[Genetics of inflammatory bowel disease].

D Franchimont, E Louis
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Abstract

Inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), result from an inappropriate immune response towards the microbial flora in a genetically susceptible host. Several epidemiological and animal studies have demonstrated the essential role of the microbial flora in the triggering and perpetuation of intestinal inflammation. IBD are multigenic and heterogeneous diseases, and result from multiple low penetrant genes or group of genes. The genetic strategy for gene hunting in multigenic studies relies on two separate approaches. A candidate gene approach which is based on a robust biological hypothesis. A more systematic/global approach is either based on linkage studies (in late 90s) on IBD families or, since 2000 on gene arrays, the genome wide arrays (GWAS) on patients and controls. In 2001, the first CD susceptible gene, NOD2, was discovered, and found to be a pattern recognition receptor for bacteria, shedding light on the role of bacterial recognition in the triggering of the disease. Since 2000, GWAs have greatly accelerated the discoveries of new genes or signalling pathways in Crohn's disease and ulcerative colitis, confirming the importance of bacterial recognition, but also of bacterial defence (i.e. autophagy genes) as well as the role of the adaptive immune response (i.e. IL-23R/Th17 pathway). Despite the role of genetics in the development of IBD, changes in the development and composition of the microbial flora, known as dysbiosis, (possibly induced by our Western life style) must alter the development and function of the mucosal immune system, and leads to disease expression.

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[炎症性肠病的遗传学]。
炎症性肠病(IBD)、克罗恩病(CD)和溃疡性结肠炎(UC)是由于对遗传易感宿主微生物菌群的不适当免疫反应引起的。一些流行病学和动物研究已经证明了微生物菌群在引发和延续肠道炎症中的重要作用。IBD是一种多基因异质性疾病,是由多个低渗透基因或基因群共同作用的结果。在多基因研究中,基因搜寻的遗传策略依赖于两种不同的方法。候选基因的方法是基于一个强大的生物学假设。一种更系统/全球的方法要么基于对IBD家族的连锁研究(在90年代末),要么基于自2000年以来对患者和对照组的基因阵列的全基因组阵列(GWAS)。2001年,首个CD易感基因NOD2被发现,并被发现是细菌的模式识别受体,从而揭示了细菌识别在疾病触发中的作用。自2000年以来,GWAs极大地加速了克罗恩病和溃疡性结肠炎中新基因或信号通路的发现,证实了细菌识别的重要性,也证实了细菌防御(即自噬基因)以及适应性免疫反应(即IL-23R/Th17途径)的作用。尽管遗传在IBD的发展中起着重要作用,但微生物菌群的发育和组成的变化,即生态失调,(可能是由我们的西方生活方式引起的)必须改变粘膜免疫系统的发育和功能,并导致疾病的表达。
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