African-derived genetic polymorphisms in TNFAIP3 mediate risk for autoimmunity.
African-derived genetic polymorphisms in TNFAIP3 mediate risk for autoimmunity.
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DOI：
10.4049/jimmunol.1000324
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发表时间：
2010-06-15
期刊：
影响因子：
--
通讯作者：
Boone DL
中科院分区：
文献类型：
--
作者：
Lodolce JP;Kolodziej LE;Rhee L;Kariuki SN;Franek BS;McGreal NM;Logsdon MF;Bartulis SJ;Perera MA;Ellis NA;Adams EJ;Hanauer SB;Jolly M;Niewold TB;Boone DL
TNF α诱导蛋白3（TNFAIP3）是一种泛素修饰酶，是炎症的重要负调节因子。全基因组关联研究表明TNFAIP3基因座与欧洲人群自身免疫性疾病的易感性有关，包括类风湿性关节炎、冠状动脉疾病、银屑病、乳糜泻、1型糖尿病、炎症性肠病和系统性红斑狼疮（SLE）。在TNFAIP3的去泛素化（DUB）结构域中有两个非同义编码多态性：F127 C，与报告的SLE风险变体处于高度连锁不平衡，以及A125 V，以前没有研究过。我们在非裔美国SLE患者中进行了一项病例对照研究，使用这些编码变异，沿着TNFAIP 3的标记多态性，并确定了一种新的非洲来源的风险单倍型，与以前报道的风险变异不同（比值比= 1.6，p = 0.006）。此外，一种罕见的保护性单倍型被定义为A125V（比值比= 0.31，p = 0.027）。尽管A125V与SLE保护相关，但令人惊讶的是，相同的等位基因与炎症性肠病风险增加相关。我们测试了TNFAIP3内非同义编码多态性的功能活性，发现A125V编码改变变体改变了蛋白质的DUB活性。最后，我们使用计算机建模来描述TNFAIP3中A125 V氨基酸的变化如何可能比F127 C更大程度地影响DUB结构域的三维结构。这是TNFAIP3多态性与非裔美国人自身免疫性之间关联的首次报道。
The TNF α-induced protein 3 (TNFAIP3) is an ubiquitin-modifying enzyme and an essential negative regulator of inflammation. Genome-wide association studies have implicated the TNFAIP3 locus in susceptibility to autoimmune disorders in European cohorts, including rheumatoid arthritis, coronary artery disease, psoriasis, celiac disease, type 1 diabetes, inflammatory bowel disease, and systemic lupus erythematosus (SLE). There are two nonsynonymous coding polymorphisms in the deubiquitinating (DUB) domain of TNFAIP3: F127C, which is in high-linkage disequilibrium with reported SLE-risk variants, and A125V, which has not been previously studied. We conducted a case–control study in African-American SLE patients using these coding variants, along with tagging polymorphisms in TNFAIP3, and identified a novel African-derived risk haplotype that is distinct from previously reported risk variants (odds ratio = 1.6, p = 0.006). In addition, a rare protective haplotype was defined by A125V (odds ratio = 0.31, p = 0.027). Although A125V was associated with protection from SLE, surprisingly the same allele was associated with increased risk of inflammatory bowel disease. We tested the functional activity of nonsynonymous coding polymorphisms within TNFAIP3, and found that the A125V coding-change variant alters the DUB activity of the protein. Finally, we used computer modeling to depict how the A125V amino acid change in TNFAIP3 may affect the three-dimensional structure of the DUB domain to a greater extent than F127C. This is the first report of an association between TNFAIP3 polymorphisms and autoimmunity in African-Americans.
