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

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.; Mason, A.; Vincent, C.; Xie, G.; Zhang, J.; 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.; Croce, 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.; Chalasani, N.; Luketic, V.; Odin, J.; Chopra, K.; 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.; 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.; 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.

doi:10.1016/j.jhep.2021.04.055

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.

Cordell H.J., Fryett J.J., Ueno K., Darlay R., Aiba Y., Hitomi Y., et al. (2021). An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs. JOURNAL OF HEPATOLOGY, 75(3), 572-581 [10.1016/j.jhep.2021.04.055].