DNA Methylation, Genetics, and Modifiable Risk Factors of Dementia in a Nationally Representative, Multi-Ethnic Cohort - Diversity Supplement

项目摘要 在美国，阿尔茨海默病和相关痴呆症（ADRD）严重影响边缘化的种族， 在考虑了医疗保健利用和其他主要风险因素后，表观遗传学方法， 例如DNA甲基化，作为分子水平上不利变化指标， 从背景效应，潜在地识别健康差异很久之前的健康结果是 可观察的DNA甲基化是一个强大的工具，可以找到不平等的来源和后果， 揭示了造成健康差距的复杂因素网络（例如生物因素、社会背景因素）。使用 表观遗传学和遗传学数据，明确表征的痴呆表型，以及各种风险因素数据， 分析了健康与退休研究（HRS）的人口代表性，多种族老龄化样本。 利用Higgins Tejera先生在生物统计学方面的专长， 建议使用父母补助金的分析框架，以扩大深入调查的作用， 痴呆症中的炎症生物标志物。他的扩展的第一个目标将估计未来的协会 炎症标志物（例如，hsCRP、IL-6、TNF-α、半胱氨酸-C）与痴呆发病率的关系 纵向回归分析。第二个目标提出了一个孟德尔随机分析的因果关系， 全身炎症对痴呆发病影响第三个目的是检验 全身性炎症和痴呆是由DNA甲基化介导的。为了确定种族/民族 修改这些关系，种族/族裔依赖关系将在所有目标中探讨。这种多样性 补充剂将扩大我们对全身炎症和DNA甲基化作用的理解， 社会不平等可能是生物学上根深蒂固的重要方式，对痴呆症的风险。 Higgins Tejera先生的职业目标是成为一名研究差异的独立研究员， 神经精神疾病的研究所为了支持他的职业发展， 在此期间，他将接受以下培训：1）高级统计分析和结果解释，包括重复 措施和调解分析，2）流行病学因果关系的方法，通过应用孟德尔 用于推断因果关系的随机化，3）健康基础的生物和社会背景因素 差异，4）通过同行评议和学术会议进行研究交流，5）教师发展 和领导力。这些领域的培训将为Higgins Tejera先生的影响力研究生涯做好准备。

PROJECT SUMMARY ABSTRACT In the US, Alzheimer’s disease and related dementias (ADRD) disproportionally affect marginalized racial and ethnic groups, after accounting for healthcare utilization and other major risk factors. Epigenetic measures, such as DNA methylation, hold great promise as indicators of adverse changes at a molecular level resulting from contextual effects, potentially identifying health disparities long before the health outcomes are observable. DNA methylation is a powerful tool to locate the sources and consequences of inequalities, further revealing the complex web of factors (e.g. biological, social-contextual) that drive health disparities. Using epigenetic and genetic data, well-characterized dementia phenotypes, and diverse risk factor data, the grant analyzes a population representative, multi-ethnic aging sample from the Health and Retirement Study (HRS). Taking advantage of Mr. Higgins Tejera’s expertise in biostatistics applied in a large, diverse cohort, he proposes to use the analytic framework of the parent grant to expand to deeply investigate the role of inflammatory biomarkers in dementia. The first aim of his expansion will estimate the prospective associations between markers of inflammation (e.g., hsCRP, IL-6, TNF-alpha, Cysteine-C) and incident dementia using longitudinal regression analyses. The second aim proposes a Mendelian randomization analysis of the causal effect of systemic inflammation on incident dementia. The third aim tests whether the relationship between systemic inflammation and dementia is mediated by DNA methylation. To determine whether race/ethnicity modifies these relationships, race/ethnicity-dependent relationships will be explored in all aims. This diversity supplement will expand our understanding of the roles of systemic inflammation and DNA methylation, two important ways that social inequality may be biologically embedded, on dementia risk. Mr. Higgins Tejera’s career goal is to be an independent researcher studying disparities and neuropsychiatric disorders at an academic institute. To support his career development, during this grant period he will receive training on: 1) advanced statistical analyses and results interpretation, including repeated measures and mediation analyses, 2) epidemiologic causal methods through the application of Mendelian randomization for inferring causal relationships, 3) biological and social-contextual factors underlying health disparities, 4) research communication through peer review and academic conferences, 5) faculty development and leadership. Training in these areas will prepare Mr. Higgins Tejera for an impactful research career.