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An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs
Open accessAbstract
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: 17 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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“These gene loci were significantly expressed in both European and Chinese populations, indicating a shared primary biliary cholangitis genetic architecture across different ethnicities.”
From Primary biliary cholangitis. (2024) · cites this paper as [18]
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“A recent genome-wide meta-analysis revealed novel risk loci, including ID2, TMEM163, PRDM1, CCR6, ETS1, and FAM177A1.18”
From Primary biliary cholangitis. (2024) · cites this paper as [18]
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“In addition to the human leukocyte antigen (HLA) locus, more than 60 non-HLA susceptibility regions have been identified in PBC pathogenesis, including tumor necrosis factor superfamily member 15 (TNFSF15), Interleukin 12 A (IL12A), Interleukin 12 receptor (IL12R), Nuclear Factor Kappa B Subunit 1 (NFKB1) and other immune-associated genes6–11.”
From A regulatory variant at 19p13.3 is associated with primary biliary cholangitis risk and ARID3A expression (2023) · cites this paper as [11]
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Metadata
- Authors
- Cordell, H. J., Fryett, J. J., Ueno, K., Darlay, R., Aiba, Y., Hitomi, Y., Kawashima, M., Nishida, N., Khor, S.-S., Gervais, O., Kawai, Y., Nagasaki, M., Tokunaga, K., Tang, R., Shi, Y., Li, Z., Juran, B. D., Atkinson, E. J., Gerussi, A., Carbone, M., Asselta, R., Cheung, A., de Andrade, M., Baras, A., Horowitz, J., Ferreira, M. A. R., Sun, D., Jones, D. E., Flack, S., Spicer, A., Mulcahy, V. L., Byan, J., Han, Y., Sandford, R. N., Lazaridis, K. N., Amos, C. I., Hirschfield, G. M., Seldin, M. F., Invernizzi, P., Siminovitch, K. A., Ma, X., Nakamura, M., Mells, G. F., Siminovitch, K. A., Hirschfield, G. M., Mason, A., Vincent, C., Xie, G., Zhang, J., Tang, R., Ma, X., Li, Z., Shi, Y., Affronti, A., Almasio, P. L., Alvaro, D., Andreone, P., Andriulli, A., Azzaroli, F., Battezzati, P. M., Benedetti, A., Bragazzi, M., Brunetto, M., Bruno, S., Calvaruso, V., Cardinale, V., Casella, G., Cazzagon, N., Ciaccio, A., Coco, B., Colli, A., Colloredo, G., Colombo, M., Colombo, S., Cristoferi, L., Cursaro, C., Crocè, L. S., Crosignani, A., D’Amato, D., Donato, F., Elia, G., Fabris, L., Fagiuoli, S., Ferrari, C., Floreani, A., Galli, A., Giannini, E., Grattagliano, I., Lampertico, P., Lleo, A., Malinverno, F., Mancuso, C., Marra, F., Marzioni, M., Massironi, S., Mattalia, A., Miele, L., Milani, C., Morini, L., Morisco, F., Muratori, L., Muratori, P., Niro, G. A., O’Donnell, S., Picciotto, A., Portincasa, P., Rigamonti, C., Ronca, V., Rosina, F., Spinzi, G., Strazzabosco, M., Tarocchi, M., Tiribelli, C., Toniutto, P., Valenti, L., Vinci, M., Zuin, M., Nakamura, H., Abiru, S., Nagaoka, S., Komori, A., Yatsuhashi, H., Ishibashi, H., Ito, M., Migita, K., Ohira, H., Katsushima, S., Naganuma, A., Sugi, K., Komatsu, T., Mannami, T., Matsushita, K., Yoshizawa, K., Makita, F., Nikami, T., Nishimura, H., Kouno, H., Kouno, H., Ota, H., Komura, T., Nakamura, Y., Shimada, M., Hirashima, N., Komeda, T., Ario, K., Nakamuta, M., Yamashita, T., Furuta, K., Kikuchi, M., Naeshiro, N., Takahashi, H., Mano, Y., Tsunematsu, S., Yabuuchi, I., Shimada, Y., Yamauchi, K., Sugimoto, R., Sakai, H., Mita, E., Koda, M., Tsuruta, S., Kamitsukasa, H., Sato, T., Masaki, N., Kobata, T., Fukushima, N., Ohara, Y., Muro, T., Takesaki, E., Takaki, H., Yamamoto, T., Kato, M., Nagaoki, Y., Hayashi, S., Ishida, J., Watanabe, Y., Kobayashi, M., Koga, M., Saoshiro, T., Yagura, M., Hirata, K., Tanaka, A., Takikawa, H., Zeniya, M., Abe, M., Onji, M., Kaneko, S., Honda, M., Arai, K., Arinaga-Hino, T., Hashimoto, E., Taniai, M., Umemura, T., Joshita, S., Nakao, K., Ichikawa, T., Shibata, H., Yamagiwa, S., Seike, M., Honda, K., Sakisaka, S., Takeyama, Y., Harada, M., Senju, M., Yokosuka, O., Kanda, T., Ueno, Y., Kikuchi, K., Ebinuma, H., Himoto, T., Yasunami, M., Murata, K., Mizokami, M., Kawata, K., Shimoda, S., Miyake, Y., Takaki, A., Yamamoto, K., Hirano, K., Ichida, T., Ido, A., Tsubouchi, H., Chayama, K., Harada, K., Nakanuma, Y., Maehara, Y., Taketomi, A., Shirabe, K., Soejima, Y., Mori, A., Yagi, S., Uemoto, S., H, E., Tanaka, T., Yamashiki, N., Tamura, S., Sugawara, Y., Kokudo, N., Juran, B. D., Atkinson, E. J., Cheung, A., de Andrade, M., Lazaridis, K. N., Chalasani, N., Luketic, V., Odin, J., Chopra, K., Baras, A., Horowitz, J., Abecasis, G., Cantor, M., Coppola, G., Economides, A., Lotta, L. A., Overton, J. D., Reid, J. G., Shuldiner, A., Beechert, C., Forsythe, C., Fuller, E. D., Gu, Z., Lattari, M., Lopez, A., Overton, J. D., Schleicher, T. D., Padilla, M. S., Toledo, K., Widom, L., Wolf, S. E., Pradhan, M., Manoochehri, K., Ulloa, R. H., Bai, X., Balasubramanian, S., Barnard, L., Blumenfeld, A., Eom, G., Habegger, L., Hawes, A., Khalid, S., Reid, J. G., Maxwell, E. K., Salerno, W., Staples, J. C., Jones, M. B., Mitnaul, L. J., Sturgess, R., Healey, C., Yeoman, A., Gunasekera, A. V., Kooner, P., Kapur, K., Sathyanarayana, V., Kallis, Y., Subhani, J., Harvey, R., McCorry, R., Rooney, P., Ramanaden, D., Evans, R., Mathialahan, T., Gasem, J., Shorrock, C., Bhalme, M., Southern, P., Tibble, J. A., Gorard, D. A., Jones, S., Mells, G., Mulcahy, V., Srivastava, B., Foxton, M. R., Collins, C. E., Elphick, D., Karmo, M., Porras-Perez, F., Mendall, M., Yapp, T., Patel, M., Ede, R., Sayer, J., Jupp, J., Fisher, N., Carter, M. J., Koss, K., Shah, J., Piotrowicz, A., Scott, G., Grimley, C., Gooding, I. R., Williams, S., Tidbury, J., Lim, G., Cheent, K., Levi, S., Mansour, D., Beckley, M., Hollywood, C., Wong, T., Marley, R., Ramage, J., Gordon, H. M., Ridpath, J., Ngatchu, T., Bob Grover, V. P., Shidrawi, R. G., Abouda, G., Corless, L., Narain, M., Rees, I., Brown, A., Taylor-Robinson, S., Wilkins, J., Grellier, L., Banim, P., Das, D., Heneghan, M. A., Curtis, H., Matthews, H. C., Mohammed, F., Aldersley, M., Srirajaskanthan, R., Walker, G., McNair, A., Sharif, A., Sen, S., Bird, G., Prince, M. I., Prasad, G., Kitchen, P., Barnardo, A., Oza, C., Sivaramakrishnan, N. N., Gupta, P., Shah, A., Evans, C. D., Saha, S., Pollock, K., Bramley, P., Mukhopadhya, A., Barclay, S. T., McDonald, N., Bathgate, A. J., Palmer, K., Dillon, J. F., Rushbrook, S. M., Przemioslo, R., McDonald, C., Millar, A., Tai, C., Mitchell, S., Metcalf, J., Shaukat, S., Ninkovic, M., Shmueli, U., Davis, A., Naqvi, A., Lee, T. J., Ryder, S., Collier, J., Klass, H., Cramp, M. E., Sharer, N., Aspinall, R., Ghosh, D., Douds, A. C., Booth, J., Williams, E., Hussaini, H., Christie, J., Mann, S., Thorburn, D., Marshall, A., Patanwala, I., Ala, A., Maltby, J., Matthew, R., Corbett, C., Vyas, S., Singhal, S., Gleeson, D., Misra, S., Butterworth, J., George, K., Harding, T., Douglass, A., Mitchison, H., Panter, S., Shearman, J., Bray, G., Roberts, M., Butcher, G., Forton, D., Mahmood, Z., Cowan, M., Das, D., Ch’ng, C. L., Rahman, M., Whatley, G. C. A., Wesley, E., Mandal, A., Jain, S., Pereira, S. P., Wright, M., Trivedi, P., Gordon, F. H., Unitt, E., Palejwala, A., Austin, A., Vemala, V., Grant, A., Higham, A. D., Brind, A., Mathew, R., Cox, M., Ramakrishnan, S., King, A., Whalley, S., Fraser, J., Thomson, S. J., Bell, A., Wong, V. S., Kia, R., Gee, I., Keld, R., Ransford, R., Gotto, J., & Millson, C.
