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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

2011; Nature Portfolio; Volume: 476; Issue: 7359 Linguagem: Inglês

10.1038/nature10251

1476-4687

Stephen Sawcer, Garrett Hellenthal, Matti Pirinen, Chris C. A. Spencer, Nikolaos A. Patsopoulos, Loukas Moutsianas, Alexander Dilthey, Zhan Su, Colin Freeman, Sarah Hunt, Sarah Edkins, Emma Gray, David R. Booth, Simon Potter, An Goris, Gavin Band, Annette Oturai, Amy Strange, Janna Saarela, Céline Bellenguez, Bertrand Fontaine, Matthew Gillman, Bernhard Hemmer, Rhian Gwilliam, Frauke Zipp, Alagurevathi Jayakumar, Roland Martinꝉ, Stephen Leslie, Stanley Hawkins, Eleni Giannoulatou, Sandra D’Alfonso, Hannah Blackburn, Filippo Martinelli Boneschi, Jennifer Liddle, Hanne F. Harbo, M. L. Perez, Anne Spurkland, Matthew Waller, Marcin P. Mycko, Michelle Ricketts, Manuel Comabella, Naomi Hammond, Ingrid Kockum, Owen T McCann, Maria Ban, Pamela Whittaker, Anu Kemppinen, Paul A. Weston, Clive Hawkins, Sara Widaa, John Zajicek, Serge Dronov, Neil P. Robertson, Suzannah J. Bumpstead, Lisa F. Barcellos, Rathi Ravindrarajah, Roby Abraham, Lars Alfredsson, Kristin Ardlie, Cristin Aubin, Amie Baker, K. Baker, Sergio E. Baranzini, Laura Bergamaschi, Roberto Bergamaschi, Allan Bernstein, Achim Berthele, Mike Boggild, Jonathan P. Bradfield, David Brassat, Simon Broadley, Dorothea Buck, Helmut Butzkueven, Ruggero Capra, William M. Carroll, Paola Cavalla, Elisabeth Gulowsen Celius, Sabine Cepok, Rosetta Chiavacci, Françoise Clerget‐Darpoux, Katleen Clysters, Gıancarlo Comı, M. Cossburn, Isabelle Cournu‐Rebeix, Mathew Cox, Wendy Cozen, Bruce Cree, Anne H. Cross, Daniele Cusi, Mark J. Daly, Emma Davis, Paul I. W. de Bakker, Marc Debouverie, Marie D’hooghe, Katherine Dixon, Rita Dobosi, Bénédicte Dubois, David Ellinghaus, Irina Elovaara, Federica Esposito, Claire Fontenille, Simon J. Foote, André Franke, Daniela Galimberti, Angelo Ghezzi, Joseph Glessner, Refujia Gomez, Olivier Gout, Colin A. Graham, Struan F.A. Grant, Franca Rosa Guerini, Hákon Hákonarson, Per Hall, Anders Hamsten, Hans Peter Hartung, Rob N. Heard, Simon Heath, Jeremy Hobart, Muna Hoshi, Carmen Infante‐Duarte, Gillian Ingram, Wendy Ingram, Talat Islam, Maja Jagodic, Michael Kabesch, Allan G. Kermode, Trevor J. Kilpatrick, Cecilia Kim, Norman Klopp, Keijo Koivisto, Malin Larsson, Mark Lathrop, Jeannette Lechner‐Scott, Maurizio Leone, Virpi Leppä, Ulrika Liljedahl, Izaura Lima Bomfim, Robin Lincoln, Jenny Link, Jianjun Liu, Åslaug Rudjord Lorentzen, Sara Lupoli, Fabìo Macciardi, Thomas M. Mack, Mark Marriott, Vittorio Martinelli, Deborah Mason, Jacob L. McCauley, Frank Mentch, I.-L. Mero, Tania Mihalova, Xavier Montalbán, John Mottershead, Kjell Morten Myhr, Paola Naldi, William Ollier, Alison Page, Aarno Palotie, Jean Pelletier, Laura Piccio, Trevor Pickersgill, Fredrik Piehl, Susan Pobywajlo, Hong Quach, Patricia P. Ramsay, Mauri Reunanen, Richard Reynolds, John D. Rioux, Mariaemma Rodegher, Sabine Roesner, Justin P. Rubio, I.-M. Ruckert, Marco Salvetti, Erika Salvi, Adam Santaniello, Catherine Schaefer, Stefan Schreiber, Christian Schulze, Rodney J. Scott, Finn Sellebjerg, Krzysztof Selmaj, David Sexton, Ling Shen, Brigid Simms-Acuna, Sheila Skidmore, Patrick Sleiman, C. Smestad, Per Soelberg Sørensen, Helle Bach Søndergaard, Jim Stankovich, Richard C. Strange, Anna-Maija Sulonen, Emilie Sundqvist, Ann Christine Syvänen, Francesca De Taddeo, Bruce Taylor, Jenefer M. Blackwell, Pentti J. Tienari, Elvira Bramon, Ayman Tourbah, Matthew A. Brown, E. Tronczyńska, Juan P. Casas, Niall Tubridy, Aiden Corvin, Jane Vickery, Janusz Jankowski, Pablo Villoslada, Hugh S. Markus, Kai Wang, Christopher G. Mathew, James Wason, Nicholette D. Palmer, Erich Wichmann, Robert Plomin, Ernest Willoughby, Anna Rautanen, Juliane Winkelmann, Michael Wittig, Richard C. Trembath, Jacqueline Yaouanq, Ananth C. Viswanathan, Haitao Zhang, Nicholas Wood, Rebecca L. Zuvich, Panos Deloukas, Cordelia Langford, Audrey Duncanson, Jorge R. Oksenberg, Margaret A. Pericak‐Vance, Jonathan L. Haines, Tomas Olsson, Jan Hillert, Adrian J. Ivinson, Philip L. De Jager, Leena Peltonen, Graeme J. Stewart, David A. Hafler, Stephen L. Hauser, Gil McVean, Peter Donnelly, Alastair Compston,

Cytokine Signaling Pathways and Interactions

Multiple sclerosis is a disease of the central nervous system that involves interplay between inflammation and neurodegeneration. Despite intensive study, much of the genetic architecture underlying susceptibility to the disease remains to be defined. A large, international, collaborative genome-wide association study involving almost 10,000 cases, all of European descent, has confirmed about 20 previously reported multiple-sclerosis-linked regions of DNA, and identified an additional 29 novel susceptibility loci. Further analysis implicates the differentiation of T-helper cells as particularly relevant to the pathogenesis of this disease. Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability1. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals2,3, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk4. Modestly powered genome-wide association studies (GWAS)5,6,7,8,9,10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility11. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.