Molecular Comparison of Adult and Pediatric Ulcerative Colitis Indicates Broad Similarity of Molecular Pathways in Disease Tissue
Molecular Comparison of Adult and Pediatric Ulcerative Colitis Indicates Broad Similarity of Molecular Pathways in Disease Tissue
复制标题
DOI：
10.1097/mpg.0000000000001898
复制
发表时间：
2018-07-01
影响因子：
2.9
通讯作者：
Friedman, Joshua R.
中科院分区：
文献类型：
--
作者：
Li, Katherine;Strauss, Richard;Friedman, Joshua R.
背景：成人溃疡性结肠炎(UC)临床试验的疗效数据经常被推断用于儿科处方。因此，了解儿童UC和成人UC的异同是很重要的。方法：使用来自成人UC(87 UC；21健康)、GSE10616儿童数据集(10 UC；11健康)和Golimumab在儿童UC(n=19)的1B期试验的结肠微阵列数据，比较UC的表达谱，并定义具有显著变化的独特基因(|FC|>；2x；调整后的P<；0.05)，但不是另一个(|FC|<；1.2x，调整后的P>；0.05)。进行了通路和上游调控因子分析。结果：儿童和成人的疾病特征有很大的重叠性，有50%到75%的重叠性，这取决于所使用的折痕变化截止点。相反，10%的疾病特征对每个人群是独一无二的。相似的典型路径在两个数据集中都得到了丰富。预测的上游调节因子也是一致的，包括内毒素、白细胞介素1β和肿瘤坏死因子-Cx。结论：UC基因表达谱由成人和儿童共享，与疾病程度无关。这支持了从成人到儿童在开发UC新疗法方面的疗效推断。
Background: Efficacy data from adult ulcerative colitis (UC) clinical trials are often extrapolated for pediatric prescribing. Consequently, it is important to understand similarities/differences in pediatric and adult UC. Pediatric UC tends to have more extensive disease at presentation, yet genetic studies have not detected pathways that distinguish the populations, and differences in mucosal gene expression between adult and pediatric UC are not well characterized.Methods: Using colonic microarray data from a phase 3 trial of golimumab in adult UC (87 UC; 21 healthy), the GSE10616 pediatric dataset (10 UC; 11 healthy), and a phase 1B trial of golimumab in pediatric UC (n=19), UC expression profiles were compared and unique genes were defined as those with significant changes (|FC|> 2x, adjusted P < 0.05) in one population, but not the other (|FC| < 1.2x, adjusted P > 0.05). Pathway and upstream regulator analyses were performed. Profiles by disease extent (extensive [pancolitis] vs limited [left-sidedj involvement) were compared within each population.Results: Pediatric and adult disease profiles overlapped substantially, with similar to 50% to 75% overlap, depending on the fold-change cutoff used. Conversely, < 10% of the disease profiles were unique to each population. Similar canonical pathways were enriched in both datasets. Predicted upstream regulators were also concordant, including lipopolysaccharide, interleukin-1 beta, and tumor necrosis factor-cx. Expression profiles of extensive UC were indistinguishable from those of patients with limited involvement in each population.Conclusions: The UC gene expression landscape is shared by adults and children, independent of disease extent. This supports extrapolation of efficacy from adults to children in developing new therapies for UC.