Cuthbert Andrew P, Fisher Sheila A, Mirza Muddassar M, King Kathy, Hampe Jochen, Croucher Peter J P, Mascheretti Silvia, Sanderson Jeremy, Forbes Alastair, Mansfield John, Schreiber Stefan, Lewis Cathryn M, Mathew Christopher G
Division of Medical and Molecular Genetics, Guy's, King's, and St Thomas' School of Medicine, London, England, United Kingdom.
Gastroenterology. 2002 Apr;122(4):867-74. doi: 10.1053/gast.2002.32415.
BACKGROUND & AIMS: Mutations in the NOD2 gene are strongly associated with susceptibility to Crohn's disease (CD). We analyzed a large cohort of European patients with inflammatory bowel disease to determine which mutations confer susceptibility, the degree of risk conferred, their prevalence in familial and sporadic forms of the disease, and whether they are associated with site of disease.
Individuals were genotyped for 4 NOD2 mutations: P268S, R702W, G908R, and 3020insC. Allelic transmission distortion to 531 CD- and 337 ulcerative colitis-affected offspring was assessed by the transmission disequilibrium test. Association was also tested in an independent cohort of 995 patients with inflammatory bowel disease and 290 controls. Cases were stratified by disease site and compared across NOD2 genotypes.
R702W, G908R, and 3020insC were strongly associated with CD but not with ulcerative colitis. Linkage disequilibrium was observed between P268S and the other mutations, forming 3 independent disease haplotypes. Genotype relative risks were 3.0 for mutation heterozygotes and 23.4 for homozygotes or compound heterozygotes. The frequency of NOD2 mutations was higher in cases from families affected only with CD and was significantly increased in ileal-specific disease cases compared with colon-specific disease (26.9% vs. 12.7%, P = 0.0004).
The R702W, G908R, and 3020insC mutations are strong independent risk factors for CD and are associated particularly with ileal disease.
NOD2基因的突变与克罗恩病（CD）易感性密切相关。我们分析了一大群欧洲炎症性肠病患者，以确定哪些突变会导致易感性、所赋予的风险程度、它们在家族性和散发性疾病中的患病率，以及它们是否与疾病部位相关。
对个体进行4种NOD2突变的基因分型：P268S、R702W、G908R和3020insC。通过传递不平衡检验评估531名患CD和337名患溃疡性结肠炎后代的等位基因传递畸变。还在一个由995名炎症性肠病患者和290名对照组成的独立队列中进行了关联测试。病例按疾病部位分层，并在NOD2基因型之间进行比较。
R702W、G908R和3020insC与CD密切相关，但与溃疡性结肠炎无关。在P268S和其他突变之间观察到连锁不平衡，形成3种独立的疾病单倍型。突变杂合子的基因型相对风险为3.0，纯合子或复合杂合子为23.4。仅患CD的家族中的病例中NOD2突变频率更高，与结肠特异性疾病相比，回肠特异性疾病病例中的突变频率显著增加（26.9%对12.7%，P = 0.0004）。
R702W、G908R和3020insC突变是CD的强大独立危险因素，尤其与回肠疾病相关。
