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

摘要 结直肠癌(CRC)的种族差异已经有了很好的记录，而且还在扩大。渐增 数据有力地表明，邻里社会经济差距导致了种族/民族健康差距。 在个人层面的风险因素之外的各种健康后果。社区社交 结构性缺陷可能会调节个体的风险，以及这些风险的分子机制 多水平的危险因素可能作用于推动结肠肿瘤的发展，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学流行病学研究，以全面检查 社区层面的社会经济地位、个人层面的危险因素与正常人的表观遗传年龄加速 结肠组织中的种族差异与早期结肠肿瘤的发生发展。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，介导了种族- 不同个体水平结肠癌致癌作用的危险因素。我们进一步假设 邻里劣势在一定程度上解释了已知个体水平的联系中的种族差异 结直肠癌的危险因素和早期结肠癌的风险。我们的提案充分利用了一种独特的资源 作为父母克利夫兰结肠筛查和危险因素队列研究的一部分，广泛的流行病学 收集了928名患者(367名非裔美国人，561名高加索人)的数据和正常的结肠组织 (436例腺瘤病例和492例非腺瘤对照)进行结肠筛查。通过将队列进行交叉链接 到neo Cando(组织的俄亥俄州东北部社区和邻里数据)数据库，该数据库包含 20多年来关于该区域社区的社会、经济和物质条件的指标，我们将使用 各种基于人口普查区域的社区社会经济数据，以评估社区的劣势 目前的建议。我们将首先研究种族和个人水平的风险因素对结肠癌特异性的影响。 表观遗传年龄加速(目标1和2)。然后我们将调查上游邻里的影响 超越个人层面风险因素的表观遗传年龄加速的背景因素(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 和个人水平的危险因素，并评估直接和间接(即，由表观遗传年龄介导) 加速)对结肠腺瘤风险的影响(目标4)。我们的研究将为邻居们提供新的洞察 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 早期结肠肿瘤的发生。我们的结果将对发展有效的小学教育具有重要的意义 减少结肠肿瘤的种族差异的预防策略。

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.