CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease
CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease
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DOI：
10.1086/339432
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发表时间：
2002-04-01
影响因子：
9.8
通讯作者：
Hugot, JP
中科院分区：
文献类型：
--
作者：
Lesage, S;Zouali, H;Hugot, JP
CARD15/NOD2编码一种参与单核细胞识别细菌的蛋白质。最近在克罗恩病(CD)患者中发现了CARD15突变，CD是一种慢性消化道炎症性疾病。本文报道了453例CD患者的CARD15基因突变分析，其中散发性166例，家族性287例，溃疡性结肠炎159例，健康对照组103例。在识别的67个序列变异中，有9个在CD患者中有5%的等位基因频率。其中6个被认为是多态，3个(R702W、G908R和1007fs)被证实与Cd的易感性独立相关。27个罕见的额外突变也被认为是潜在的致病突变(DCM)。三个主要突变(R702W、G908R和1007fs)分别占CD突变总数的32%、18%和31%，而27个罕见突变的总和占DCMS的19%。总体而言，93%的突变位于该基因的远端三分之一。未发现与UC相关的突变。相比之下，50%的CD患者至少携带一种DCM，其中17%的患者具有双突变。这一观察证实了CD的基因剂量效应。与无突变的患者相比，具有双剂量突变的患者具有以下特点：发病年龄更早(16.9岁比19.8岁)，狭窄表型更常见(53%比28%；P=0.00003；优势比2.92)，结肠受累更少(43%比62%；优势比0.44)。疾病的严重程度和肠外表现在任何CARD15基因型中都没有不同。在有或无突变的CD患者组中，家族性和散发性病例的比例以及有吸烟习惯的患者比例相似。这些发现为基于DNA的易感性测试和炎症性肠病的遗传咨询提供了工具。
CARD15/NOD2 encodes a protein involved in bacterial recognition by monocytes. Mutations in CARD15 have recently been found in patients with Crohn disease (CD), a chronic inflammatory condition of the digestive tract. Here, we report the mutational analyses of CARD15 in 453 patients with CD, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (UC), and 103 healthy control subjects. Of 67 sequence variations identified, 9 had an allele frequency >5% in patients with CD. Six of them were considered to be polymorphisms, and three (R702W, G908R, and 1007fs) were confirmed to be independently associated with susceptibility to CD. Also considered as potential disease-causing mutations (DCMs) were 27 rare additional mutations. The three main variants (R702W, G908R, and 1007fs) represented 32%, 18%, and 31%, respectively, of the total CD mutations, whereas the total of the 27 rare mutations represented 19% of DCMs. Altogether, 93% of the mutations were located in the distal third of the gene. No mutations were found to be associated with UC. In contrast, 50% of patients with CD carried at least one DCM, including 17% who had a double mutation. This observation confirmed the gene-dosage effect in CD. The patients with double-dose mutations were characterized by a younger age at onset (16.9 years vs. 19.8 years;), a more frequent stricturing phenotype (53% vs. 28%; P = .00003; odds ratio 2.92), and a less frequent colonic involvement (43% vs. 62%; odds ratio 0.44) than were seen in those patients who had no mutation. The severity of the disease and extraintestinal manifestations were not different for any of the CARD15 genotypes. The proportion of familial and sporadic cases and the proportion of patients with smoking habits were similar in the groups of patients with CD with or without mutation. These findings provide tools for a DNA-based test of susceptibility and for genetic counseling in inflammatory bowel disease.