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

吸烟对克罗恩病和溃疡性结肠炎转录组和表观基因组的差异影响"

• 批准号: 10263320
• 负责人: Ashwin N Ananthakrishnan
• 金额: $ 16.75万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263320
• 关键词: Affect; Anti-Inflammatory Agents; Aryl Hydrocarbon Receptor; Atlases; Attenuated; Biological; Biology; Biopsy; Chronic Obstructive Airway Disease; Cigarette; Clinical; Colon; Complex; Cotinine; Crohn' s disease; DNA Methylation; Data; Disease; Disease Pathway; Disease Progression; Environment; Environmental Risk Factor; Enzymes; Epigenetic Process; Foundations; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Genetic Variation; Genotype; Health Care Costs; Immune; Immune response; Immunologics; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; International; Link; Location; Malignant neoplasm of lung; Measurement; Measures; Methylation; Modality; Morbidity - disease rate; Mucous Membrane; National Institute of Diabetes and Digestive and Kidney Diseases; Natural History; Onset of illness; Pathogenesis; Pathway interactions; Patients; Play; Predisposition; Regulation; Relapse; Risk; Role; Serum; Smoking; Smoking History; Smoking Status; Technology; Tissues; Translations; Ulcerative Colitis; United States; Variant; cigarette smoke; cohort; defined contribution; disorder prevention; disorder risk; dysbiosis; epigenome; exome sequencing; exposure to cigarette smoke; gene environment interaction; genetic variant; ileum; inflammatory disease of the intestine; innovation; insight; methylation pattern; microbial; microbiome; novel; novel therapeutics; peripheral blood; protective effect; resilience; single-cell RNA sequencing; smoking cessation; smoking exposure; systemic inflammatory response; transcriptome; transcriptome sequencing; vaping

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.

项目概要 克罗恩病 (CD) 和溃疡性结肠炎 (UC) 在美国影响着超过 200 万人，并且 它们与相当大的发病率有关，是由于对菌群失调的免疫反应失调而产生的。 遗传易感性背景下的微生物群在其中发挥着重要作用。 然而，人们对环境决定因素的影响机制知之甚少，并且 因此，对疾病预防的见解不能被推断为唯一一致可复制的。 有趣的是，它对前 CD 和 UC 产生了无法解释的不同影响。 相比之下，当前吸烟和吸烟都与 CD 风险增加和进展更大相关。 当前吸烟可预防 UC，并且与较轻的病程相关，而以前吸烟则可预防 UC 吸烟会引发旧病复发，并且与疾病风险增加两倍有关。 在包括香烟烟雾的复杂暴露以及这种不同效应的机制中 尚未确定这种不同效应的决定因素将提供基本见解。 CD 和 UC 的不同生物学途径（以及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会提供帮助。 在本提案中，我们提出了一种可用于治疗的新治疗途径的见解。 总体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 对 CD 和 UC 中粘膜转录组和表观基因组的影响我们也发现了这种效应。 当前吸烟和以前吸烟之间的差异 在前两个目标中，我们将量化接触香烟烟雾的情况。 通过测量血清可替宁，并通过以下方式检查其对转录组和表观基因组的生物学影响 来自回肠和结肠活检的 RNAseq，以及来自外周血的 DNA 甲基化图谱。 成对比较，我们将能够根据疾病类型来定义吸烟的不同生物学影响， 在第三个目标中，我们将定义基因型对这些的贡献。 通过对三个大型特征良好的基因进行新颖的基因吸烟相互作用分析来观察生物效应 队列来识别全外显子组测序的变异，这些变异改变了吸烟对转录和转录的影响 CD 或 UC 中的表观遗传特征从这一创新性和探索性提案中获得的见解。 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，以及 全面的组织免疫分析将为更稳健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。