12, 19q13.33) and one (6p21) chromosome region previously associated with PBC and PSC, respectively. The SNP, rs35730843, mapping to the POLR2G gene promoter (P = 1.2 × 10-5, OR = 0.39) demonstrated the highest effect size, and was protective for PBC, whereas for PSC respective SNPs were: rs13191240 in the intron of ADGRB3 gene (P = 0.0095, OR = 0.2) and rs3822659 (P = 0.0051, OR = 0.236) along with rs9686714 (P = 0.00077, OR = 0.2), both located in the WWC1 gene.Our cost-effective GWAS approach followed by individual genotyping confirmed several previously identified associations and discovered new susceptibility loci associated with PBC and/or PSC in Polish patients. However, further functional studies are warranted to understand the roles of these newly identified variants in the development of the two disorders.

Project description:Background & aimsPrimary sclerosing cholangitis (PSC) is a rare cholangiopathy of unknown aetiopathogenesis. The aim of this study was to evaluate cellular senescence (CS) marker expression in cholangiocytes of patients with PSC and their correlation with clinical-pathological features and prognosis.MethodsThirty-five patients with PSC with at least 1 available liver sampling were included. Clinical laboratory data at the time of liver sampling were collected. The endpoints were survival without liver transplantation (LT), time to LT, and survival without LT or cirrhosis decompensation. Histological grading and staging were assessed according to Nakanuma. Immunohistochemical stains for CS markers, p16INK4A (p16) and p21WAF1/Cip1 (p21), were performed and scored by a 3-tier scale based on positivity extent in native bile duct (NBD) and ductular reaction (DR).Results: p16 expression in NBD and DR was directly correlated with fibrosis (p ≤0.001 for both) and stage (p = 0.006 and p <0.001, respectively). Moreover, p16 in NBD was positively correlated with hepatitis activity (HA) (p = 0.026), whereas p16 in DR was directly correlated with bile duct loss (BDL) (p = 0.005) and metaplastic hepatocytes (MH) (p <0.01). p21 expression in NBD and DR was directly correlated with HA (p = 0.004 and p = 0.043, respectively), fibrosis (p = 0.006 and p <0.001, respectively), stage (p = 0.006 and p = 0.001, respectively), BDL (p = 0.002 and p = 0.03, respectively), and DR and MH (p ≤0.004 for all). By multivariate analysis, p16 expression in DR was independently associated with stage (p = 0.001), fibrosis (p = 0.001), and BDL (p = 0.011). p21 expression in NBD was independently associated with HA (p = 0.012), BDL (p = 0.04), and DR (p = 0.014). Finally, p21 expression in DR was independently associated with LT-free survival, time to LT, and adverse outcome-free survival (p = 0.001, p = 0.017, and p = 0.001, respectively).ConclusionsCholangiocyte senescence is detectable in all stages of PSC and is associated with histological and clinical disease severity, potentially representing a new prognostic and therapeutic target.Lay summaryIn this study, we showed that cholangiocyte senescence (CS), previously demonstrated in liver of patients with end-stage primary sclerosing cholangitis (PSC), is an early event and is detectable in all disease stages. Moreover, we observed that CS is associated with histological and clinical disease severity and patients' outcome. Thus, we suggest that CS may represent a new prognostic tool and a potential therapeutic target in PSC.Clinical trial numberProtocol number 0034435, 08/06/2020.

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Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis.

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Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis.

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