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

项目总结/摘要 子宫内膜异位症是引起盆腔疼痛和不孕的常见疾病。它影响着数百万人的生活质量， 这对美国的卫生经济产生了重大影响。大多数疾病源于月经逆行 将子宫内膜组织和细胞从子宫内膜（在位子宫内膜）接种到盆腔 发展为损伤并引起炎症反应和瘢痕的结构。它是通过手术诊断出来的， 在外观和分期上是异质的，其特征是对手术和 医学治疗子宫内流产诱发疾病的原因要么是先天的， （遗传）或后天（环境/生活方式），如果是后者，提高生活方式改变的可能性， 改变疾病风险和进展。NIH人类基因组计划和NIH表观基因组学计划路线图 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， 为多种疾病提供了新的见解。然而，没有研究使用这些组合 解决与子宫内膜异位症相关的基本问题所需的规模技术-科学差距 在此解决。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与表型之间的生物学联系。 我们的建议是确定子宫内膜异位症特异性在位子宫内膜DNA甲基化信号， 与外科疾病表型和特定患者特征（遗传和非遗传）的相关性 这些DNA甲基化信号的贡献，并可能识别可改变的疾病风险因素。我们 该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， 子宫内膜异位症（UCSF，哈佛，牛津，QIMR和墨尔本大学（“联盟”）），以解决 假设1）环境和遗传影响有助于子宫内膜异位症，并留下长期 在位子宫内膜中DNA甲基化组的特征有助于疾病的发病机制， 病理生理学; 2）这些可以用于对疾病风险进行分层，并为药物靶向提供新的途径 发现和诊断发展。我们建议进行全基因组DNA甲基化分析， 对近1000个良好注释的现有在位子宫内膜样本进行基因分型（以及持续的 400个样品重复研究），通过标准操作程序和广泛的表型分析收集， 由我们的世界子宫内膜异位症研究基金会建立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).