A microarray screen for novel candidate genes in coeliac disease pathogenesis
A microarray screen for novel candidate genes in coeliac disease pathogenesis
复制标题
DOI：
10.1136/gut.2003.018374
复制
发表时间：
2004-07-01
期刊：
影响因子：
24.5
通讯作者：
Wijmenga, C
中科院分区：
文献类型：
--
作者：
Diosdado, B;Wapenaar, MC;Wijmenga, C
背景和目的：乳糜泻发病机制的致病分子途径尚不清楚。为了揭示疾病发病机制的新方面，我们使用微阵列来确定十二指肠活检中基因表达的变化。方法：采用19200个基因的cDNA微阵列技术，比较15例乳糜泻绒毛萎缩患者（Marsh III型）和7例正常活检对照（Marsh 0型）的十二指肠活检基因表达谱。此外，通过比较7名接触谷蛋白的患者与4名无谷蛋白饮食的患者的Marsh III病变的表达谱，研究了谷蛋白的特异性作用。结果：比较Marsh III和Marsh 0病变，发现109个基因在患者和对照组之间的表达水平有显著差异（p< 0.001）。这些基因中有大量在增殖和分化途径中起作用，可能对隐绒毛单位的正确发育起重要作用。这些通路的改变可能导致乳糜泻特征性的增生和绒毛萎缩。分析还显示，当比较无麸质饮食的患者和接触麸质饮食的患者时，有120个差异表达基因（p< 0.005）。这些基因进一步加强了我们对谷蛋白存在时细胞增殖增加的观察。结论：本研究为乳糜泻的发病机制提供了新的候选基因。基于我们的结果，我们假设乳糜泻患者的绒毛萎缩是由于细胞分化失败。这些基因参与了以前未涉及乳糜泻发病机制的途径，它们可能为治疗提供新的靶点。
Background and aims: The causative molecular pathways underlying the pathogenesis of coeliac disease are poorly understood. To unravel novel aspects of disease pathogenesis, we used microarrays to determine changes in gene expression of duodenal biopsies.Methods: cDNA microarrays representing 19 200 genes were used to compare gene expression profiles of duodenal biopsies from 15 coeliac disease patients with villous atrophy ( Marsh III) and seven control individuals with normal biopsies ( Marsh 0). In addition, the specific effect of gluten was studied by comparing the expression profiles of Marsh III lesions of seven patients exposed to gluten with four patients on a gluten free diet.Results: Comparing Marsh III with Marsh 0 lesions identified 109 genes that differed significantly ( p< 0.001) in expression levels between patients and controls. A large number of these genes have functions in proliferation and differentiation pathways and might be important for correct development of crypt-villous units. Alterations in these pathways may lead to the characteristic hyperplasia and villous atrophy seen in coeliac disease. The analyses also revealed 120 differentially expressed genes ( p< 0.005) when comparing patients on a gluten free diet with those exposed to gluten. These genes further strengthen our observation of increased cell proliferation in the presence of gluten.Conclusions: Our study provides new candidate genes in the pathogenesis of coeliac disease. Based on our results, we hypothesise that villous atrophy in coeliac disease patients is due to failure in cell differentiation. These genes are involved in pathways not previously implicated in coeliac disease pathogenesis and they may provide new targets for therapy.