A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF.
A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF.
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DOI：
10.1053/j.gastro.2016.06.045
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发表时间：
2016-10
期刊：
影响因子：
29.4
通讯作者：
Cho JH
中科院分区：
文献类型：
--
作者：
Chuang LS;Villaverde N;Hui KY;Mortha A;Rahman A;Levine AP;Haritunians T;Evelyn Ng SM;Zhang W;Hsu NY;Facey JA;Luong T;Fernandez-Hernandez H;Li D;Rivas M;Schiff ER;Gusev A;Schumm LP;Bowen BM;Sharma Y;Ning K;Remark R;Gnjatic S;Legnani P;George J;Sands BE;Stempak JM;Datta LW;Lipka S;Katz S;Cheifetz AS;Barzilai N;Pontikos N;Abraham C;Dubinsky MJ;Targan S;Taylor K;Rotter JI;Scherl EJ;Desnick RJ;Abreu MT;Zhao H;Atzmon G;Pe'er I;Kugathasan S;Hakonarson H;McCauley JL;Lencz T;Darvasi A;Plagnol V;Silverberg MS;Muise AM;Brant SR;Daly MJ;Segal AW;Duerr RH;Merad M;McGovern DP;Peter I;Cho JH
克罗恩病（CD）在德系犹太人中的患病率最高。我们试图确定罕见的，CD相关的高功能和统计学效应的移码变体。我们对1477名患有CD的德系犹太人和2614名没有CD的德系犹太人（对照）进行了外显子组测序和基于阵列的基因型分析。为了验证我们的发现，我们对另外1515例CD病例和7052例对照进行了基因型分析，以检测殖民地刺激因子2受体β共同亚基基因（CSF 2 RB）中的移码突变。从CD患者中采集肠组织和血液样本;分离固有层白细胞，并通过质谱细胞术（CyTOF分析）确定CSF 2 RB和GMCSF应答细胞的表达。将CSF 2 RB的变体转染到HEK 293细胞中，并比较基因产物的表达和功能。在发现队列中，我们将CD与CSF 2 RB中的移码突变相关联（P=8.52×10-4）;该结果在复制队列中得到验证（合并P=3.42×10-6）。肠固有层白细胞与GMCSF的孵育导致STAT 5的高水平磷酸化和ERK和AKT的磷酸化的较小增加。与用对照CSF 2 RB转染的细胞相比，用全长和突变形式的CSF 2 RB共转染的细胞在用GMCSF刺激后具有减少的pSTAT 5，表明突变基因的显性负效应。来自移码突变杂合子CD患者的单核细胞（分析的CD病例的6%）对GMCSF的反应降低，醛脱氢酶活性显著降低;该酶的活性与免疫耐受相关。在德系犹太人个体的遗传分析中，我们将CD与CSF 2 RB中的移码突变相关联。来自该突变携带者的肠单核细胞对GMCSF的反应降低，这为CD患者先天免疫反应的改变提供了另一种机制。克罗恩病相关的CSF 2 RB移码突变导致STAT 5激活以显性负性方式降低。
Crohn’s disease (CD) has the highest prevalence in Ashkenazi Jewish populations. We sought to identify rare, CD-associated frameshift variants of high functional and statistical effects. We performed exome-sequencing and array-based genotype analyses of 1477 Ashkenazi Jewish individuals with CD and 2614 Ashkenazi Jewish individuals without CD (controls). To validate our findings, we performed genotype analyses of an additional 1515 CD cases and 7052 controls for frameshift mutations in the colony stimulating factor 2 receptor beta common subunit gene (CSF2RB). Intestinal tissues and blood samples were collected from patients with CD; lamina propria leukocytes were isolated and expression of CSF2RB and GMCSF-responsive cells were defined by mass cytometry (CyTOF analysis). Variants of CSF2RB were transfected into HEK293 cells and expression and functions of gene products were compared. In the discovery cohort, we associated CD with a frameshift mutation in CSF2RB (P=8.52×10–4); the finding was validated in the replication cohort (combined P=3.42×10–6). Incubation of intestinal lamina propria leukocytes with GMCSF resulted in high levels of phosphorylation of STAT5 and lesser increases in phosphorylation of ERK and AKT. Cells co-transfected with full-length and mutant forms of CSF2RB had reduced pSTAT5 following stimulation with GMCSF, compared to cells transfected with control CSF2RB, indicating a dominant negative effect of the mutant gene. Monocytes from patients with CD who were heterozygous for the frameshift mutation (6% of CD cases analyzed) had reduced responses to GMCSF and markedly decreased activity of aldehyde dehydrogenase; activity of this enzyme has been associated with immune tolerance. In a genetic analysis of Ashkenazi Jewish individuals, we associated CD with a frameshift mutation in CSF2RB. Intestinal monocytes from carriers of this mutation had reduced responses to GMCSF, providing an additional mechanism for alterations to the innate immune response in individuals with CD. Crohn’s disease associated frameshift mutation in CSF2RB results in decreased STAT5 activation in a dominant negative manner.
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DOI：
10.1084/jem.20091683
发表时间：
2009-08-31
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Casanova JL;Abel L
通讯作者：
Abel L
MOR103，一种对粒细胞巨噬细胞刺激因子的人类单克隆抗体，用于治疗中等类风湿关节炎患者：IB/IIA期随机，双盲，安慰剂对照，剂量 - 剂量 - 降低试验的结果。
影响因子：
27.4
作者：
Behrens F;Tak PP;Østergaard M;Stoilov R;Wiland P;Huizinga TW;Berenfus VY;Vladeva S;Rech J;Rubbert-Roth A;Korkosz M;Rekalov D;Zupanets IA;Ejbjerg BJ;Geiseler J;Fresenius J;Korolkiewicz RP;Schottelius AJ;Burkhardt H
通讯作者：
Burkhardt H
影响因子：
29.4
作者：
Han X;Uchida K;Jurickova I;Koch D;Willson T;Samson C;Bonkowski E;Trauernicht A;Kim MO;Tomer G;Dubinsky M;Plevy S;Kugathsan S;Trapnell BC;Denson LA
通讯作者：
Denson LA
影响因子：
8
作者：
Dijkers, PF;van Dijk, TB;Coffer, PJ
通讯作者：
Coffer, PJ
白细胞GM-CSF受体（CD116）表达和功能缺陷在炎症性肠病中。
影响因子：
29.4
作者：
Goldstein JI;Kominsky DJ;Jacobson N;Bowers B;Regalia K;Austin GL;Yousefi M;Falta MT;Fontenot AP;Gerich ME;Golden-Mason L;Colgan SP
通讯作者：
Colgan SP