Cummings J R Fraser, Cooney R M, Clarke G, Beckly J, Geremia A, Pathan S, Hancock L, Guo C, Cardon L R, Jewell D P
IBD Genetics Group, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Tissue Antigens. 2010 Jul;76(1):48-56. doi: 10.1111/j.1399-0039.2010.01470.x. Epub 2010 Apr 6.
The first Crohn's disease (CD) susceptibility gene identified was CARD15, which is a member of the emerging NOD-like receptor (NLR) family. These function as intracellular cystosolic pattern recognition receptors (PRRs) and play a central role in the innate immune response. We studied other members of the NLR family using a gene-wide haplotype tagging approach in a well-characterised collection of 547 CD patients and 465 controls. Four single nucleotide polymorphisms (SNPs) in NLRP3 had P values < 0.05 and are in high linkage disequilibrium (LD) with each other (r(2) > 0.90 for all four SNPs). rs4925648 and rs10925019 were the most strongly associated with CD susceptibility (P = 0.001, odds ratio (OR) 1.62, 95% CI 1.2-2.18; and P = 6.5 x 10(-4), OR 1.65, 95% CI 1.23-2.19, respectively). rs1363758 located in NLRP11 was associated with CD susceptibility [P = 0.002 (1.64, 1.19-2.25)], which was weakly confirmed in an independent case-cohort collection on joint analysis [P = 0.05, (1.28, 1-1.64)]. On sub-phenotype analysis, an interesting association between NLRP1 and skin extra-intestinal manifestations and colonic, inflammatory CD was identified. None of these results was replicated in the Wellcome Trust Case Control Consortium study and therefore need replication in a further large cohort.
首个被鉴定出的克罗恩病（CD）易感基因是CARD15，它是新出现的NOD样受体（NLR）家族的成员。这些基因作为细胞内胞质模式识别受体（PRR）发挥作用，并在先天免疫反应中起核心作用。我们在一个由547例CD患者和465例对照组成的特征明确的样本集中，使用全基因单倍型标签方法研究了NLR家族的其他成员。NLRP3中的四个单核苷酸多态性（SNP）的P值<0.05，且彼此处于高度连锁不平衡（LD）状态（所有四个SNP的r²>0.90）。rs4925648和rs10925019与CD易感性的关联最为强烈（P = 0.001，比值比（OR）为1.62，95%置信区间为1.2 - 2.18；以及P = 6.5×10⁻⁴，OR为1.65，95%置信区间分别为1.23 - 2.19）。位于NLRP11中的rs1363758与CD易感性相关[P = 0.002（1.64，1.19 - 2.25）]，在一项独立的病例 - 队列联合分析样本集中得到了较弱的证实[P = 0.05，（1.28，1 - 1.64）]。在亚表型分析中，发现NLRP1与皮肤肠外表现以及结肠炎症性CD之间存在有趣的关联。这些结果在威康信托病例对照协会研究中均未得到重复验证，因此需要在更大的队列中进行重复验证。
