Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.
Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.
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DOI：
10.1038/nature10251
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发表时间：
2011-08-10
期刊：
影响因子：
64.8
通讯作者：
Compston, Alastair
中科院分区：
文献类型：
--
作者：
Sawcer, Stephen;Hellenthal, Garrett;Pirinen, Matti;Spencer, Chris C. A.;Patsopoulos, Nikolaos A.;Moutsianas, Loukas;Dilthey, Alexander;Su, Zhan;Freeman, Colin;Hunt, Sarah E.;Edkins, Sarah;Gray, Emma;Booth, David R.;Potter, Simon C.;Goris, An;Band, Gavin;Oturai, Annette Bang;Strange, Amy;Saarela, Janna;Bellenguez, Celine;Fontaine, Bertrand;Gillman, Matthew;Hemmer, Bernhard;Gwilliam, Rhian;Zipp, Frauke;Jayakumar, Alagurevathi;Martin, Roland;Leslie, Stephen;Hawkins, Stanley;Giannoulatou, Eleni;D'alfonso, Sandra;Blackburn, Hannah;Boneschi, Filippo Martinelli;Liddle, Jennifer;Harbo, Hanne F.;Perez, Marc L.;Spurkland, Anne;Waller, Matthew J.;Mycko, Marcin P.;Ricketts, Michelle;Comabella, Manuel;Hammond, Naomi;Kockum, Ingrid;McCann, Owen T.;Ban, Maria;Whittaker, Pamela;Kemppinen, Anu;Weston, Paul;Hawkins, Clive;Widaa, Sara;Zajicek, John;Dronov, Serge;Robertson, Neil;Bumpstead, Suzannah J.;Barcellos, Lisa F.;Ravindrarajah, Rathi;Abraham, Roby;Alfredsson, Lars;Ardlie, Kristin;Aubin, Cristin;Baker, Amie;Baker, Katharine;Baranzini, Sergio E.;Bergamaschi, Laura;Bergamaschi, Roberto;Bernstein, Allan;Berthele, Achim;Boggild, Mike;Bradfield, Jonathan P.;Brassat, David;Broadley, Simon A.;Buck, Dorothea;Butzkueven, Helmut;Capra, Ruggero;Carroll, William M.;Cavalla, Paola;Celius, Elisabeth G.;Cepok, Sabine;Chiavacci, Rosetta;Clerget-Darpoux, Francoise;Clysters, Katleen;Comi, Giancarlo;Cossburn, Mark;Cournu-Rebeix, Isabelle;Cox, Mathew B.;Cozen, Wendy;Cree, Bruce A. C.;Cross, Anne H.;Cusi, Daniele;Daly, Mark J.;Davis, Emma;de Bakker, Paul I. W.;Debouverie, Marc;D'hooghe, Marie Beatrice;Dixon, Katherine;Dobosi, Rita;Dubois, Benedicte;Ellinghaus, David;Elovaara, Irina;Esposito, Federica;Fontenille, Claire;Foote, Simon;Franke, Andre;Galimberti, Daniela;Ghezzi, Angelo;Glessner, Joseph;Gomez, Refujia;Gout, Olivier;Graham, Colin;Grant, Struan F. A.;Guerini, Franca Rosa;Hakonarson, Hakon;Hall, Per;Hamsten, Anders;Hartung, Hans-Peter;Heard, Rob N.;Heath, Simon;Hobart, Jeremy;Hoshi, Muna;Infante-Duarte, Carmen;Ingram, Gillian;Ingram, Wendy;Islam, Talat;Jagodic, Maja;Kabesch, Michael;Kermode, Allan G.;Kilpatrick, Trevor J.;Kim, Cecilia;Klopp, Norman;Koivisto, Keijo;Larsson, Malin;Lathrop, Mark;Lechner-Scott, Jeannette S.;Leone, Maurizio A.;Leppa, Virpi;Liljedahl, Ulrika;Bomfim, Izaura Lima;Lincoln, Robin R.;Link, Jenny;Liu, Jianjun;Lorentzen, Aslaug R.;Lupoli, Sara;Macciardi, Fabio;Mack, Thomas;Marriott, Mark;Martinelli, Vittorio;Mason, Deborah;McCauley, Jacob L.;Mentch, Frank;Mero, Inger-Lise;Mihalova, Tania;Montalban, Xavier;Mottershead, John;Myhr, Kjell-Morten;Naldi, Paola;Ollier, William;Page, Alison;Palotie, Aarno;Pelletier, Jean;Piccio, Laura;Pickersgill, Trevor;Piehl, Fredrik;Pobywajlo, Susan;Quach, Hong L.;Ramsay, Patricia P.;Reunanen, Mauri;Reynolds, Richard;Rioux, Johnd.;Rodegher, Mariaemma;Roesner, Sabine;Rubio, Justin P.;Rueckert, Ina-Maria;Salvetti, Marco;Salvi, Erika;Santaniello, Adam;Schaefer, Catherine A.;Schreiber, Stefan;Schulze, Christian;Scott, Rodney J.;Sellebjerg, Finn;Selmaj, Krzysztof W.;Sexton, David;Shen, Ling;Simms-Acuna, Brigid;Skidmore, Sheila;Sleiman, Patrick