Russell Richard K, Drummond Hazel E, Nimmo Elaine E, Anderson Niall, Smith Linda, Wilson David C, Gillett Peter M, McGrogan Paraic, Hassan Kamal, Weaver Lawrence T, Bisset Michael, Mahdi Gamal, Satsangi Jack
MRCPCH, Gastrointestinal Unit, Western General Hospital, Crewe Road, Edinburgh, Scotland.
Inflamm Bowel Dis. 2005 Nov;11(11):955-64. doi: 10.1097/01.mib.0000183423.38037.f3.
The incidence of early-onset CD in Scotland is among the highest worldwide. Three single nucleotide polymorphisms (SNPs) R702W, G908R and Leu1007finsC in the NOD2/CARD15 gene predispose to adult CD. We investigated the contribution of these variants to disease susceptibility and phenotype in the Scottish early-onset IBD population.
906 individuals including 247 Scottish IBD patients aged <16 years at diagnosis, 414 parents and 245 controls were genotyped. Transmission disequilibrium testing (TDT), case-control analysis and detailed genotype-phenotype analysis were performed.
The Leu1007finsC variant was associated with susceptibility to CD by case-control (4.2% versus. 1.4%, P = 0.01) and TDT analysis (P = 0.006). The Population Attributable Risk (PAR) for the 3 NOD2/CARD15 mutations was 7.9%. Carriage of NOD2/CARD15 variants was associated with, at diagnosis: decreased albumin (31.0% versus. 9.0%, P = 0.001) and raised CRP (25% versus. 9.5%, P = 0.04) and at follow up: need for surgery (39.5% versus. 12.8%, P = 0.0002) jejunal involvement (50% versus. 18.4%, P = 0.01) jejunal and ileal involvement (50% versus. 10.7%, P = 0.009), raised CRP (57.1% and 12.8%, P = 0.0009), lower weight/height centile (75.0% versus. 20.2%, P = 0.03, 50.0% versus. 16.0%, P = 0.001 respectively) and stricturing disease (45.5% versus. 19.4%, P < 0.05). Multifactorial analysis demonstrated carriage was associated with need for surgery (P = 0.004, OR 4.9 [1.5-14.7]).
These NOD2/CARD 15 variants in the Scottish early onset CD population have a definite, albeit relatively small contribution to CD susceptibility (PAR 7.9%) but a major impact on phenotype. In particular NOD2/CARD15 variants are strongly associated with several markers of disease severity in pediatric CD, notably need for surgery.
苏格兰早发性克罗恩病（CD）的发病率位居全球前列。NOD2/CARD15基因中的三个单核苷酸多态性（SNP），即R702W、G908R和Leu1007finsC，易导致成人CD。我们研究了这些变异对苏格兰早发性炎症性肠病（IBD）人群疾病易感性和表型的影响。
对906名个体进行基因分型，包括247名确诊时年龄小于16岁的苏格兰IBD患者、414名父母及245名对照。进行了传递不平衡检验（TDT）、病例对照分析及详细的基因型-表型分析。
通过病例对照分析（4.2%对1.4%，P = 0.01）和TDT分析（P = 0.006），Leu1007finsC变异与CD易感性相关。3个NOD2/CARD15突变的人群归因风险（PAR）为7.9%。NOD2/CARD15变异的携带者在诊断时：白蛋白降低（31.0%对9.0%，P = 0.001）、C反应蛋白（CRP）升高（25%对9.5%，P = 0.04）；在随访时：需要手术（39.5%对12.8%，P = 0.0002）、空肠受累（50%对18.4%，P = 0.01）、空肠和回肠受累（50%对10.7%，P = 0.009）、CRP升高（57.1%对12.8%，P = 0.0009）、体重/身高百分位数较低（分别为75.0%对20.2%，P = 0.03；50.0%对16.0%，P = 0.001）以及狭窄性疾病（45.5%对19.4%，P < 0.05）。多因素分析表明，携带变异与需要手术相关（P = 0.004，比值比4.9 [1.5 - 14.7]）。
这些NOD2/CARD 15变异在苏格兰早发性CD人群中对CD易感性有一定贡献，尽管相对较小（PAR 7.9%），但对表型有重大影响。特别是NOD2/CARD15变异与儿童CD疾病严重程度 的几个标志物密切相关，尤其是需要手术。
