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 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 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 × 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 × 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.
X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis / 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; Douds, Andrew; Hoeroldt, Barbara; Booth, Jonathan; Williams, Earl; Hussaini, Hyder; Stableforth, William; Ayres, Reuben; Thorburn, Douglas; Marshall, Eileen; Burroughs, Andrew; Mann, Steven; Lombard, Martin; Richardson, Paul; Patanwala, Imran; Maltby, Julia; Brookes, Matthew; Mathew, Ray; Vyas, Samir; Singhal, Saket; Gleeson, Dermot; Misra, Sharat; Butterworth, Jeff; George, Keith; Harding, Tim; Douglass, Andrew; Panter, Simon; Shearman, Jeremy; Bray, Gary; Butcher, Graham; Forton, Daniel; Mclindon, John; Cowan, Matthew; Whatley, Gregory; Mandal, Aditya; Gupta, Hemant; Sanghi, Pradeep; Jain, Sanjiv; Pereira, Steve; Prasad, Geeta; Watts, Gill; Wright, Mark; Neuberger, James; Gordon, Fiona; Unitt, Esther; Grant, Allister; Delahooke, Toby; Higham, Andrew; Brind, Alison; Cox, Mark; Ramakrishnan, Subramaniam; King, Alistair; Collins, Carole; Whalley, Simon; Li, Andy; Fraser, Jocelyn; Bell, Andrew; Wong, Voi Shim; Singhal, Amit; Gee, Ian; Ang, Yeng; Ransford, Rupert; Gotto, James; Millson, Charles; Bowles, Jane; Thomas, Caradog; Harrison, Melanie; Galaska, Roman; Kendall, Jennie; Whiteman, Jessica; Lawlor, Caroline; Gray, Catherine; Elliott, Keith; Mulvaney-Jones, Caroline; Hobson, Lucie; Van Duyvenvoorde, Greta; Loftus, Alison; Seward, Katie; Penn, Ruth; Maiden, Jane; Damant, Rose; Hails, Janeane; Cloudsdale, Rebecca; Silvestre, Valeria; Glenn, Sue; Dungca, Eleanor; Wheatley, Natalie; Doyle, Helen; Kent, Melanie; Hamilton, Caroline; Braim, Delyth; Wooldridge, Helen; Abrahams, Rachel; Paton, Alison; Lancaster, Nicola; Gibbins, Andrew; Hogben, Karen; Desousa, Phillipa; Muscariu, Florin; Musselwhite, Janine; McKay, Alexandra; Tan, LaiTing; Foale, Carole; Brighton, Jacqueline; Flahive, Kerry; Nambela, Estelle; Townshend, Paula; Ford, Chris; Holder, Sophie; Palmer, Caroline; Featherstone, James; Nasseri, Mariam; Sadeghian, Joy; Williams, Bronwen; Thomas, Carol; Rolls, Sally-Ann; Hynes, Abigail; Duggan, Claire; Jones, Sarah; Crossey, Mary; Stansfield, Glynis; MacNicol, Carolyn; Wilkins, Joy; Wilhelmsen, Elva; Raymode, Parizade; Lee, Hye-Jeong; Durant, Emma; Bishop, Rebecca; Ncube, Noma; Tripoli, Sherill; Casey, Rebecca; Cowley, Caroline; Miller, Richard; Houghton, Kathryn; Ducker, Samantha; Wright, Fiona; Bird, Bridget; Baxter, Gwen; Keggans, Janie; Hughes, Maggie; Grieve, Emma; Young, Karin; Williams, D.; Ocker, Kate; Hines, Frances; Martin, Kirsty; Innes, Caron; Valliani, Talal; Fairlamb, Helen; Thornthwaite, Sarah; Eastick, Anne; Tanqueray, Elizabeth; Morrison, Jennifer; Holbrook, Becky; Browning, Julie; Walker, Kirsten; Congreave, Susan; Verheyden, Juliette; Slininger, Susan; Stafford, Lizzie; O’Donnell, Denise; Ainsworth, Mark; Lord, Susan; Kent, Linda; March, Linda; Dickson, Christine; Simpson, Diane; Longhurst, Beverley; Hayes, Maria; Shpuza, Ervin; White, Nikki; Besley, Sarah; Pearson, Sallyanne; Wright, Alice; Jones, Linda; Gunter, Emma; Dewhurst, Hannah; Fouracres, Anna; Farrington, Liz; Graves, Lyn; Marriott, Suzie; Leoni, Marina; Tyrer, David; Martin, Kate; Dali-kemmery, Lola; Lambourne, Victoria; Green, Marie; Sirdefield, Dawn; Amor, Kelly; Colley, Julie; Shinder, Bal; Jones, Jayne; Mills, Marisa; Carnahan, Mandy; Taylor, Natalie; Boulton, Kerenza; Tregonning, Julie; Brown, Carly; Clifford, Gayle; Archer, Emily; Hamilton, Maria; Curtis, Janette; Shewan, Tracey; Walsh, Sue; Warner, Karen; Netherton, Kimberley; Mupudzi, Mcdonald; Gunson, Bridget; Gitahi, Jane; Gocher, Denise; Batham, Sally; Pateman, Hilary; Desmennu, Senayon; Conder, Jill; Clement, Darren; Gallagher, Susan; Orpe, Jacky; Chan, PuiChing; Currie, Lynn; O’Donohoe, Lynn; Oblak, Metod; Morgan, Lisa; Quinn, Marie; Amey, Isobel; Baird, Yolanda; Cotterill, Donna; Cumlat, Lourdes; Winter, Louise; Greer, Sandra; Spurdle, Katie; Allison, Joanna; Dyer, Simon; Sweeting, Helen; Kordula, Jean; Aiba, Yoshihiro; Nakamura, Hitomi; Abiru, Seigo; Nagaoka, Shinya; Komori, Atsumasa; Yatsuhashi, Hiroshi; Ishibashi, Hiromi; Ito, Masahiro; Kawai, Yosuke; Kohn, Seik-Soon; Gervais, Olivier; Migita, Kiyoshi; Katsushima, Shinji; Naganuma, Atsushi; Sugi, Kazuhiro; Komatsu, Tatsuji; Mannami, Tomohiko; Matsushita, Kouki; Yoshizawa, Kaname; Makita, Fujio; Nikami, Toshiki; Nishimura, Hideo; Kouno, Hiroshi; Kouno, Hirotaka; Ota, Hajime; Komura, Takuya; Nakamura, Yoko; Shimada, Masaaki; Hirashima, Noboru; Komeda, Toshiki; Ario, Keisuke; Nakamuta, Makoto; Yamashita, Tsutomu; Furuta, Kiyoshi; Kikuchi, Masahiro; Naeshiro, Noriaki; Takahashi, Hironao; Mano, Yutaka; Tsunematsu, Seiji; Yabuuchi, Iwao; Shimada, Yusuke; Yamauchi, Kazuhiko; Sugimoto, Rie; Sakai, Hironori; Mita, Eiji; Koda, Masaharu; Tsuruta, Satoru; Kamitsukasa, Hiroshi; Sato, Takeaki; Masaki, Naohiko; Kobata, Tatsuro; Fukushima, Nobuyoshi; Higuchi, Nobito; Ohara, Yukio; Muro, Toyokichi; Takesaki, Eiichi; Takaki, Hitoshi; Yamamoto, Tetsuo; Kato, Michio; Nagaoki, Yuko; Hayashi, Shigeki; Ishida, Jinya; Watanabe, Yukio; Kobayashi, Masakazu; Koga, Michiaki; Saoshiro, Takeo; Yagura, Michiyasu; Hirata, Keisuke; Takikawa, Hajime; Ohira, Hiromasa; Zeniya, Mikio; Abe, Masanori; Onji, Morikazu; Kaneko, Shuichi; Honda, Masao; Arai, Kuniaki; Arinaga-Hino, Teruko; Hashimoto, Etsuko; Taniai, Makiko; Umemura, Takeji; Joshita, Satoru; Nakao, Kazuhiko; Ichikawa, Tatsuki; Shibata, Hidetaka; Yamagiwa, Satoshi; Seike, Masataka; Honda, Koichi; Sakisaka, Shotaro; Takeyama, Yasuaki; Harada, Masaru; Senju, Michio; Yokosuka, Osamu; Kanda, Tatsuo; Ueno, Yoshiyuki; Kikuchi, Kentaro; Ebinuma, Hirotoshi; Himoto, Takashi; Yasunami, Michio; Murata, Kazumoto; Mizokami, Masashi; Shimoda, Shinji; Miyake, Yasuhiro; Takaki, Akinobu; Yamamoto, Kazuhide; Hirano, Katsuji; Ichida, Takafumi; Ido, Akio; Tsubouchi, Hirohito; Chayama, Kazuaki; Harada, Kenichi; Nakanuma, Yasuni; Maehara, Yoshihiko; Taketomi, Akinobu; Shirabe, Ken; Soejima, Yuji; Mori, Akira; Yagi, Shintaro; Uemoto, Shinji; Tanaka, Tomohiro; Yamashiki, Noriyo; Tamura, Sumito; Sugawara, Yasuhiro; Kokudo, Norihiro. - In: GASTROENTEROLOGY. - ISSN 0016-5085. - ELETTRONICO. - 160:(2021), pp. 2483-2495.e26. [10.1053/j.gastro.2021.02.061]
X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis
Galli, Andrea;Marra, Fabio;Tarocchi, Mirko;
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 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 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 × 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 × 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.
I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