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影响因子：
30.8
作者：
Nair RP;Duffin KC;Helms C;Ding J;Stuart PE;Goldgar D;Gudjonsson JE;Li Y;Tejasvi T;Feng BJ;Ruether A;Schreiber S;Weichenthal M;Gladman D;Rahman P;Schrodi SJ;Prahalad S;Guthery SL;Fischer J;Liao W;Kwok PY;Menter A;Lathrop GM;Wise CA;Begovich AB;Voorhees JJ;Elder JT;Krueger GG;Bowcock AM;Abecasis GR;Collaborative Association Study of Psoriasis
通讯作者：
Collaborative Association Study of Psoriasis
影响因子：
64.8
作者：
Frazer, Kelly A.;Ballinger, Dennis G.;Cox, David R.;Hinds, David A.;Stuve, Laura L.;Gibbs, Richard A.;Belmont, John W.;Boudreau, Andrew;Hardenbol, Paul;Leal, Suzanne M.;Pasternak, Shiran;Wheeler, David A.;Willis, Thomas D.;Yu, Fuli;Yang, Huanming;Zeng, Changqing;Gao, Yang;Hu, Haoran;Hu, Weitao;Li, Chaohua;Lin, Wei;Liu, Siqi;Pan, Hao;Tang, Xiaoli;Wang, Jian;Wang, Wei;Yu, Jun;Zhang, Bo;Zhang, Qingrun;Zhao, Hongbin;Zhao, Hui;Zhou, Jun;Gabriel, Stacey B.;Barry, Rachel;Blumenstiel, Brendan;Camargo, Amy;Defelice, Matthew;Faggart, Maura;Goyette, Mary;Gupta, Supriya;Moore, Jamie;Nguyen, Huy;Onofrio, Robert C.;Parkin, Melissa;Roy, Jessica;Stahl, Erich;Winchester, Ellen;Ziaugra, Liuda;Altshuler, David;Shen, Yan;Yao, Zhijian;Huang, Wei;Chu, Xun;He, Yungang;Jin, Li;Liu, Yangfan;Shen, Yayun;Sun, Weiwei;Wang, Haifeng;Wang, Yi;Wang, Ying;Xiong, Xiaoyan;Xu, Liang;Waye, Mary M. Y.;Tsui, Stephen K. W.;Wong, J. Tze-Fei;Galver, Luana M.;Fan, Jian-Bing;Gunderson, Kevin;Murray, Sarah S.;Oliphant, Arnold R.;Chee, Mark S.;Montpetit, Alexandre;Chagnon, Fanny;Ferretti, Vincent;Leboeuf, Martin;Olivier, Jean-Franccois;Phillips, Michael S.;Roumy, Stephanie;Sallee, Clementine;Verner, Andrei;Hudson, Thomas J.;Kwok, Pui-Yan;Cai, Dongmei;Koboldt, Daniel C.;Miller, Raymond D.;Pawlikowska, Ludmila;Taillon-Miller, Patricia;Xiao, Ming;Tsui, Lap-Chee;Mak, William;Song, You Qiang;Tam, Paul K. H.;Nakamura, Yusuke;Kawaguchi, Takahisa;Kitamoto, Takuya;Morizono, Takashi;Nagashima, Atsushi;Ohnishi, Yozo;Sekine, Akihiro;Tanaka, Toshihiro;Tsunoda, Tatsuhiko;Deloukas, Panos;Bird, Christine P.;Delgado, Marcos;Dermitzakis, Emmanouil T.;Gwilliam, Rhian;Hunt, Sarah;Morrison, Jonathan;Powell, Don;Stranger, Barbara E.;Whittaker, Pamela;Bentley, David R.;Daly, Mark J.;de Bakker, Paul I. W.;Barrett, Jeff;Chretien, Yves R.;Maller, Julian;McCarroll, Steve;Patterson, Nick;Pe'er, Itsik;Price, Alkes;Purcell, Shaun;Richter, Daniel J.;Sabeti, Pardis;Saxena, Richa;Schaffner, Stephen F.;Sham, Pak C.;Varilly, Patrick;Altshuler, David;Stein, Lincoln D.;Krishnan, Lalitha;Smith, Albert Vernon;Tello-Ruiz, Marcela K.;Thorisson, Gudmundur A.;Chakravarti, Aravinda;Chen, Peter E.;Cutler, David J.;Kashuk, Carl S.;Lin, Shin;Abecasis, Goncalo R.;Guan, Weihua;Li, Yun;Munro, Heather M.;Qin, Zhaohui Steve;Thomas, Daryl J.;McVean, Gilean;Auton, Adam;Bottolo, Leonardo;Cardin, Niall;Eyheramendy, Susana;Freeman, Colin;Marchini, Jonathan;Myers, Simon;Spencer, Chris;Stephens, Matthew;Donnelly, Peter;Cardon, Lon R.;Clarke, Geraldine;Evans, David M.;Morris, Andrew P.;Weir, Bruce S.;Tsunoda, Tatsuhiko;Johnson, Todd A.;Mullikin, James C.;Sherry, Stephen T.;Feolo, Michael;Skol, Andrew
通讯作者：
Skol, Andrew
影响因子：
7.7
作者：
Boonyasrisawat, Watip;Eberle, Delphine;Doria, Alessandro
通讯作者：
Doria, Alessandro
影响因子：
56.9
作者：
Lee, EG;Boone, DL;Ma, A
通讯作者：
Ma, A
6q23 上 TNFAIP3 附近的遗传变异与系统性红斑狼疮相关。
影响因子：
30.8
作者：
Graham, Robert R.;Cotsapas, Chris;Davies, Leela;Hackett, Rachel;Lessard, Christopher J.;Leon, Joanlise M.;Burtt, Noel P.;Guiducci, Candace;Parkin, Melissa;Gates, Casey;Plenge, Robert M.;Behrens, Timothy W.;Wither, Joan E.;Rioux, John D.;Fortin, Paul R.;Graham, Deborah Cunninghame;Wong, Andrew K.;Vyse, Timothy J.;Daly, Mark J.;Altshuler, David;Moser, Kathy L.;Gaffney, Patrick M.
通讯作者：
Gaffney, Patrick M.