Integrative Analysis of Genomic, Epigenomic and Phenotypic Data for Disease Stratification of Endometriosis

项目摘要/摘要 子宫内膜异位症是导致盆腔疼痛和不孕的常见病。它影响着数百万人的生活质量 并对美国卫生经济产生重大影响。大多数疾病源于月经逆行。 将子宫内膜组织和细胞从子宫衬里(在位内膜)种植到盆腔 形成病变并引发炎症反应和结疤的结构。它是通过手术确诊的， 在外观和分期上是不同的，其特点是对手术和 医疗疗法。子宫内的异常易导致这种疾病，要么是先天的 (遗传)或后天(环境/生活方式)，如果是后者，则将生活方式改变的可能性提高到 改变疾病风险和进展。美国国立卫生研究院人类基因组计划和美国国立卫生研究院路线图表观基因组计划 正在生成基因组和表观基因组数据，并利用强大的生物信息学和生物统计学工具 为多种疾病提供新的见解。然而，还没有研究综合利用这些因素。 解决与子宫内膜异位症相关的基本问题所需规模的技术--一个科学鸿沟 在此注明。越来越多的人类疾病与获得性DNA缺陷有关 甲基化和表观遗传变化提供了个体暴露和表型之间的生物学联系。 我们的建议旨在识别子宫内膜异位症特异的在位子宫内膜DNA甲基化信号，其 遗传性和非遗传性与外科疾病表型和特定患者特征的关系 对这些DNA甲基化信号的贡献，并潜在地识别可修改的疾病风险因素。我们的 团队涉及全球领先的基因组和流行病学研究中心之间的合作，重点是 子宫内膜异位症(加州大学旧金山分校、哈佛大学、牛津大学、QIMR和墨尔本大学(“联盟”)) 假设1)环境和遗传影响导致子宫内膜异位症并长期存在 在位子宫内膜DNA甲基组中与疾病发生和发展有关的信号 病理生理学；和2)这些可以用来分层疾病风险和提供药物靶点的新途径。 发现和诊断发展。我们建议进行全基因组DNA甲基化分析和 对近1000个注解良好的现有在位子宫内膜样本进行基因分型(以及正在进行的 400个样本重复研究)，通过标准操作程序和广泛的表型鉴定收集， 由我们的世界子宫内膜异位症研究基金会建立的子宫内膜异位症表型和生物库 协调项目(WERF-EPHect)。

Project Summary/Abstract Endometriosis is a common disease causing pelvic pain and infertility. It affects the quality of life of millions of women and has a major impact on the U.S. health economy. Most disease derives from retrograde menstrual seeding of endometrial tissue and cells from the lining of the uterus (eutopic endometrium) onto pelvic structures that develop as lesions and elicit an inflammatory response and scarring. It is surgically diagnosed, is heterogeneous in appearance and staging and is characterized by unpredictable responses to surgical and medical therapies. Abnormalities within the uterus predisposing to establishing the disease are either inherent (genetic) or acquired (environmental/lifestyle), and if the latter, raise the possibility of life-style modification to alter disease risk and progression. The NIH Human Genome Project and NIH Roadmap Epigenomics Project are generating genomic and epigenomic data, and with powerful bioinformatics and biostatistical tools, are providing novel insights into multiple diseases. However, no studies have utilized these combined technologies at the scale required to address fundamental questions related to endometriosis - a scientific gap addressed herein. A growing number of human diseases are associated with acquired defects in DNA methylation, and epigenetic changes provide a biological link between individual exposures and phenotype. Our proposal addresses identifying endometriosis-specific, eutopic endometrial DNA methylation signals, their associations with surgical disease phenotypes and specific patient characteristics, genetic and non-genetic contributions to these DNA methylation signals and potentially identifying modifiable disease risk factors. Our team involves a collaboration among global leading genomic and epidemiological research centers focused on endometriosis (UCSF, Harvard, Oxford, QIMR, and University of Melbourne (the “Consortium”)) to address the hypotheses that 1) environmental and genetic influences contribute to endometriosis and leave long-term signatures in the DNA methylome in the eutopic endometrium that contribute to disease pathogenesis and pathophysiology; and 2) these can serve to stratify disease risk and inform new avenues for drug target discoveries and diagnostic development. We propose to perform genome-wide DNA methylation analyses and genotyping of nearly 1000 well annotated, existing eutopic endometrium samples (and ongoing accrual for a 400 sample replication study), collected by standard operating procedures and extensive phenotyping, established by our World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project (WERF-EPHect).