M. A.;Smestad, Cathrine;Sorensen, Per Soelberg;Sondergaard, Helle Bach;Stankovich, Jim;Strange, Richard C.;Sulonen, Anna-Maija;Sundqvist, Emilie;Syvaenen, Ann-Christine;Taddeo, Francesca;Taylor, Bruce;Blackwell, Jenefer M.;Tienari, Pentti;Bramon, Elvira;Tourbah, Ayman;Brown, Matthew A.;Tronczynska, Ewa;Casas, Juan P.;Tubridy, Niall;Corvin, Aiden;Vickery, Jane;Jankowski, Janusz;Villoslada, Pablo;Markus, Hugh S.;Wang, Kai;Mathew, Christopher G.;Wason, James;Palmer, Colin N. A.;Wichmann, H-Erich;Plomin, Robert;Willoughby, Ernest;Rautanen, Anna;Winkelmann, Juliane;Wittig, Michael;Trembath, Richard C.;Yaouanq, Jacqueline;Viswanathan, Ananth C.;Zhang, Haitao;Wood, Nicholas W.;Zuvich, Rebecca;Deloukas, Panos;Langford, Cordelia;Duncanson, Audrey;Oksenberg, Jorge R.;Pericak-Vance, Margaret A.;Haines, Jonathan L.;Olsson, Tomas;Hillert, Jan;Ivinson, Adrian J.;De Jager, Philip L.;Peltonen, Leena;Stewart, Graeme J.;Hafler, David A.;Hauser, Stephen L.;McVean, Gil;Donnelly, Peter;Compston, Alastair
多发性硬化症（OMIM 126200）是一种常见的中枢神经系统疾病，其中炎症和神经退行性过程之间的相互作用通常导致间歇性神经障碍，随后是残疾的进行性累积。流行病学研究表明，遗传因素是患病个体亲属中患病频率大幅增加的主要原因;系统地试图确定多重家庭中的连锁关系，已证实主要组织相容性复合体（MHC）内的变异对风险产生最大的个体影响。适度动力的全基因组关联研究（GWAS）已经确定了20多个额外的风险位点，并表明多个变异发挥适度的个体效应在疾病易感性中起着关键作用。对这种疾病易感性的大部分遗传结构仍有待确定，预计需要分析的样本量超出了个别研究小组目前可获得的数量。在一项涉及15个不同国家的23个研究小组收集的9772例欧洲血统病例的合作GWAS中，我们几乎复制了所有先前提出的关联，并确定了至少29个新的易感基因座。在MHC内，我们已经完善了DRB 1风险等位基因的身份，并证实HLA-A基因的变异是I类区域的独立保护作用的基础。免疫学相关基因在那些接近所鉴定的基因座的基因中显著过度表达，特别是在多发性硬化症的发病机制中涉及辅助性T细胞分化。
Multiple sclerosis (OMIM 126200) 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 disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals; 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 risk. Modestly powered Genome-Wide Association Studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects play a key role in disease susceptibility. 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 9772 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 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 over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis.
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影响因子：
3.7
作者：
Field J;Browning SR;Johnson LJ;Danoy P;Varney MD;Tait BD;Gandhi KS;Charlesworth JC;Heard RN;Australia and New Zealand Multiple Sclerosis Genetics Consortium;Stewart GJ;Kilpatrick TJ;Foote SJ;Bahlo M;Butzkueven H;Wiley J;Booth DR;Taylor BV;Brown MA;Rubio JP;Stankovich J
通讯作者：
Stankovich J
影响因子：
3.5
作者：
UK Parkinson's Disease Consortium;Wellcome Trust Case Control Consortium 2;Spencer CC;Plagnol V;Strange A;Gardner M;Paisan-Ruiz C;Band G;Barker RA;Bellenguez C;Bhatia K;Blackburn H;Blackwell JM;Bramon E;Brown MA;Brown MA;Burn D;Casas JP;Chinnery PF;Clarke CE;Corvin A;Craddock N;Deloukas P;Edkins S;Evans J;Freeman C;Gray E;Hardy J;Hudson G;Hunt S;Jankowski J;Langford C;Lees AJ;Markus HS;Mathew CG;McCarthy MI;Morrison KE;Palmer CN;Pearson JP;Peltonen L;Pirinen M;Plomin R;Potter S;Rautanen A;Sawcer SJ;Su Z;Trembath RC;Viswanathan AC;Williams NW;Morris HR;Donnelly P;Wood NW
通讯作者：
Wood NW
影响因子：
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作者：
Bielekova, Bibiana;Howard, Thomas;Packer, Amy N.;Richert, Nancy;Blevins, Gregg;Ohayon, Joan;Waldmann, Thomas A.;McFarland, Henry F.;Martin, Roland
通讯作者：
Martin, Roland
影响因子：
2.2
作者：
Hemminki, Kari;Li, Xinjun;Sundquist, Kristina
通讯作者：
Sundquist, Kristina
影响因子：
30.8
作者：
通讯作者：
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