Transcriptome Profiling of Human Ulcerative Colitis Mucosa Reveals Altered Expression of Pathways Enriched in Genetic Susceptibility Loci

Human colonic mucosa altered by inflammation due to ulcerative colitis (UC) displays a drastically altered pattern of gene expression compared with healthy tissue. We aimed to understand the underlying molecular pathways influencing these differences by analyzing three publically-available, independently-generated microarray datasets of gene expression from endoscopic biopsies of the colon. Gene set enrichment analysis (GSEA) revealed that all three datasets share 87 gene sets upregulated in UC lesions and 8 gene sets downregulated (false discovery rate P = 1.49×10–19). This study supports the hypothesis that heritable variation in gene expression as measured by GWAS signals can influence key pathways in the development of disease, and that comparison of genetic susceptibility loci with gene expression signatures can differentiate key drivers of inflammation from secondary effects on gene expression of the inflammatory process.

因溃疡性结肠炎（Ulcerative Colitis, UC）引发炎症而发生病变的人类结肠黏膜，与健康结肠组织相比，其基因表达模式发生了显著改变。本研究通过分析三项公开可得、独立构建的结肠内镜活检组织基因表达微阵列数据集，旨在解析导致上述表达差异的潜在分子通路。基因集富集分析（Gene Set Enrichment Analysis, GSEA）结果显示，三项数据集共同筛选出87个在UC病变组织中上调的基因集，以及8个下调基因集（错误发现率P值=1.49×10^–19）。本研究验证了如下假说：通过全基因组关联研究（Genome-Wide Association Study, GWAS）信号检测到的基因表达可遗传变异，可影响疾病发生发展过程中的关键通路；同时，将遗传易感位点与基因表达特征进行比对，能够区分炎症的核心驱动因素与炎症过程对基因表达产生的次级效应。