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）在美国影响超过200万个体， 与相当高的发病率有关。它们是由于对微生态系统的免疫反应失调而产生的 微生物组在遗传易感性的背景下。环境因素在其中起着重要作用。 疾病然而，人们对环境决定因素的影响机制知之甚少， 因此，无法推断对疾病预防的认识。吸烟是唯一持续复制的 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差异效应。前 和目前吸烟都与CD的风险增加和更大的进展有关。与此相反， 目前的吸烟可以预防UC，并且与较轻的病程相关， 吸烟会引发复发，并与疾病风险增加两倍有关。准确的成分 在包括香烟烟雾在内的复杂暴露中， 尚未建立。确定这种差异效应的决定因素将有助于我们对以下问题的基本认识： CD和UC中不同的生物学途径（因此，不同的自然史和进展）。 此外，确定香烟烟雾对UC活动的保护性影响的机制可能提供 对新的治疗途径的见解，可以利用治疗。在这个提议中，我们提出了一个 总体假设认为，吸烟对疾病风险和进展的影响是通过其差异， 对CD和UC中粘膜转录组和表观基因组的影响。我们还假设这种效应 现在吸烟和以前吸烟的区别。在前两个目标中，我们将量化香烟烟雾的暴露 通过测量血清可替宁，并检查其对转录组和表观基因组的生物学影响， 来自回肠和结肠活组织检查的RNAseq，以及来自外周血的DNA甲基化谱。通过执行 通过成对比较，我们将能够确定吸烟对疾病类型的不同生物学影响， 吸烟史和疾病部位。在第三个目标中，我们将定义基因型对这些的贡献。 通过对三个大的、表征良好的基因组进行新的基因-吸烟相互作用分析， 队列，以确定改变吸烟对转录和转录水平的影响的全外显子组测序的变体， CD或UC中的表观遗传谱。从这一创新和探索性的提案中获得的见解， 大型国际基因分型队列的优势，基因-环境相互作用分析的专业知识， 全面的组织免疫谱分析将为更可靠的生物学研究奠定重要基础。 环境的影响及其对CD和UC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.