Ileal S100A9 expression distinguishes Crohn's disease patients by age at diagnosis

Crohn's disease (CD) is a debilitating gastrointestinal disorder that can impact the entirety of the GI tract. While substantial progress has been made in the medical management of CD, it remains incurable, frequently relapses, and is a significant financial and medical burden. The pathophysiology of CD is not well understood, but it is thought to arise in genetically susceptible individuals upon an environmental insult. Further elucidation of the disease etiology promises to expose additional therapeutic avenues, with the hope of reducing the burden of CD. One approach to understanding disease pathophysiology is to identify clinically relevant molecular disease subsets using transcriptomics. In this report, we use hierarchical clustering of the ileal transcriptomes of 34 patients to identify two CD subsets. Clinically, these clusters differed in the age of the patients at CD diagnosis, suggesting that age of disease onset impacts the pathophysiology of the disease. We found that the ileal transcriptomes of the early diagnosis cluster are enriched in inflammatory transcripts, including S100A9, which encodes a calprotectin subunit. Furthermore, levels of S100A9 distinguished individuals diagnosed before the age of 30 from those diagnosed after 30. Together, these findings suggest that medical management of CD patients should consider their age at diagnosis and therapeutic blockade of calprotectin may be beneficial in patients diagnosed earlier in life. Overall design: Gene expression profiles from the surgically resected, diseased, ileal tissue of 34 Crohn's disease patients were generated by deep sequencing.

克罗恩病（Crohn's disease, CD）是一种可累及全胃肠道（gastrointestinal tract, GI tract）的致残性胃肠道疾病。尽管CD的临床管理已取得显著进展，但该病仍无法治愈，且常反复发作，给患者带来显著的经济与医疗负担。目前CD的病理生理学（pathophysiology）机制尚未完全阐明，一般认为其发生于遗传易感个体受到环境刺激后。进一步阐明该病的病因学（etiology）机制，有望发掘更多潜在治疗途径，以期减轻CD带来的疾病负担。

解析疾病病理生理学机制的方法之一，是借助转录组学（transcriptomics）鉴定临床相关的分子疾病亚型。本研究通过对34例患者的回肠转录组（ileal transcriptomes）进行层级聚类（hierarchical clustering），鉴定出两种CD亚型。临床特征分析显示，这两个聚类簇在患者CD确诊年龄上存在显著差异，提示疾病发病年龄会影响该病的病理生理学进程。我们发现，确诊年龄较早的聚类簇的回肠转录组中，炎症相关转录本显著富集，其中包括编码钙卫蛋白（calprotectin）亚基的S100A9基因。此外，S100A9的表达水平可有效区分30岁前确诊与30岁后确诊的患者。综上，上述研究结果表明，CD患者的临床管理应纳入确诊年龄这一考量因素，而靶向钙卫蛋白的治疗策略或许对早年确诊的CD患者具有临床获益。

整体实验设计：本研究对34例克罗恩病患者手术切除的病变回肠组织进行深度测序（deep sequencing），获取了其基因表达谱。