Browsing by Author "Hirschfield, Gideon M."

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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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    A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis
    (Elsevier, 2020-07) Kowdley, Kris V.; Vuppalanchi, Raj; Levy, Cynthia; Floreani, Annarosa; Andreone, Pietro; LaRusso, Nicholas F.; Shrestha, Roshan; Trotter, James; Goldberg, David; Rushbrook, Simon; Hirschfield, Gideon M.; Schiano, Thomas; Jin, Yuying; Pencek, Richard; MacCone, Leigh; Shapiro, David; Bowlus, Christopher L.; Medicine, School of Medicine
    Background & aims: Primary sclerosing cholangitis (PSC) is a rare, cholestatic liver disease with no currently approved therapies. Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis. We investigated the efficacy and safety of OCA in patients with PSC. Methods: AESOP was a phase II, randomized, double-blind, placebo-controlled, dose-finding study. Eligible patients were 18 to 75 years of age with a diagnosis of PSC and serum alkaline phosphatase (ALP) ≥2× the upper limit of normal (ULN) and total bilirubin <2.5× ULN. Patients were randomized 1:1:1 to receive placebo, OCA 1.5-3.0 mg, or OCA 5-10 mg once daily for a 24-week, double-blind phase followed by a 2-year, long-term safety extension (LTSE). Primary endpoints were change in ALP from baseline to week 24, and safety. Results: The intent-to-treat population comprised 76 patients randomized to placebo (n = 25), OCA 1.5-3.0 mg (n = 25), and OCA 5-10 mg (n = 26). At week 24, serum ALP was significantly reduced with OCA 5-10 mg vs. placebo (least-square [LS] mean difference = -83.4 [SE = 40.3] U/L; 95% CI -164.28 to -2.57; p = 0.043). Serum ALP was not significantly reduced with OCA 1.5-3.0 mg vs. placebo at week 24 (LS mean [SE] difference = -78.29 [41.81] U/L; 95% CI -162.08 to 5.50; p = 0.067). Total bilirubin remained comparable to baseline in all groups. The most common treatment-emergent adverse event was dose-related pruritus (placebo 46%; OCA 1.5-3.0 mg 60%; OCA 5-10 mg 67%). Reductions in ALP were maintained during the LTSE, and no new safety signals emerged. Conclusions: Treatment with OCA 5-10 mg reduced serum ALP in patients with PSC. Mild to moderate dose-related pruritus was the most common adverse event.