Single nucleotide polymorphisms that increase expression of the guanosine triphosphatase RAC1 are associated with ulcerative colitis.
Single nucleotide polymorphisms that increase expression of the guanosine triphosphatase RAC1 are associated with ulcerative colitis.
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DOI：
10.1053/j.gastro.2011.04.057
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发表时间：
2011-08
期刊：
影响因子：
29.4
通讯作者：
Brumell JH
中科院分区：
文献类型：
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作者：
Muise AM;Walters T;Xu W;Shen-Tu G;Guo CH;Fattouh R;Lam GY;Wolters VM;Bennitz J;van Limbergen J;Renbaum P;Kasirer Y;Ngan BY;Turner D;Denson LA;Sherman PM;Duerr RH;Cho J;Lees CW;Satsangi J;Wilson DC;Paterson AD;Griffiths AM;Glogauer M;Silverberg MS;Brumell JH
RAC 1是一种GT3，在协调从植物到哺乳动物的免疫防御中具有进化上保守的作用。慢性炎症性肠病（IBD）与免疫防御失调有关。我们使用人类遗传和功能研究以及结肠炎动物模型研究了RAC 1在IBD中的作用。我们在一个发现队列中使用了HapMap-Tag单核苷酸多态性（SNP）的候选基因方法;在另外2个队列中证实了研究结果。检测患者外周血细胞中RAC 1 mRNA的表达。通过给予葡聚糖硫酸钠（DSS）在吞噬细胞中有条件地破坏Rac 1，在小鼠中诱导结肠炎。我们在发现队列、2个独立复制队列以及SNP rs 10951982的联合分析中观察到RAC 1与溃疡性结肠炎（UC）之间的遗传关联（P合并UC = 3.3 × 10-8，OR =1.43 [1.26-1.63]）和rs 4720672（P合并UC=4.7 × 10-6，OR=1.36 [1.19-1.58]）。与没有rs 10951982等位基因的IBD患者相比，具有该等位基因的IBD患者具有增加的RAC 1表达。小鼠巨噬细胞和中性粒细胞中Rac 1的条件性破坏保护它们免受DSS诱导的结肠炎。对人体组织样本和基因敲除小鼠的研究表明，GTdR RAC 1在UC的发展中发挥作用; RAC 1表达增加与结肠炎易感性相关。
RAC1 is a GTPase that has an evolutionarily conserved role in coordinating immune defenses, from plants to mammals. Chronic inflammatory bowel diseases (IBD) are associated with dysregulation of immune defenses. We studied the role of RAC1 in IBD using human genetic and functional studies and animal models of colitis. We used a candidate gene approach to HapMap-Tag single nucleotide polymorphisms (SNPs) in a discovery cohort; findings were confirmed in 2 additional cohorts. RAC1 mRNA expression was examined from peripheral blood cells of patients. Colitis was induced in mice with conditional disruption of Rac1 in phagocytes by administration of dextran sulphate sodium (DSS). We observed a genetic association between RAC1 with ulcerative colitis (UC) in a discovery cohort, 2 independent replication cohorts, and in combined analysis for the SNPs rs10951982 (Pcombined UC = 3.3 × 10–8, odds ratio [OR]=1.43 [1.26–1.63]) and rs4720672 (Pcombined UC=4.7 × 10–6, OR=1.36 [1.19–1.58]). Patients with IBD who had the rs10951982 risk allele had increased expression of RAC1, compared to those without this allele. Conditional disruption of Rac1 in macrophage and neutrophils of mice protected them against DSS-induced colitis. Studies of human tissue samples and knockout mice demonstrated a role for the GTPase RAC1 in the development of UC; increased expression of RAC1 was associated with susceptibility to colitis.
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影响因子：
30.8
作者：
通讯作者：
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影响因子：
30.8
作者：
Imielinski, Marcin;Baldassano, Robert N.;Griffiths, Anne;Russell, Richard K.;Annese, Vito;Dubinsky, Marla;Kugathasan, Subra;Bradfield, Jonathan P.;Walters, Thomas D.;Sleiman, Patrick;Kim, Cecilia E.;Muise, Aleixo;Wang, Kai;Glessner, Joseph T.;Saeed, Shehzad;Zhang, Haitao;Frackelton, Edward C.;Hou, Cuiping;Flory, James H.;Otieno, George;Chiavacci, Rosetta M.;Grundmeier, Robert;Castro, Massimo;Latiano, Anna;Dallapiccola, Bruno;Stempak, Joanne;Abrams, Debra J.;Taylor, Kent;McGovern, Dermot;Heyman, Melvin B.;Ferry, George D.;Kirschner, Barbara;Lee, Jessica;Essers, Jonah;Grand, Richard;Stephens, Michael;Levine, Arie;Piccoli, David;Van Limbergen, Johan;Cucchiara, Salvatore;Monos, Dimitri S.;Guthery, Stephen L.;Denson, Lee;Wilson, David C.;Grant, Struan F. A.;Daly, Mark;Silverberg, Mark S.;Satsangi, Jack;Hakonarson, Hakon
通讯作者：
Hakonarson, Hakon
影响因子：
30.8
作者：
de Bakker, PIW;Yelensky, R;Altshuler, D
通讯作者：
Altshuler, D
影响因子：
30.8
作者：
Hampe, Jochen;Franke, Andre;Schreiber, Stefan
通讯作者：
Schreiber, Stefan
影响因子：
11.6
作者：
Nakashima, Ayako;Chen, Letian;Shimamoto, Ko
通讯作者：
Shimamoto, Ko