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 系统性红斑狼疮（SLE 或狼疮）是一种典型的自身免疫性疾病，其特征是不成比例的 非洲血统女性 (AA) 的患病率和严重程度负担 迫切需要努力确定。 健康的积极和消极社会决定因素通过分子机制促进健康 狼疮健康差异，以便在改善疾病结果和健康差异方面取得进展 该研究项目旨在实现 PAR-19-372 的目标：“1) 增进理解。 社会因素导致影响少数群体健康和健康的表观遗传变化的机制 差异，2) 促进表观遗传学研究，以更好地预测健康差异中的疾病或弹性 “我们正在寻求识别和表征表观遗传机制，通过这些机制，积极和 负面的社会经历会影响 AA 女性的基因功能并影响 SLE。 研究表明，种族歧视与 AA 女性更糟糕的疾病结果相关，而社会支持 多种环境暴露（包括心理社会因素）似乎会产生积极影响。 DNA 甲基化的变异尽管对 AA 女性的 SLE 有影响，但尚不清楚环境如何影响。 经历影响并通过个体表观基因组来影响疾病。我们将测试以下内容。 AA 女性的假设：1）暴露于不利和保护性的社会环境与表观基因组相关 涉及免疫、炎症和能量代谢途径的变化，而这些变化又与 疾病结果；2) 社会支持补偿种族的痛苦和独立影响 我们将利用我们现有的登记系统对 SLE 进行歧视。 和基础设施，以及我们的社区伙伴关系，以实现这一社区参与的综合性 我们将招募 300 名患有 SLE 的 AA 女性和 300 名未受影响的 AA 女性，收集 社会人口统计、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命全程的种族歧视和社会支持。 DNA 甲基化 (DNAm) 的变异与 (a) 遭受种族歧视、(b) 暴露于社会 支持，以及 (c) 表观遗传年龄加速（目标 1）；以评估社会 DNAm 位点是否影响基因 表达（目标 2）；并确定社会因素对 SLE 的 DNAm 变化的协同影响并制定 疾病结果的社会因素 DNAm 预测模型（目标 3）这将是第一项调查研究。 风险和弹性因素影响 AA 女性基因功能和狼疮的表观遗传机制。 结果将极大地扩展关于社会因素如何影响基因功能、疾病结果和 健康差异，这可能有助于制定有效的干预措施来缩小健康差异 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。