Toll-like receptor-1,-2, and-6 polymorphisms influence disease extension in inflammatory bowel diseases
Toll-like receptor-1,-2, and-6 polymorphisms influence disease extension in inflammatory bowel diseases
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DOI：
10.1097/01.mib.0000195389.11645.ab
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发表时间：
2006-01-01
影响因子：
4.9
通讯作者：
Vermeire, S
中科院分区：
文献类型：
--
作者：
Pierik, M;Joossens, S;Vermeire, S
背景资料：越来越多的证据表明，对肠道细菌植物群的先天免疫应答缺陷在炎症性肠病（IBD）的发病机制中起作用。CARD 15变体与克罗恩病（CD）和Toll样受体（TLR）4中的D299 G和IBD之间的关联发现强调了这一点。本研究的目的是研究其他TLR基因的非同义多态性与IBD的关系。方法：从公共数据库中筛选出TLR 1 -10的35个单核苷酸多态性（SNP）。采用聚合酶链反应-限制性片段长度多态性对284名IBD父母子女三人组和第二个独立队列的285名IBD患者和191名健康对照进行基因分型。合并患者进行基因型-表型分析。结果：虽然没有一个SNP参与疾病易感性，但一些变异影响疾病表型。发现TLR 1 R80 T与UC的全结肠炎正相关（P = 0.045，OR [95%CI] 2.844 [1.026-7.844]），TLR 2 R753 G SNP也与全结肠炎相关（P = 0.027，OR [95%CI] 4.741 [1.197-18.7731）。R80 T和R753 G杂合子患者发生全结肠炎的相对风险分别为5.8和3.3。TLR 6 S249 P与溃疡性结肠炎伴直肠炎呈负相关（P = 0.026，OR [95%CI] 0.223 [0.096-0.705]）。结论：TLR 2及其辅助因子TLR 1和TLR 6通过识别肽聚糖参与了对细菌的初始免疫应答。TLR 1、TLR 2和TLR 6基因的非同义变异与UC和CD患者的广泛性结肠疾病之间存在关联，我们的研究结果进一步强调了先天性免疫应答异常在IBD发病机制中的作用。
Background: Evidence that a deficient innate immune response toward the bacterial flora of the gut plays a role in the pathogenesis of inflammatory bowel disease (IBD) is growing. This is underscored by the finding of the association between CARD15 variants and Crohn's disease (CD) and D299G in Toll-like receptor (TLR) 4 and IBD. Our aims were to study nonsynonymous polymorphisms in other TLR genes in IBD.Methods: Thirty-five single nucleotide polymorphisms (SNP) in TLR1-10 were identified from public databases. 284 IBD parent child trios and a second independent cohort of 285 IBD patients and 191 healthy controls were genotyped with polymerase chain reaction-restriction fragment length polymorphisms. Patients were pooled for genotype-phenotype analyses.Results: Although none of the SNPs was involved in disease susceptibility, a number of variants influenced the disease phenotype. A positive association between TLR1 R80T and pancolitis in UC (P = .045, OR [95% CI] 2.844 [1.026-7.844]) was found. The TLR2 R753G SNP was also associated with pancolitis (P = .027, OR [95% CI] 4.741 [1.197-18.7731). The relative risks for heterozygous patients to develop pancolitis were 5.8 and 3.3 for R80T and R753G, respectively. There was a negative association between TLR6 S249P and ulcerative colitis with proctitis only (P = .026, OR [95% CI] 0.223 [0.096-0.705]). In CD, we found a negative association between ileal disease involvement and TLR1 S6021 (P = .03, OR [95% CI] 0.522 [0.286-0.950]).Conclusion: TLR2 and its cofactors TLR1 and TLR6 are involved in the initial immune response to bacteria by recognizing peptidoglycan. An association between nonsynonymous variants in the TLR1, -2, and -6 genes and extensive colonic disease in UC and CD was found. Our findings further highlight the role of an abnormal innate immune response in the pathogenesis of IBD.