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.

概括 结直肠癌（CRC）的种族差异已得到充分证明并正在扩大。增加 数据强烈表明，社区社会经济差异有助于种族/种族健康差异 在各种健康状况中，超出了个人级别的风险因素。社区如何社交 结构上的缺点可能会调节个人的风险，以及这些分子机制 多层危险因素可能会采取行动来推动结肠肿瘤的发展。 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 邻里级别的社会经济状况，个人级别危险因素和正常的表观遗传年龄加速 种族差异和发展早期结肠肿瘤的结肠组织。我们的中心假设是 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度介导种族 个体级别CRC风险因素的差异结肠致癌作用。我们进一步假设 邻里的劣势部分是由于已知个人级别关联的种族差异 CRC风险因素和早期结肠肿瘤的风险。我们的提案资本利用了建立的独特资源 作为父母克利夫兰结肠筛查和风险因素队列研究的一部分，广泛的流行病学 从928（367名非裔美国人，561名高加索人）患者收集了数据和正常的结肠组织 （436例腺瘤病例和492例无腺瘤对照）接受结肠筛查。通过交联该队列 到包含的Neo Cando（东北俄亥俄州社区和组织数据库） 在该地区社区中有关社会，经济和身体状况的20年以上，我们将使用 各种基于人口普查的社区社会经济数据，以评估 当前的建议。我们将首先研究种族和个人级别风险因素对结肠特异性的影响 表观遗传年龄加速（目标1和2）。然后，我们将研究上游社区的效果 表观遗传年龄加速的上下文因素超出了个体级别的风险因素（AIM 3）。最后的， 我们将使用一种结构方程建模方法来综合邻里劣势的信息 以及个人级别的风险因素，并评估直接和间接的风险因素（即，由表观遗传年龄介导 加速度）对结肠腺瘤风险的影响（AIM 4）。我们的研究将提供有关邻里如何的新见解 劣势和个人生活方式可能会加速结肠的表观遗传衰老，并推动种族差异 早期结肠肿瘤的发展。我们的结果将对开发有效的初级产生重大影响 预防策略减少结肠肿瘤中的种族差异。