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: 10005929
• 负责人: Li Li
• 金额: $ 34.08万
• 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/10005929
• 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记录，并且正在扩大。增加 数据强烈表明，社区社会经济差异导致种族/族裔健康差异 超越个人层面风险因素的各种健康结果。邻里社交如何 和结构上的缺点可能会调节个体的风险，以及这些风险的分子机制 可能驱动结肠肿瘤发展的多层次风险因素在很大程度上尚未被探索。 我们提出了一项创新的表观遗传流行病学研究，以全面检查以下因素之间的复杂相互作用： 社区层面的社会经济地位、个人层面的风险因素和表观遗传年龄加速正常 结肠组织的种族差异和早期结肠肿瘤的发展。我们的中心假设是 通过全基因组 DNA 甲基化评估，结肠组织表观遗传年龄加速介导种族 个体水平的结直肠癌危险因素对结肠癌的不同影响。我们进一步假设 邻里劣势在一定程度上解释了已知个人水平交往中的种族差异 CRC 危险因素和早期结肠肿瘤的风险。我们的提案利用了已建立的独特资源 作为父级克利夫兰结肠筛查和危险因素队列研究的一部分，其中广泛的流行病学研究 数据和正常结肠组织收集自 928 名患者（367 名非裔美国人，561 名白种人） （436 例腺瘤病例和 492 例无腺瘤对照）正在接受结肠筛查。通过交叉链接队列 到 NEO CANDO（东北俄亥俄州社区和邻里组织数据）数据库，其中包含 我们将使用 20 多年来有关该地区社区社会、经济和物质条件的指标 各种基于人口普查区的社区社会经济数据，以评估社区的劣势 当前的提案。我们将首先检查种族和个人水平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邻域的影响 表观遗传年龄加速的背景因素超出了个人水平的风险因素（目标 3）。最后的， 我们将使用结构方程建模方法来综合邻域劣势信息 和个人层面的风险因素，并评估直接和间接（即由表观遗传年龄介导的） 加速）对结肠腺瘤风险的影响（目标 4）。我们的研究将为邻里如何 劣势和个人生活方式可能会加速结肠的表观遗传老化并导致种族差异 早期结肠肿瘤的发展。我们的结果将对开发有效的初级教育产生重大影响 减少结肠肿瘤种族差异的预防策略。