Browsing by Author "Carbone, Marco"

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    An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs
    (Elsevier, 2021) Cordell, Heather J.; Fryett, James J.; Ueno, Kazuko; Darlay, Rebecca; Aiba, Yoshihiro; Hitomi, Yuki; Kawashima, Minae; Nishida, Nao; Khor, Seik-Soon; Gervais, Olivier; Kawai, Yosuke; Nagasaki, Masao; Tokunaga, Katsushi; Tang, Ruqi; Shi, Yongyong; Li, Zhiqiang; Juran, Brian D.; Atkinson, Elizabeth J.; Gerussi, Alessio; Carbone, Marco; Asselta, Rosanna; Cheung, Angela; de Andrade, Mariza; Baras, Aris; Horowitz, Julie; Ferreira, Manuel A. R.; Sun, Dylan; Jones, David E.; Flack, Steven; Spicer, Ann; Mulcahy, Victoria L.; Byan, Jinyoung; Han, Younghun; Sandford, Richard N.; Lazaridis, Konstantinos N.; Amos, Christopher I.; Hirschfield, Gideon M.; Seldin, Michael F.; Invernizzi, Pietro; Siminovitch, Katherine A.; Ma, Xiong; Nakamura, Minoru; Mells, George F.; PBC Consortia; Canadian PBC Consortium; Chinese PBC Consortium; Italian PBC Study Group; Japan-PBC-GWAS Consortium; US PBC Consortium; UK-PBC Consortium; Medicine, School of Medicine
    Backgrounds & aims: Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intrahepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. Methods: We combined new and existing genotype data for 10,516 cases and 20,772 controls from 5 European and 2 East Asian cohorts. Results: We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, which each play key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, JAK-STAT signalling, and differentiation of T helper (TH)1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some of which are well-established in the treatment of other autoimmune disorders. Conclusions: This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. Lay summary: Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10,516 people with PBC and 20,772 healthy individuals recruited in Canada, China, Italy, Japan, the UK, or the USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these 'candidate genes' to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC.
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    Role of ductular reaction and ductular-canalicular junctions in identifying severe primary biliary cholangitis
    (Elsevier, 2022-08-19) Overi, Diletta; Carpino, Guido; Cristoferi, Laura; Onori, Paolo; Kennedy, Lindsey; Francis, Heather; Zucchini, Nicola; Rigamonti, Cristina; Viganò, Mauro; Floreani, Annarosa; D’Amato, Daphne; Gerussi, Alessio; Venere, Rosanna; Alpini, Gianfranco; Glaser, Shannon; Alvaro, Domenico; Invernizzi, Pietro; Gaudio, Eugenio; Cardinale, Vincenzo; Carbone, Marco; Medicine, School of Medicine
    Background & aims: Primary biliary cholangitis (PBC) is a chronic cholangiopathy characterised by immuno-mediated injury of interlobular bile ducts leading to intrahepatic cholestasis and progressive liver fibrosis. PBC histology is characterised by portal inflammation, progressive fibrosis, ductopenia, and the appearance of the so-called ductular reaction. The aim of the present study was to investigate the pathogenetic relevance of ductular reaction in PBC. Methods: Liver biopsies were collected from naïve people with PBC (N = 87). Clinical-serological parameters were obtained at diagnosis and after 1 year of ursodeoxycholic acid (UDCA) treatment. Histological staging was performed on all slides according to multiple scoring systems and criteria for PBC. Liver samples were obtained from Mdr2 -/- mice treated with or without UDCA. Samples were processed for histology, immunohistochemistry, and immunofluorescence. Results: Ductular reaction in people with PBC correlated with the disease stage and liver fibrosis, but not with disease activity; an extensive ductular reaction correlated with serum alkaline phosphatase levels at diagnosis, response to UDCA, and individuals' estimated survival, independently from other histological parameters, including disease stage. In people with PBC, reactive ductules were associated with the establishment of junctions with bile canaliculi and with fibrogenetic cell activation. Consistently, in a mouse model of intrahepatic cholestasis, UDCA treatment was effective in reducing ductular reaction and fibrosis and increasing ductular-canalicular junctions. Conclusions: Extensive ductular reaction outlines a severe histologic phenotype in PBC and is associated with an inadequate therapy response and a worse estimated prognosis. Lay summary: In people affected by primary biliary cholangitis (PBC), the histological appearance of extensive ductular reaction identifies individuals at risk of progressive fibrosis. Ductular reaction at diagnosis correlates with the lack of response to first-line therapy with ursodeoxycholic acid and serves to restore ductular-canalicular junctions in people with PBC. Assessing ductular reaction extension at diagnosis may add valuable information for clinicians.
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    Secretin/secretin receptor signaling mediates biliary damage and liver fibrosis in early-stage primary biliary cholangitis
    (Wiley, 2019-06-28) Kennedy, Lindsey; Francis, Heather; Invernizzi, Pietro; Venter, Julie; Wu, Nan; Carbone, Marco; Gershwin, M. Eric; Bernuzzi, Francesca; Franchitto, Antonio; Alvaro, Domenico; Marzioni, Marco; Onori, Paolo; Gaudio, Eugenio; Sybenga, Amelia; Fabris, Luca; Meng, Fanyin; Glaser, Shannon; Alpini, Gianfranco; Medicine, School of Medicine
    Primary biliary cholangitis (PBC) primarily targets cholangiocytes and is characterized by liver fibrosis and biliary proliferation. Activation of the secretin (Sct)/secretin receptor (SR) axis, expressed only by cholangiocytes, increases biliary proliferation, liver fibrosis, and bicarbonate secretion. We evaluated the effectiveness of SR antagonist treatment for early-stage PBC. Male and female dominant-negative TGF-β receptor II (dnTGF-βRII) (model of PBC) and wild-type mice at 12 wk of age were treated with saline or the SR antagonist, Sec 5–27, for 1 wk. dnTGF-βRII mice expressed features of early-stage PBC along with enhanced Sct/SR axis activation and Sct secretion. dnTGF-βRII mice had increased biliary proliferation or senescence, inflammation, and liver fibrosis. In dnTGF-βRII mice, there was increased microRNA-125b/TGF-β1/TGF-β receptor 1/VEGF-A signaling. Human early-stage PBC patients had an increase in hepatobiliary Sct and SR expression and serum Sct levels. Increased biliary Sct/SR signaling promotes biliary and hepatic damage during early-stage PBC.—Kennedy, L., Francis, H., Invernizzi, P., Venter, J., Wu, N., Carbone, M., Gershwin, M. E., Bernuzzi, F., Franchitto, A., Alvaro, D., Marzioni, M., Onori, P., Gaudio, E., Sybenga, A., Fabris, L., Meng, F., Glaser, S., Alpini, G. Secretin/secretin receptor signaling mediates biliary damage and liver fibrosis in early-stage primary biliary cholangitis.