De Jager P L, Franchimont D, Waliszewska A, Bitton A, Cohen A, Langelier D, Belaiche J, Vermeire S, Farwell L, Goris A, Libioulle C, Jani N, Dassopoulos T, Bromfield G P, Dubois B, Cho J H, Brant S R, Duerr R H, Yang H, Rotter J I, Silverberg M S, Steinhart A H, Daly M J, Podolsky D K, Louis E, Hafler D A, Rioux J D
Department of Neurology, Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA.
Genes Immun. 2007 Jul;8(5):387-97. doi: 10.1038/sj.gene.6364398. Epub 2007 May 31.
The intestinal flora has long been thought to play a role either in initiating or in exacerbating the inflammatory bowel diseases (IBD). Host defenses, such as those mediated by the Toll-like receptors (TLR), are critical to the host/pathogen interaction and have been implicated in IBD pathophysiology. To explore the association of genetic variation in TLR pathways with susceptibility to IBD, we performed a replication study and pooled analyses of the putative IBD risk alleles in NFKB1 and TLR4, and we performed a haplotype-based screen for association to IBD in the TLR genes and a selection of their adaptor and signaling molecules. Our genotyping of 1539 cases of IBD and pooled analysis of 4805 cases of IBD validates the published association of a TLR4 allele with risk of IBD (odds ratio (OR): 1.30, 95% confidence interval (CI): 1.15-1.48; P=0.00017) and Crohn's disease (OR: 1.33, 95% CI: 1.16-1.54; P=0.000035) but not ulcerative colitis. We also describe novel suggestive evidence that TIRAP (OR: 1.16, 95% CI: 1.04-1.30; P=0.007) has a modest effect on risk of IBD. Our analysis, therefore, offers additional evidence that the TLR4 pathway - in this case, TLR4 and its signaling molecule TIRAP - plays a role in susceptibility to IBD.
长期以来，人们一直认为肠道菌群在引发或加剧炎症性肠病（IBD）方面发挥着作用。宿主防御机制，如由Toll样受体（TLR）介导的防御机制，对于宿主与病原体的相互作用至关重要，并且与IBD的病理生理学有关。为了探究TLR通路中的基因变异与IBD易感性之间的关联，我们进行了一项重复研究，并对NFKB1和TLR4中假定的IBD风险等位基因进行了汇总分析，还对TLR基因及其一些衔接子和信号分子进行了基于单倍型的IBD关联筛查。我们对1539例IBD患者进行基因分型，并对4805例IBD患者进行汇总分析，验证了已发表的TLR4等位基因与IBD风险的关联（比值比（OR）：1.30，95%置信区间（CI）：1.15 - 1.48；P = 0.00017）以及与克罗恩病的关联（OR：1.33，95% CI：1.16 - 1.54；P = 0.000035），但与溃疡性结肠炎无关。我们还描述了新的提示性证据，即TIRAP（OR：1.16，95% CI：1.04 - 1.30；P = 0.007）对IBD风险有适度影响。因此，我们的分析提供了更多证据，表明TLR4通路——在本研究中，即TLR4及其信号分子TIRAP——在IBD易感性中发挥作用。