- Affiliations
- Newcastle University (GB)
- National Center for Global Health and Medicine (JP)
- Nagasaki Medical Center (JP)
- The University of Tokyo (JP)
- Kyoto University (JP)
- Azienda Ospedaliera San Gerardo (IT)
- Humanitas University (IT)
- Regeneron (United States) (US)
- University of Cambridge (GB)
- Baylor College of Medicine (US)
- University of California, Davis (US)
- Mayo Clinic (US)
- Mount Sinai Hospital (CA)
- ORCID
- 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
- Gerussi, Alessio
- Carbone, Marco
- Asselta, Rosanna
- Ferreira, Manuel A.R.
- Sun, Dylan
- Jones, David E.
- Flack, Steven
- Mulcahy, Victoria L.
- Han, Younghun
- Sandford, Richard N.
- Amos, Christopher I.
- Invernizzi, Pietro
- Mells, George F.
- Mason, Andrew
- Vincent, Catherine
- Zhang, Jinyi
- Almasio, Piero L.
- Alvaro, Domenico
- Andriulli, Angelo
- Azzaroli, Francesco
- Battezzati, Pier Maria
- Benedetti, Antonio
- Brunetto, Maurizia
- Calvaruso, Vincenza
- Cardinale, Vincenzo
- Casella, Giovanni
- Cazzagon, Nora
- Ciaccio, Antonio
- Coco, Barbara
- Colli, Agostino
- Colombo, Massimo
- Cristoferi, Laura
- Cursaro, Carmela
- Crocè, Lory Saveria
- D’Amato, Daphne
- Fabris, Luca
- Fagiuoli, Stefano
- Ferrari, Carlo
- Floreani, Annarosa
- Galli, Andrea
- Giannini, Edoardo
- Lampertico, Pietro
- Mancuso, Clara
- Marra, Fabio
- Marzioni, Marco
- Massironi, Sara
- Miele, Luca
- Milani, Chiara
- Morisco, Filomena
- Muratori, Luigi
- Muratori, Paolo
- Niro, Grazia A.
- Portincasa, Piero
- Rigamonti, Cristina
- Ronca, Vincenzo
- Spinzi, Giancarlo
- Strazzabosco, Mario
- Tarocchi, Mirko
- Tiribelli, Claudio
- Toniutto, Pierluigi
- Valenti, Luca
- Zuin, Massimo
- Nakamura, Hitomi
- Nagaoka, Shinya
- Komori, Atsumasa
- Yatsuhashi, Hiroshi
- Ishibashi, Hiromi
- Ito, Masahiro
- Migita, Kiyoshi
- Ohira, Hiromasa
- Katsushima, Shinji
- Naganuma, Atsushi
- Mannami, Tomohiko
- Yoshizawa, Kaname
- Komura, Takuya
- Nakamura, Yoko
- Shimada, Masaaki
- Nakamuta, Makoto
- Kikuchi, Masahiro
- Shimada, Yusuke
- Sugimoto, Rie
- Sakai, Hironori
- Tsuruta, Satoru
- Sato, Takeaki
- Masaki, Naohiko
- Nagaoki, Yuko
- Ishida, Jinya
- Watanabe, Yukio
- Kobayashi, Masakazu
- Takikawa, Hajime
- Zeniya, Mikio
- Abe, Masanori
- Kaneko, Shuichi
- Honda, Masao
- Arai, Kuniaki
- Taniai, Makiko
- Umemura, Takeji
- Joshita, Satoru
- Nakao, Kazuhiko
- Ichikawa, Tatsuki
- Yamagiwa, Satoshi
- Seike, Masataka
- Honda, Koichi
- Sakisaka, Shotaro
- Takeyama, Yasuaki
- Harada, Masaru
- Yokosuka, Osamu
- Kanda, Tatsuo
- Ueno, Yoshiyuki
- Kikuchi, Kentaro
- Ebinuma, Hirotoshi
- Himoto, Takashi
- Yasunami, Michio
- Murata, Kazumoto
- Mizokami, Masashi
- Kawata, Kazuhito
- Shimoda, Shinji
- Miyake, Yasuhiro
- Takaki, Akinobu
- Tsubouchi, Hirohito
- Chayama, Kazuaki
- Harada, Kenichi
- Nakanuma, Yasuni
- Maehara, Yoshihiko
- Taketomi, Akinobu
- Soejima, Yuji
- Mori, Akira
- Yagi, Shintaro
- Tanaka, Tomohiro
- Yamashiki, Noriyo
- Kokudo, Norihiro
- Chalasani, Naga
- Odin, Joseph
- Cantor, Michael
- Coppola, Giovanni
- Economides, Aris
- Lotta, Luca A.
