Homozygosity for the CARD15 frameshift mutation 1007fs is predictive of early onset of Crohn's disease with ileal stenosis, entero-enteral fistulas, and frequent need for surgical intervention with high risk of re-stenosis
Homozygosity for the CARD15 frameshift mutation 1007fs is predictive of early onset of Crohn's disease with ileal stenosis, entero-enteral fistulas, and frequent need for surgical intervention with high risk of re-stenosis
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DOI：
10.1080/00365520600703900
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发表时间：
2006-12-01
影响因子：
1.9
通讯作者：
Ochsenkuhn, Thomas
中科院分区：
文献类型：
--
作者：
Seiderer, Julia;Schnitzler, Fabian;Ochsenkuhn, Thomas
Objective. CARD 15作为克罗恩病（CD）易感基因的鉴定为患者分类和风险评估提供了新的可能性。本研究的目的是在一个大型单中心IBD队列中进行CARD 15序列分析，并研究不同基因型对疾病表型的影响。材料和方法。共445例无关IBD患者（68.1% CD，28.5%溃疡性结肠炎（UC），3.4%不确定性结肠炎（IC））被纳入研究。通过详细的问卷调查和图表分析记录临床数据。通过DNA序列分析鉴定CARD 15变体（R702 W、G908 R、1007 fs（移码））。结果在142例炎症性肠病（IBD）患者（31.9%）中发现了CARD 15变异，其中包括120例CD患者（39.6%）。在CD中，两种CARD 15变体的存在与回肠疾病（p = 0.008 vs野生型（wt）; OR 4.04; 95% CI 1.36-11.96）和纤维狭窄表型（p = 0.002 vs wt; OR 5.47; 95% CI 1.61-18.58）相关。对19名CARD 15变异体1007 fs（3020 ins C）纯合子患者（4.3%）进行的亚组分析显示，CD发病年龄较早（p = 0.014 vs wt）、回肠受累（p = 0.001）和所有患者肠狭窄（p = 0.001）频繁需要手术（73.7%; p = 0.093）。在这些患者中，78.6%在手术切除后出现再狭窄; 52.6%的纯合子被诊断为肠-肠瘘。结论. 1007 fs突变纯合子的患者发病较早，有长段回肠狭窄和肠-肠瘘。他们经常需要手术干预，并有很高的再狭窄风险。因此，基因分型似乎是一个重要的诊断工具，在确定严重影响的患者需要个性化的治疗策略，在疾病的早期阶段。
Objective. The identification of CARD15 as a susceptibility gene for Crohn's disease (CD) offers new possibilities for patient classification and risk assessment. The purpose of this study was to carry out a CARD15 sequence analysis in a large single-center IBD cohort and to investigate the impact of different genotypes on disease phenotypes. Material and methods. A total of 445 unrelated patients with IBD (68.1% CD, 28.5% ulcerative colitis (UC), 3.4% indeterminate colitis (IC)) were included in the study. Clinical data were recorded by detailed questionnaire and analysis of the charts. CARD15 variants (R702W, G908R, 1007fs (frameshift)) were identified by DNA sequence analysis. Results. CARD15 variants were found in 142 inflammatory bowel disease (IBD) patients (31.9%) including 120 CD patients (39.6%). In CD, the presence of two CARD15 variants was associated with ileal disease (p = 0.008 versus wild-type (wt); OR 4.04; 95% CI 1.36-11.96) and a fibrostenotic phenotype (p = 0.002 versus wt; OR 5.47; 95% CI 1.61-18.58). Subgroup analysis of 19 patients (4.3%) homozygous for the CARD15 variant 1007fs (3020ins C) revealed an association with onset of CD at an early age (p = 0.014 versus wt), ileal involvement (p = 0.001), and intestinal stenoses in all patients (p = 0.001) frequently requiring surgery (73.7%; p = 0.093). Of these patients 78.6% developed re-stenoses after surgical resection; 52.6% of the homozygotes were diagnosed as having entero-enteral fistulas. Conclusions. Patients homozygous for the 1007fs mutation had an early disease onset with long-segment ileal stenoses and entero-enteral fistulas. They frequently needed surgical intervention and had a high risk of re-stenosis. Genotyping therefore appears to be an important diagnostic tool in identifying severely affected patients requiring individualized treatment strategies at an early stage of the disease.