Department of Medicine II--Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
PLoS One. 2010 Dec 30;5(12):e14466. doi: 10.1371/journal.pone.0014466.
The aims were to analyze two novel NOD2 variants (rs2066843 and rs2076756) in a large cohort of patients with inflammatory bowel disease and to elucidate phenotypic consequences.
METHODOLOGY/PRINCIPAL FINDINGS: Genomic DNA from 2700 Caucasians including 812 patients with Crohn's disease (CD), 442 patients with ulcerative colitis (UC), and 1446 healthy controls was analyzed for the NOD2 SNPs rs2066843 and rs2076756 and the three main CD-associated NOD2 variants p.Arg702Trp (rs2066844), p.Gly908Arg (rs2066847), and p.Leu1007fsX1008 (rs2066847). Haplotype and genotype-phenotype analyses were performed. The SNPs rs2066843 (p = 3.01×10(-5), OR 1.48, [95% CI 1.23-1.78]) and rs2076756 (p = 4.01×10(-6); OR 1.54, [95% CI 1.28-1.86]) were significantly associated with CD but not with UC susceptibility. Haplotype analysis revealed a number of significant associations with CD susceptibility with omnibus p values <10(-10). The SNPs rs2066843 and rs2076756 were in linkage disequilibrium with each other and with the three main CD-associated NOD2 mutations (D'>0.9). However, in CD, SNPs rs2066843 and rs2076756 were more frequently observed than the other three common NOD2 mutations (minor allele frequencies for rs2066843 and rs2076756: 0.390 and 0.380, respectively). In CD patients homozygous for these novel NOD2 variants, genotype-phenotype analysis revealed higher rates of a penetrating phenotype (rs2076756: p = 0.015) and fistulas (rs2076756: p = 0.015) and significant associations with CD-related surgery (rs2076756: p = 0.003; rs2066843: p = 0.015). However, in multivariate analysis only disease localization (p<2×10(-16)) and behaviour (p = 0.02) were significantly associated with the need for surgery.
CONCLUSION/SIGNIFICANCE: The NOD2 variants rs2066843 and rs2076756 are novel and common CD susceptibility gene variants.
本研究旨在对炎症性肠病患者的大样本进行两种新型 NOD2 变异体（rs2066843 和 rs2076756）的分析，并阐明其表型后果。
方法/主要发现：对 2700 名高加索人（包括 812 名克罗恩病患者、442 名溃疡性结肠炎患者和 1446 名健康对照者）的基因组 DNA 进行了 NOD2 SNPs rs2066843 和 rs2076756 以及三个主要克罗恩病相关的 NOD2 变异体 p.Arg702Trp（rs2066844）、p.Gly908Arg（rs2066847）和 p.Leu1007fsX1008（rs2066847）的分析。进行了单倍型和基因型-表型分析。SNP rs2066843（p=3.01×10(-5)，OR 1.48，[95% CI 1.23-1.78]）和 rs2076756（p=4.01×10(-6)；OR 1.54，[95% CI 1.28-1.86]）与 CD 显著相关，但与 UC 易感性无关。单倍型分析显示，与 CD 易感性相关的许多关联具有小于 10(-10)的总 p 值。SNP rs2066843 和 rs2076756 彼此之间以及与三个主要的 CD 相关的 NOD2 突变（D' > 0.9）之间存在连锁不平衡。然而，在 CD 中，rs2066843 和 rs2076756 的出现频率高于其他三个常见的 NOD2 突变（rs2066843 和 rs2076756 的次要等位基因频率分别为 0.390 和 0.380）。在这些新型 NOD2 变异体纯合的 CD 患者中，基因型-表型分析显示穿透性表型（rs2076756：p=0.015）和瘘管（rs2076756：p=0.015）的发生率更高，并且与 CD 相关的手术显著相关（rs2076756：p=0.003；rs2066843：p=0.015）。然而，在多变量分析中，只有疾病定位（p<2×10(-16)）和行为（p=0.02）与手术需求显著相关。
结论/意义：NOD2 变异体 rs2066843 和 rs2076756 是新型的、常见的 CD 易感基因变异体。
