Data di Pubblicazione:
2021
Abstract:
BACKGROUND & AIMS: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. METHODS: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). RESULTS: Single-marker association analyses found approximately 100 loci displaying P < 5 x 10(-4), with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 x 10(-6); odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 x 10(-8)), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 x 10(-9); OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). CONCLUSIONS: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.
Tipologia CRIS:
1.1 Articolo in rivista
Keywords:
X-Wide Association Study; Meta-analysis; Superenhancer
Elenco autori:
Asselta, Rosanna; Paraboschi, Elvezia M.; Gerussi, Alessio; Cordell, Heather J.; Mells, George F.; Sandford, Richard N.; Jones, David E.; Nakamura, Minoru; Ueno, Kazuko; Hitomi, Yuki; Kawashima, Minae; Nishida, Nao; Tokunaga, Katsushi; Nagasaki, Masao; Tanaka, Atsushi; Tang, Ruqi; Li, Zhiqiang; Shi, Yongyong; Liu, Xiangdong; Xiong, Ma; Hirschfield, Gideon; Siminovitch, Katherine A.; Carbone, Marco; Cardamone, Giulia; Duga, Stefano; Gershwin, M. Eric; Seldin, Michael F.; Invernizzi, Pietro; Walker, Erin; Xie, Gang; Mason, Andy; Myers, Robert; Peltekian, Kevork; Ghent, Cameron; Atkinson, Elizabeth; Juran, Bruce; Lazaridis, Kostas; Lu, Yue; Gu, Xiangjun; Jing, Kaiyan; Amos, Chris; Affronti, Andrea; Brunetto, Maurizia; Coco, Barbara; Spinzi, Giancarlo; Elia, Gianfranco; Ferrari, Carlo; Lleo, Ana; Muratori, Luigi; Muratori, Paolo; Portincasa, Piero; Colli, Agostino; Bruno, Savino; Colloredo, Guido; Azzaroli, Francesco; Andreone, Pietro; Bragazzi, Mariaconsiglia; Alvaro, Domenico; Cardinale, Vincenzo; Cazzagon, Nora; Rigamonti, Cristina; Floreani, Annarosa; Rosina, Floriano; Ciaccio, Antonio; Cristoferi, Laura; D’Amato, Daphne; Malinverno, Federica; Mancuso, Clara; Massironi, Sara; Milani, Chiara; O’Donnell, Sarah E.; Ronca, Vincenzo; Barisani, Donatella; Lampertico, Pietro; Donato, Francesca; Fagiuoli, Stefano; Almasio, Piero L.; Giannini, Edoardo; Cursaro, Carmela; Colombo, Massimo; Valenti, Luca; Miele, Luca; Andriulli, Angelo; Niro, Grazia A.; Grattagliano, Ignazio; Morini, Lorenzo; Casella, Giovanni; Vinci, Maria; Battezzati, Pier Maria; Crosignani, Andrea; Zuin, Massimo; Mattalia, Alberto; Calvaruso, Vincenza; Colombo, Silvia; Benedetti, Antonio; Marzioni, Marco; Galli, Andrea; Marra, Fabio; Tarocchi, Mirko; Picciotto, Antonio; Morisco, Filomena; Fabris, Luca; Crocè, Lory Saveria; Tiribelli, Claudio; Toniutto, Pierluigi; Strazzabosco, Mario; Ch’Ng, Chin Lye; Rahman, Mesbah; Yapp, Tom; Sturgess, Richard; Healey, Christopher; Czajkowski, Marek; Gunasekera, Anton; Gyawali, Pranab; Premchand, Purushothaman; Kapur, Kapil; Marley, Richard; Foster, Graham; Watson, Alan; Dias, Aruna; Subhani, Javaid; Harvey, Rory; Mccorry, Roger; Ramanaden, David; Gasem, Jaber; Evans, Richard; Mathialahan, Thiriloganathan; Shorrock, Christopher; Lipscomb, George; Southern, Paul; Tibble, Jeremy; Gorard, David; Palegwala, Altaf; Jones, Susan; Dawwas, Mohamed; Alexander, Graeme; Dolwani, Sunil; Prince, Martin; Foxton, Matthew; Elphick, David; Mitchison, Harriet; Gooding, Ian; Karmo, Mazn; Saksena, Sushma; Mendall, Mike; Patel, Minesh; Ede, Roland; Austin, Andrew; Sayer, Joanna; Hankey, Lorraine; Hovell, Christopher; Fisher, Neil; Carter, Martyn; Koss, Konrad; Piotrowicz, Andrzej; Grimley, Charles; Neal, David; Lim, Guan; Levi, Sass; Ala, Aftab; Broad, Andrea; Saeed, Athar; Wood, Gordon; Brown, Jonathan; Wilkinson, Mark; Gordon, Harriet; Ramage, John; Ridpath, Jo; Ngatchu, Theodore; Grover, Bob; Shaukat, Syed; Shidrawi, Ray; Abouda, George; Ali, Faiz; Rees, Ian; Salam, Imroz; Narain, Mark; Brown, Ashley; Taylor-Robinson, Simon; Williams, Simon; Grellier, Leonie; Banim, Paul; Das, Debasish; Chilton, Andrew; Heneghan, Michael; Curtis, Howard; Gess, Markus; Drake, Ian; Aldersley, Mark; Davies, Mervyn; Jones, Rebecca; Mcnair, Alastair; Srirajaskanthan, Raj; Pitcher, Maxton; Sen, Sambit; Bird, George; Barnardo, Adrian; Kitchen, Paul; Yoong, Kevin; Chirag, Oza; Sivaramakrishnan, Nurani; Macfaul, George; Jones, David; Shah, Amir; Evans, Chris; Saha, Subrata; Pollock, Katharine; Bramley, Peter; Mukhopadhya, Ashis; Fraser, Andrew; Mills, Peter; Shallcross, Christopher; Campbell, Stewart; Bathgate, Andrew; Shepherd, Alan; Dillon, John; Rushbrook, Simon; Przemioslo, Robert; Macdonald, Christopher; Metcalf, Jane; Shmueli, Udi; Davis, Andrew; Naqvi, Asifabbas; Lee, Tom; Ryder, Stephen D.; Collier, Jane; Klass, Howard; Ninkovic, Mary; Cramp, Matthew; Sharer, Nicholas; Aspinall, Richard; Goggin, Patrick; Ghosh, Deb; Doud
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