- Shuldiner, Alan
- Lopez, Alexander
- Ulloa, Ricardo H.
- Bai, Xiaodong
- Balasubramanian, Suganthi
- Blumenfeld, Andrew
- Maxwell, Evan K.
- Salerno, William
- Staples, Jeffrey C.
- Jones, Marcus B.
- Yeoman, Andrew
- Kapur, Kapil
- Kallis, Yiannis
- Tibble, Jeremy A.
- Collins, Carole E.
- Mendall, Michael
- Fisher, Neil
- Cheent, Kuldeep
- Mansour, Dina
- Ramage, John
- Shidrawi, Ray G.
- Corless, L.
- Taylor-Robinson, Simon
- Grellier, Leonie
- Banim, Paul
- Das, Debasish
- Heneghan, Michael A.
- Aldersley, Mark
- Barclay, Stephen T.
- McDonald, Natasha
- Dillon, John F.
- Rushbrook, Simon M.
- Przemioslo, Robert
- Millar, Andrew
- Lee, Tom JW.
- Ryder, Stephen
- Collier, Jane
- Cramp, Matthew E.
- Aspinall, Richard
- Ghosh, Deb
- Douds, Andrew C.
- Thorburn, Douglas
- Marshall, Aileen
- Patanwala, Imran
- Ala, Aftab
- Gleeson, Dermot
- Harding, Tim
- Forton, Daniel
- Ch’ng, Chin Lye
- Rahman, Mesbah
- Pereira, Stephen P.
- Wright, Mark
- Trivedi, Palak
- Gordon, Fiona H.
- Whalley, Simon
- Keld, Richard
- Millson, Charles
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2021-09
- Volume
- 75
- Issue
- 3
- Pages
- 572-581
- ISSN
- 0168-8278 (ISSN-L)
- PMC
- PMC8811537
- OpenAlex
- W3165249197
- Cited by
- 182
- References
- 35
- Citations by year
- 2026: 27 · 2025: 46 · 2024: 50 · 2023: 36 · 2022: 19 · 2021: 4
- FWCI
- 3.72
- Type
- journal article
- Language
- en
- Update notices
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Hepatology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, cc-by-nc-nd)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion, cc-by)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, cc-by)
- Florence Research (University of Florence) (submittedVersion, other-oa)
- Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion, cc-by)
- PEARL (University of Plymouth) (submittedVersion)
- Institutional Research Information System (University of Udine) (submittedVersion)
- ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion, other-oa)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion, cc-by)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- PubliCatt (Università Cattolica del Sacro Cuore) (submittedVersion, cc-by)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion, other-oa)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- Japan Society for the Promotion of Science (26293181, 17H04169)
- Biotechnology and Biological Sciences Research Council (BB/M011186/1)
- Ontario Research Foundation (RE-09090)
- Cancer Prevention and Research Institute of Texas (CA186566, RR170048)
- Canadian Institutes of Health Research (353710)
- Ministero dell’Istruzione, dell’Università e della Ricerca
- University of Bristol
- American Medical Association Foundation
- National Institute for Health Research
- Wellcome Trust (102858/Z/13/Z)
- Japan Agency for Medical Research and Development (JP20km0405205, JP20km0405501)
- Medical Research Council (MR/L001489/1, 217065/Z/19/Z)
- National Institutes of Health (DK80670)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- primary biliary cirrhosis, genetic susceptibility loci, candidate genes, drug repurposing, autoimmune liver disease, bile duct destruction, liver cirrhosis, genetic susceptibility
- MeSH terms
- Humans, Liver Cirrhosis, Biliary, Genome-Wide Association Study
About these checks
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