Variants in TRIM22 That Affect NOD2 Signaling Are Associated With Very-Early-Onset Inflammatory Bowel Disease.
Variants in TRIM22 That Affect NOD2 Signaling Are Associated With Very-Early-Onset Inflammatory Bowel Disease.
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DOI：
10.1053/j.gastro.2016.01.031
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发表时间：
2016-05
期刊：
影响因子：
29.4
通讯作者：
Muise AM
中科院分区：
文献类型：
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作者：
Li Q;Lee CH;Peters LA;Mastropaolo LA;Thoeni C;Elkadri A;Schwerd T;Zhu J;Zhang B;Zhao Y;Hao K;Dinarzo A;Hoffman G;Kidd BA;Murchie R;Al Adham Z;Guo C;Kotlarz D;Cutz E;Walters TD;Shouval DS;Curran M;Dobrin R;Brodmerkel C;Snapper SB;Klein C;Brumell JH;Hu M;Nanan R;Snanter-Nanan B;Wong M;Le Deist F;Haddad E;Roifman CM;Deslandres C;Griffiths AM;Gaskin KJ;Uhlig HH;Schadt EE;Muise AM
在非常年幼的儿童中发展的严重形式的炎症性肠病（IBD）可能由单个基因的变异引起。我们进行了全外显子序列（WES）分析，以确定可能导致肉芽肿性结肠炎和严重的肛周疾病，反复细菌和病毒感染，在一个婴儿的近亲父母的遗传因素。我们对从患者及其父母身上收集的DNA进行了有针对性的WES分析。我们通过对来自多伦多、牛津和慕尼黑的150例与已知遗传因素无关的极早发型IBD患者的DNA进行类似分析，验证了我们的发现。我们比较了从参加乌司奴单抗试验的耐药克罗恩病患者中收集的发炎与非发炎肠道和直肠组织中的基因表达特征。我们对来自患者和细胞培养物的原代细胞中鉴定的变体进行了功能研究。我们在患者的包含22个基因（TRIM 22）的三部分基序中鉴定了一个纯合变体，以及2名具有疾病相似表型的患者。功能研究表明，该变体破坏了TRIM 22调节含核苷酸结合寡聚化结构域2（NOD 2）依赖性干扰素β信号传导和NF-κB活化的能力。计算研究表明TRIM 22-NOD 2网络与信号通路和遗传因素之间存在相关性，这些遗传因素与极早发作和成人发作IBD相关。该网络还与抗病毒和分枝杆菌效应物以及炎症标记物如粪便钙卫蛋白、c反应蛋白和克罗恩病活动指数评分相关。在WES和有针对性的外显子序列分析的婴儿严重IBD，其特征在于肉芽肿性结肠炎和严重的肛周疾病，我们确定了TRIM 22的纯合变体，影响其产品的能力，以调节NOD 2。结合计算和功能研究表明，TRIM 22-NOD 2网络调节有助于炎症的抗病毒和抗菌信号通路。对该网络的进一步研究可能会为极早期和成人发病的IBD患者带来新的疾病标志物和治疗靶点。
Severe forms of inflammatory bowel disease (IBD) that develop in very young children can be caused by variants in a single gene. We performed whole-exome sequence (WES) analysis to identify genetic factors that might cause granulomatous colitis and severe perianal disease, with recurrent bacterial and viral infections, in an infant of consanguineous parents. We performed targeted WES analysis of DNA collected from the patient and her parents. We validated our findings by a similar analysis of DNA from 150 patients with very early onset IBD not associated with known genetic factors analyzed in Toronto, Oxford, and Munich. We compared gene expression signatures in inflamed vs. non-inflamed intestinal and rectal tissues collected from patients with treatment-resistant Crohn's disease who participated in a trial of ustekinumab. We performed functional studies of identified variants in primary cells from patients and cell culture. We identified a homozygous variant in the tripartite motif containing 22 gene (TRIM22) of the patient, as well as in 2 patients with a disease similar phenotype. Functional studies showed that the variant disrupted the ability of TRIM22 to regulate nucleotide binding oligomerization domain containing 2 (NOD2)-dependent activation of interferon-beta signaling and NF-κB. Computational studies demonstrated a correlation between the TRIM22–NOD2 network and signaling pathways and genetic factors associated very early onset and adult-onset IBD. The network also associated with antiviral and mycobacterial effectors and markers of inflammation such as fecal calprotectin, c-reactive protein, and Crohn's disease activity index scores. In WES and targeted exome sequence analyses of an infant with severe IBD, characterized by granulomatous colitis and severe perianal disease, we identified a homozygous variant of TRIM22 that affect the ability of its product to regulate NOD2. Combined computational and functional studies showed that the TRIM22–NOD2 network regulates antiviral and anti-bacterial signaling pathways that contribute to inflammation. Further study of this network could lead to new disease markers and therapeutic targets for patients with very early and adult-onset IBD.