Villani Alexandra-Chloé, Lemire Mathieu, Fortin Geneviève, Louis Edouard, Silverberg Mark S, Collette Catherine, Baba Nobuyasu, Libioulle Cécile, Belaiche Jacques, Bitton Alain, Gaudet Daniel, Cohen Albert, Langelier Diane, Fortin Paul R, Wither Joan E, Sarfati Marika, Rutgeerts Paul, Rioux John D, Vermeire Severine, Hudson Thomas J, Franchimont Denis
Division of Gastroenterology, McGill University Health Centre, Montreal General Hospital, Montréal, Québec, Canada.
Nat Genet. 2009 Jan;41(1):71-6. doi: 10.1038/ng.285. Epub 2008 Dec 21.
We used a candidate gene approach to identify a set of SNPs, located in a predicted regulatory region on chromosome 1q44 downstream of NLRP3 (previously known as CIAS1 and NALP3) that are associated with Crohn's disease. The associations were consistently replicated in four sample sets from individuals of European descent. In the combined analysis of all samples (710 father-mother-child trios, 239 cases and 107 controls), these SNPs were strongly associated with risk of Crohn's disease (P(combined) = 3.49 x 10(-9), odds ratio = 1.78, confidence interval = 1.47-2.16 for rs10733113), reaching a level consistent with the stringent significance thresholds imposed by whole-genome association studies. In addition, we observed significant associations between SNPs in the associated regions and NLRP3 expression and IL-1beta production. Mutations in NLRP3 are known to be responsible for three rare autoinflammatory disorders. These results suggest that the NLRP3 region is also implicated in the susceptibility of more common inflammatory diseases such as Crohn's disease.
我们采用候选基因方法来鉴定一组单核苷酸多态性（SNP），这些SNP位于NLRP3（以前称为CIAS1和NALP3）下游1q44染色体上的一个预测调控区域，与克罗恩病相关。这些关联在来自欧洲血统个体的四个样本集中得到了一致的重复验证。在对所有样本（710个父母子三联体、239例病例和107例对照）的综合分析中，这些SNP与克罗恩病风险密切相关（对于rs10733113，合并P值 = 3.49×10⁻⁹，优势比 = 1.78，置信区间 = 1.47 - 2.16），达到了全基因组关联研究所设定的严格显著性阈值水平。此外，我们观察到相关区域的SNP与NLRP3表达及白细胞介素 - 1β产生之间存在显著关联。已知NLRP3中的突变会导致三种罕见的自身炎症性疾病。这些结果表明，NLRP3区域也与诸如克罗恩病等更常见的炎症性疾病的易感性有关。
