Differential impact of smoking on the transcriptome and epigenome in Crohn's disease and ulcerative colitis"

项目摘要 克罗恩病(CD)和溃疡性结肠炎(UC)在美国影响着200多万人， 与相当高的发病率相关。它们的发生是由于对一种非生物制剂的免疫反应失调所致 在遗传易感性背景下的微生物组。环境因素在这些因素中起着重要作用 疾病。然而，环境决定因素的影响机制却知之甚少。 因此，无法推断对疾病预防的见解。吸烟是唯一被反复复制的 IBD的环境决定因素。有趣的是，它对CD和UC产生了一种无法解释的分化效应。原 和目前吸烟都与CD的风险增加和进展更快相关。相比之下， 目前吸烟对UC有保护作用，并且与较轻的病程有关，而以前 吸烟会引发复发，并与疾病风险增加两倍相关。确切的组件 在包含香烟烟雾的复杂暴露中以及这种发散效应的机制 还没有建立起来。定义这种不同效应的决定因素将从根本上洞察 CD和UC中不同的生物途径(因此，不同的自然历史和进展)。 此外，识别香烟烟雾对UC活动的保护影响的机制可能会提供 对可用于治疗的新治疗途径的见解。在本提案中，我们提出了一种 最重要的假设是吸烟对疾病风险和进展的影响是通过其差异来实现的 慢性萎缩性结肠炎和溃疡性结肠炎对黏膜转录组和表观基因组的影响我们还假设这一效应 现在和以前吸烟是不同的。在前两个目标中，我们将量化暴露在香烟烟雾中 通过测定血清可替宁，检测其对转录组和表观基因组的生物学影响。 来自回肠和结肠活检的RNAseq，以及来自外周血的DNA甲基化图谱。通过执行 两两比较，我们将能够根据疾病类型定义吸烟的不同生物影响， 吸烟史和患病地点。在第三个目标中，我们将定义基因对这些指标的贡献 通过对三个特征良好的大型基因进行新的基因-吸烟交互作用分析的生物效应 确定整个外显子组测序中改变吸烟对转录和基因表达的影响的变异的队列 CD或UC的表观遗传学特征。从这一创新和探索性提案中获得的见解 国际大型基因分型队列的优势，基因-环境相互作用分析的专业知识，以及 全面的组织免疫图谱将为更强有力的生物学研究奠定重要基础 CD和UC中环境的影响及其对疾病预防的转化。

Project Summary Crohn’s disease (CD) and ulcerative colitis (UC) affect over 2 million individuals in the United States and are associated with considerable morbidity. They develop due to a dysregulated immune response to a dysbiotic microbiome on a background of genetic susceptibility. Environmental factors play an important role in these diseases. However, the mechanisms of influence of environmental determinants is poorly understood, and consequently, insights into disease prevention cannot be inferred. Smoking is the only consistently replicated environmental determinant of IBD. It intriguingly exerts an unexplained divergent effect on CD and UC. Former and current smoking are both associated with an increased risk and greater progression of CD. In contrast, current smoking confers protection against UC and is associated with a milder disease course while former smoking triggers relapses and is associated with a two-fold increase in disease risk. The exact component within the complex exposures comprising cigarette smoke as well as the mechanisms for this divergent effect have not been established. Defining the determinants of this divergent effect will shed fundamental insights on the different biologic pathways (and consequently, differing natural history and progression) in CD and UC. Further, identifying mechanisms for the protective influence of cigarette smoke on UC activity may offer insights into novel therapeutic pathways that can be harnessed for treatment. In this propose, we present an overarching hypothesis that the effect of smoking on disease risk and progression is through its differential impact on the mucosal transcriptome and epigenome in CD and UC. We also hypothesize that this effect differs between current and former smoking. In the first two aims, we will quantify exposure to cigarette smoke by measuring serum cotinine, and examine its biologic impact on the transcriptome and epigenome through RNAseq from ileal and colonic biopsies, and DNA methylation profiles from peripheral blood. By performing pairwise comparisons, we will be able to define the differential biologic impact of smoking by disease-type, smoking history, and disease-location. In the third aim, we will define the contribution of genotype to these biologic effects by performing a novel gene-smoking interaction analysis on three, large well-characterized cohorts to identify variants on whole exome sequencing that modify effect of smoking on transcriptional and epigenetic profiles in CD or UC. The insights obtained from this innovative and exploratory proposal leveraging the strengths of large international genotyped cohorts, expertise in gene-environment interaction analysis, and comprehensive tissue immune-profiling will lay an important foundation for more robust study on the biologic effects of the environment and their translation to disease prevention in CD and UC.