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Meta-Analysis
. 2021 Sep;75(3):572-581.
doi: 10.1016/j.jhep.2021.04.055. Epub 2021 May 23.

An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs

Heather J Cordell  1 , James J Fryett  1 , Kazuko Ueno  2 , Rebecca Darlay  1 , Yoshihiro Aiba  3 , Yuki Hitomi  4 , Minae Kawashima  4 , Nao Nishida  4 , Seik-Soon Khor  2 , Olivier Gervais  5 , Yosuke Kawai  2 , Masao Nagasaki  5 , Katsushi Tokunaga  2 , Ruqi Tang  6 , Yongyong Shi  7 , Zhiqiang Li  7 , Brian D Juran  8 , Elizabeth J Atkinson  9 , Alessio Gerussi  10 , Marco Carbone  10 , Rosanna Asselta  11 , Angela Cheung  8 , Mariza de Andrade  9 , Aris Baras  12 , Julie Horowitz  12 , Manuel A R Ferreira  12 , Dylan Sun  12 , David E Jones  13 , Steven Flack  14 , Ann Spicer  14 , Victoria L Mulcahy  14 , Jinyoung Byan  15 , Younghun Han  15 , Richard N Sandford  14 , Konstantinos N Lazaridis  8 , Christopher I Amos  15 , Gideon M Hirschfield  16 , Michael F Seldin  17 , Pietro Invernizzi  10 , Katherine A Siminovitch  18 , Xiong Ma  6 , Minoru Nakamura  19 , George F Mells  20 ; PBC Consortia; Canadian PBC Consortium; Chinese PBC Consortium; Italian PBC Study Group; Japan-PBC-GWAS Consortium; US PBC Consortium; UK-PBC Consortium
Collaborators, Affiliations
Meta-Analysis

An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs

Heather J Cordell et al. J Hepatol. 2021 Sep.

Erratum in

  • Corrigendum to 'An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs' [J Hepatol 2021;75(3):572-581].
    Cordell HJ, Fryett JJ, Ueno K, Darlay R, Aiba Y, Hitomi Y, Kawashima M, Nishida N, Khor SS, Gervais O, Kawai Y, Nagasaki M, Tokunaga K, Tang R, Shi Y, Li Z, Juran BD, Atkinson EJ, Gerussi A, Carbone M, Asselta R, Cheung A, de Andrade M, Baras A, Horowitz J, Ferreira MAR, Sun D, Jones DE, Flack S, Spicer A, Mulcahy VL, Byun J, Han Y, Sandford RN, Lazaridis KN, Amos CI, Hirschfield GM, Seldin MF, Invernizzi P, Siminovitch KA, Ma X, Nakamura M, Mells GF; PBC Consortia; Canadian PBC Consortium; Chinese PBC Consortium; Italian PBC Study Group; Japan-PBC-GWAS Consortium; US PBC Consortium; UK-PBC Consortium. Cordell HJ, et al. J Hepatol. 2022 Feb;76(2):489. doi: 10.1016/j.jhep.2021.11.015. Epub 2021 Dec 9. J Hepatol. 2022. PMID: 34895949 Free PMC article. No abstract available.
  • Corrigendum to: "An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs" [J Hepatol 75 (2021) 572-581].
    Cordell HJ, Fryett JJ, Ueno K, Darlay R, Aiba Y, Hitomi Y, Kawashima M, Nishida N, Khor SS, Gervais O, Kawai Y, Nagasaki M, Tokunaga K, Tang R, Shi Y, Li Z, Juran BD, Atkinson EJ, Gerussi A, Carbone M, Asselta R, Cheung A, de Andrade M, Baras A, Horowitz J, Ferreira MAR, Sun D, Jones DE, Flack S, Spicer A, Mulcahy VL, Byan J, Han Y, Sandford RN, Lazaridis KN, Amos CI, Hirschfield GM, Seldin MF, Invernizzi P, Siminovitch KA, Ma X, Nakamura M, Mells GF; Canadian PBC Consortium; Chinese PBC Consortium; Italian PBC Study Group; Japan-PBC-GWAS Consortium; US PBC Consortium; UK-PBC Consortium. Cordell HJ, et al. J Hepatol. 2023 Apr;78(4):883. doi: 10.1016/j.jhep.2022.12.001. Epub 2023 Jan 11. J Hepatol. 2023. PMID: 36639314 No abstract available.

Abstract

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.

Keywords: ALSPAC; ERN RARE-LIVER; Genomic co-localization; Network-based in silico drug efficacy screening; UK-PBC.

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Conflict of interest statement

Conflicts of interest GMH has consulted and/or been a speaker for Intercept, Genfit, Cymabay, GSK, and Falk. RNS and GFM have each received research funding from Intercept Pharmaceuticals. HJC, JJF, KU, RD, YA, YH, MK, NN, S-SK, OG, YK, MN, KT, RT, YS, ZL, BDJ, EJA, AG, MC, RA, AC, MdA, AB, JH, MARF, DS, DEJ, SF, AS, VLM, KNL, CIA, MFS, PI, KAS, XM and MN report no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details.

Figures

None
Graphical abstract
Fig. 1
Fig. 1
Biological processes implicated by candidate genes formula image prioritised in the current study. (A) T and B cell activation, and differentiation of T follicular helper, TH1, TH17, and TREG cells; (B) pattern recognition receptor and TNF signalling in antigen presenting cells; and (C) signalling by the IL-12 family of cytokines. TH, T helper; TREG, regulatory T. (Figure created with BioRender.com).
See this image and copyright information in PMC

Comment in

References

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