Social Factors, Epigenomics, and Lupus in African American women (SELA)

非裔美国女性的社会因素、表观基因组学和狼疮 (SELA)

• 批准号: 10458001
• 负责人: Paula Sofia Ramos
• 金额: $ 65.11万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-28 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10458001
• 关键词: Acceleration; Address; Advisory Committees; Affect; African American; African American population; African ancestry; Age; Anxiety; Autoantibodies; Autoimmune Diseases; Behavioral; Bioinformatics; Blood Cells; Blood specimen; Cell physiology; Characteristics; Chronic; Clinical Medicine; Communities; DNA Methylation; Data; Death Rate; Development; Disease; Disease Outcome; Energy Metabolism Pathway; Enrollment; Environmental Exposure; Environmental Risk Factor; Epigenetic Process; Etiology; Exposure to; Family; Gene Expression; Genetic; Genotype; Goals; Health; Health Disparities Research; Household; Human; Immune; Income; Individual; Inflammatory; Infrastructure; Island; Joints; Knowledge; Lead; Leukocytes; Life Cycle Stages; Linear Regressions; Lupus; Measures; Mediation; Medical; Mendelian randomization; Mental Depression; Methylation; Modeling; Modification; Molecular; Morbidity - disease rate; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Outcome; Participant; Patient Self-Report; Physiological; Population; Prevalence; Production; Psychosocial Factor; Public Health; Registries; Regulator Genes; Research; Research Project Grants; Risk; Sea; Severities; Severity of illness; Site; Social Environment; Social support; Systemic Lupus Erythematosus; Testing; Variant; Woman; aged; behavioral genomics; cohort; community partnership; effective intervention; effective therapy; epigenome; epigenomics; experience; gene function; genetic variant; health disparity; health disparity populations; improved; machine learning method; minority health disparity; mortality; negative affect; perceived stress; physiologic stressor; precision medicine; predictive modeling; preventive intervention; racial discrimination; racism; recruit; resilience; response; social; social epidemiology; social factors; social health determinants; social stressor; sociodemographics; socioeconomics; statistics; stressor; transcriptome sequencing; transcriptomics

ABSTRACT Systemic lupus erythematosus (SLE, or lupus) is a prototypic autoimmune disease marked by a disproportionate prevalence and severity burden in women of African ancestry (AA). There is a critical need for efforts that identify the molecular mechanisms through which positive and negative social determinants of health contribute to the lupus health disparity, so that progress in improving disease outcomes can be made and the health disparities gap can be closed. This research project addresses the objectives of PAR-19-372 to “1) advance understanding of mechanisms by which social factors lead to epigenetic changes that affect minority health and health disparities, and 2) promote epigenetics research to better predict disease or resiliency among health disparity populations.” We are seeking to identify and characterize the epigenetic mechanisms by which positive and negative social experiences affect gene function and thereby influence SLE in AA women. We have previously shown that racial discrimination is associated with worse disease outcomes in AA women, while social support seems to have a positive impact. Multiple environmental exposures, including psychosocial factors, affect variation in DNA methylation. Despite their influence on SLE in AA women, it is not known how environmental experiences affect and operate through the individual epigenome to influence disease. We will test the following hypotheses in AA women: 1) exposure to adverse and protective social contexts is associated with epigenomic changes involving immune, inflammatory, and energy metabolism pathways, which in turn are associated with disease outcomes; and 2) social support compensates for the detrimental, independent effect of racial discrimination on SLE through epigenetic and gene regulatory mechanisms. We will leverage our existing registry and infrastructure, together with our community partnership, to accomplish this community-engaged integrative mechanistic study. We will enroll 300 AA women with SLE and 300 unaffected AA women, collect sociodemographic, medical, genotypic, leukocyte proportion, DNA methylation, and gene expression data, and use validated measures to assess life course racial discrimination and social support. We propose to: identify variation in DNA methylation (DNAm) associated with (a) exposure to racial discrimination, (b) exposure to social support, and (c) epigenetic age acceleration (Aim 1); to assess whether social DNAm sites affect gene expression (Aim 2); and identify the synergistic effects of social factors on DNAm changes on SLE and develop a social factors-DNAm predictive model for disease outcomes (Aim 3). This will be the first study investigating epigenetic mechanisms by which risk and resiliency factors affect gene function and lupus in AA women. These results will greatly expand the knowledge of how social factors affect gene function, disease outcomes, and health disparities, which might inform the development of effective interventions to close the health disparities gap. Finally, given the shared etiologic mechanisms, these findings have broader applicability to other autoimmune diseases.

抽象的 全身性红斑狼疮（SLE或狼疮）是一种原型自身免疫性疾病，标志着不成比例 非洲血统妇女（AA）的患病率和严重性燃烧。努力确定的迫切需要 正面和负面社会决定者的分子机制有助于 狼疮的健康差异，因此可以改善疾病结局的进展以及健康差异 差距可以封闭。该研究项目涉及第19-372款至“ 1）提前理解的目标 社会因素导致表观遗传变化的机制，影响少数族裔健康和健康 差异和2）促进表观遗传学研究，以更好地预测健康差异的疾病或韧性 人口。“我们正在寻求识别和表征积极和阳性的表观遗传机制 负面的社会经历会影响基因功能，从而影响AA女性的SLE。我们以前有 表明种族歧视与AA妇女的疾病结果较差有关，而社会支持则 似乎有积极的影响。多种环境暴露，包括社会心理因素，影响 DNA甲基化的变化。尽管她们对AA女性的SLE有影响，但尚不知道环境如何 经历会影响和通过个体表观基因组进行影响，以影响疾病。我们将测试以下 AA妇女的假设：1）暴露于不利和受保护的社会环境与表观基因组有关 涉及免疫，炎症和能量代谢途径的变化，这又与 疾病结果； 2）社会支持弥补了种族的决心，独立的影响 通过表观遗传和基因调节机制对SLE的歧视。我们将利用我们现有的注册表 以及基础设施以及我们的社区合作伙伴关系，以完成这一社区参与的综合 机械研究。我们将注册300名AA女性，患有SLE和300名未受影响的AA妇女，收集 社会人口统计学，医学，基因型，白细胞比例，DNA甲基化和基因表达数据，以及 使用经过验证的措施来评估生活课程种族歧视和社会支持。我们建议：确定 与（a）暴露于种族歧视相关的DNA甲基化（DNAM）的变化，（b）暴露于社会 支持和（c）表观遗传年龄的加速度（AIM 1）；评估社交DNAM网站是否影响基因 表达（目标2）；并确定社会因素对DNAM变化对SLE和发展的协同影响 疾病结局的社会因素-DNAM预测模型（AIM 3）。这将是第一个研究 风险和弹性因素会影响AA女性基因功能和狼疮的表观遗传机制。这些 结果将大大扩展有关社会因素如何影响基因功能，疾病结果和 健康分配，这可能告知开发有效干预措施以关闭健康分配 差距。最后，鉴于共同的病因机制，这些发现具有更广泛的适用性 自身免疫性疾病。