Epigenetic age acceleration, neighborhood disadvantage, and racial disparities in risk of colon adenoma

表观遗传年龄加速、邻里劣势和结肠腺瘤风险的种族差异

• 批准号: 10469705
• 负责人: Li Li
• 金额: $ 9.58万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-18 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10469705
• 关键词: Acceleration; African American; Age; Aging; Biological Aging; Caucasians; Censuses; Chronology; Cohort Studies; Colon; Colonic Adenoma; Colonic Neoplasms; Colorectal Cancer; Communities; Complex; Comprehensive Cancer Center; DNA Methylation; Data; Databases; Development; Disadvantaged; Disease; Economics; Epigenetic Process; Equation; Ethnic Origin; Ethnic group; Genome; Grant; Health; Heritability; Human; Incidence; Individual; Life Style; Linear Models; Malignant Neoplasms; Measures; Mediating; Methylation; Modeling; Modification; Molecular; Neighborhoods; Obesity; Ohio; Outcome; Parents; Patients; Prevention strategy; Primary Prevention; Race; Resources; Risk; Risk Factors; Sampling; Site; Smoking; Socioeconomic Status; Structure; Tissues; adenoma; age related; base; burden of illness; cancer health disparity; carcinogenicity; case control; cohort; colorectal cancer risk; contextual factors; crosslink; environmental change; epidemiologic data; epidemiology study; ethnic health disparity; genome-wide; innovation; insight; mortality; neighborhood disadvantage; novel; racial and ethnic; racial difference; racial disparity; racial health disparity; screening; social; social structure; socioeconomic disparity; socioeconomics; whole genome

Summary Racial disparities in colorectal cancer (CRC) have been well documented and are widening. Increasing data strongly suggest that neighborhood socioeconomic disparities contribute to racial/ethnic health disparities across a variety of health outcomes above and beyond individual-level risk factors. How neighborhood social and structural disadvantages may modulate an individual's risk, and the molecular mechanisms by which these multiple-level risk factors may act upon to drive the development of colon neoplasia are largely unexplored. We propose an innovative epigenetic epidemiology study to comprehensively examine the complex interplay of neighborhood-level socioeconomic status, individual-level risk factors, and epigenetic age acceleration of normal colonic tissues in racial disparities and the development early colon neoplasia. Our central hypothesis is that colonic tissue epigenetic age acceleration, assessed by genome-wide DNA methylation, mediates the race- differential colon carcinogenic effects of individual-level CRC risk factors. We further hypothesize that neighborhood disadvantage in part accounts for racial disparities in the association of known individual-level CRC risk factors and risk of early colon neoplasia. Our proposal capitalizes upon a unique resource established as part of the parent Cleveland Colon Screening and Risk Factors Cohort Study where extensive epidemiological data and normal colonic tissues have been collected from 928 (367 African Americans, 561 Caucasians) patients (436 adenoma cases and 492 adenoma-free controls) undergoing colon screening. By cross-linking the cohort to the NEO CANDO (NorthEast Ohio Community and Neighborhood Data for Organizing) database that contains over 20 years of indicators on social, economic and physical conditions in the region's communities, we will use various census tract-based neighborhood socioeconomic data to assess neighborhood disadvantage for the current proposal. We will first examine the effect of race and individual-level risk factors on colon specific epigenetic age acceleration (Aims 1 and 2). We will then investigate the effect of upstream neighborhood contextual factors on epigenetic age acceleration above and beyond individual-level risk factors (Aim 3). Last, we will use a structural equation modeling approach to synthesize the information of neighborhood disadvantage and individual-level risk factors and evaluate both the direct and indirect (i.e., mediated by epigenetic age acceleration) effects on risk of colon adenoma (Aim 4). Our study will provide novel insight of how neighborhood disadvantage and individual lifestyle may accelerate epigenetic aging of colon and drive racial disparities in the development of early colon neoplasia. Our results will have significant implication for developing effective primary prevention strategy to reduce racial disparities in colon neoplasia.

总结 结直肠癌（CRC）的种族差异已得到充分证明，并正在扩大。增加 数据有力地表明，邻里社会经济差异有助于种族/民族健康差异 超越个人层面风险因素的各种健康结果。邻里社交 和结构上的缺陷可能会调节个体的风险，以及这些缺陷的分子机制。 多水平的危险因素可能作用于结肠瘤形成的发展，这在很大程度上是未知的。 我们提出了一项创新的表观遗传流行病学研究，以全面研究以下因素的复杂相互作用： 邻里水平的社会经济地位，个人水平的危险因素，和正常的表观遗传年龄加速 结肠组织中的种族差异与结肠肿瘤的早期发展有关。我们的核心假设是， 通过全基因组DNA甲基化评估的结肠组织表观遗传年龄加速， 个体水平CRC危险因素的不同结肠致癌作用。我们进一步假设， 邻里的劣势在一定程度上解释了已知个人水平的关联中的种族差异 结直肠癌的危险因素和早期结肠肿瘤的风险。我们的建议利用了一种独特的资源， 作为母公司克利夫兰结肠筛查和风险因素队列研究的一部分， 收集了928例患者（367例非裔美国人，561例高加索人）的数据和正常结肠组织 (436腺瘤病例和492例无腺瘤对照）进行结肠筛查。通过交叉连接队列 NEO CANDO（东北俄亥俄州社区和邻里数据组织）数据库，其中包含 20多年来，我们将利用该地区社区的社会、经济和物质条件指标， 各种基于人口普查区的邻里社会经济数据，以评估邻里的不利因素， 目前的提案。我们将首先研究种族和个体水平的风险因素对结肠特异性 表观遗传年龄加速（目标1和2）。然后，我们将研究上游邻居的影响， 表观遗传年龄加速的背景因素高于和超越个人水平的风险因素（目标3）。最后， 我们将使用一个结构方程模型的方法来综合邻域劣势的信息 和个人水平的风险因素，并评估直接和间接（即，表观遗传年龄介导 加速）对结肠腺瘤风险的影响（目标4）。我们的研究将提供新的见解如何邻里 不利条件和个人生活方式可能会加速结肠的表观遗传老化，并导致结肠癌的种族差异。 早期结肠肿瘤的发展。我们的研究结果将对开发有效的初级 预防策略，以减少结肠肿瘤的种族差异。