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

子宫内膜异位症疾病分层的基因组、表观基因组和表型数据的综合分析

基本信息

批准号：
9356327
负责人：
ATUL J BUTTE
金额：
$ 60.67万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-26 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9356327
关键词：
Aberrant DNA Methylation Address Affect Age Appearance Behavior Therapy Binding Sites Bioinformatics Biological Biological Markers Biometry Cells Characteristics Cicatrix Collaborations Communities Complex DNA DNA Methylation Data Data Set Defect Detection Development Diagnosis Diagnostic Disease Disease Marker Disease Progression Disease stratification Drug Targeting Endometrial Endometriomas Endometrium Epigenetic Process Estrogens Etiology Exhibits Foundations Functional disorder Genes Genetic Genomic Segment Genomics Genotype Goals Grant Health Human Genome Project Individual Infertility Inflammatory Response Intercistronic Region LIF gene Lesion Life Style Link Medical Menstrual cycle Methylation Modification Operative Surgical Procedures Pain Pathogenesis Pathway interactions Patient risk Patients Pelvic Pain Pelvis Peritoneal Phase Phenotype Polycomb Procedures Progesterone Quality of life Regulatory Element Research Resistance Risk Risk Factors Sampling Severity of illness Signal Pathway Signal Transduction Staging Structure Symptoms Technology Testing Tissue Sample Tissues Transcription Initiation Site United States National Institutes of Health Universities Uterus Variant Woman biobank disease phenotype disorder control disorder risk endometriosis epidemiology study epigenomics genetic variant genome wide association study genome-wide human disease insight member methylation pattern methylome non-genetic novel phenome phenotypic data promoter repository response steroid hormone therapeutic target tool trait transcription factor transcriptome translational diagnostics

项目摘要

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).

项目概要/摘要子宫内膜异位症是一种导致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。女性，并对美国健康经济产生重大影响，大多数疾病都源于月经逆行。将子宫内膜组织和细胞从子宫内膜（在位子宫内膜）种植到盆腔上发展为病变并引发炎症反应和疤痕的结构。其外观和分期具有异质性，其特点是对手术和治疗的反应不可预测。导致该疾病的子宫内异常或者是固有的。（遗传）或后天（环境/生活方式），如果是后者，则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 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工具，提供了对多种疾病的新见解然而，还没有研究将这些结合起来。解决与子宫内膜异位症相关的基本问题所需的技术规模——科学差距本文阐述了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。我们的提案致力于识别子宫内膜异位症特异性、在位子宫内膜 DNA 甲基化信号、它们的与外科疾病表型和特定患者特征（遗传和非遗传）的关联对这些 DNA 甲基化信号的贡献以及潜在地识别可改变的疾病风险因素。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，重点关注子宫内膜异位症（UCSF、哈佛大学、牛津大学、QIMR 和墨尔本大学（“联盟”）），以解决假设 1) 环境和遗传影响会导致子宫内膜异位症并导致长期子宫内膜异位症在位子宫内膜 DNA 甲基化组中有助于疾病发病机制的特征病理生理学；2) 这些可以用于对疾病风险进行分层并为药物靶点提供新途径我们建议进行全基因组 DNA 甲基化分析和对近 1000 个注释良好的现有在位子宫内膜样本进行基因分型（并持续累积 400 个样本重复研究），通过标准操作程序和广泛的表型分析收集，由世界子宫内膜异位症研究基金会子宫内膜异位症现象组和生物库建立协调项目（WERF-EPHect）。