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: 10299857
• 负责人: Paula Sofia Ramos
• 金额: $ 66.96万
• 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/10299857
• 关键词: Acceleration; Address; Advisory Committees; Affect; African; African American; 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; 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; 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.

摘要 系统性红斑狼疮(SLE，或狼疮)是一种典型的自身免疫性疾病，以不成比例的 非洲裔妇女的患病率和严重负担(AA)。迫切需要作出努力，以确定 积极和消极的社会健康决定因素对健康的分子机制 狼疮健康差距，以便在改善疾病结局方面取得进展，并改善健康差距 差距是可以弥合的。本研究项目旨在解决PAR-19-372的目标，以“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，以及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 人口数量。“我们正在寻求识别和表征表观遗传机制，通过这些机制，积极的和 负面社会经历会影响基因功能，从而影响再生障碍性贫血患者的系统性红斑狼疮。我们之前已经 研究表明，种族歧视与再生障碍性贫血妇女更糟糕的疾病结局有关，而社会支持 似乎产生了积极的影响。多重环境暴露，包括心理社会因素，会影响 DNA甲基化的变异。尽管它们对再生障碍性贫血女性的系统性红斑狼疮有影响，但环境因素如何影响尚不清楚 经验影响并通过个体表观基因组影响疾病。我们将测试以下内容 再生障碍性贫血女性的假说：1)暴露在不利和保护性的社会环境中与表观基因组学有关 涉及免疫、炎症和能量代谢途径的变化，这些途径反过来又与 疾病后果；和2)社会支持补偿种族的有害、独立的影响 表观遗传学和基因调控机制对系统性红斑狼疮的歧视。我们将利用现有的注册表 和基础设施，以及我们的社区合作伙伴关系，以实现社区参与的一体化 机械学研究。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， 社会人口学、医学、基因分型、白细胞比例、DNA甲基化和基因表达数据； 使用有效的措施来评估生命周期、种族歧视和社会支持。我们建议：确定 DNA甲基化(DNaM)的变异与(A)受到种族歧视、(B)暴露于社会 支持；和(C)表观遗传年龄加速(目标1)；评估社交dNaM站点是否影响基因 表达(目标2)；并确定社会因素对系统性红斑狼疮dNaM变化和发展的协同作用 社会因素--疾病结局的dNaM预测模型(目标3)。这将是第一项研究调查 风险和弹性因素影响再生障碍性贫血患者基因功能和狼疮的表观遗传机制。这些 结果将极大地扩展关于社会因素如何影响基因功能、疾病结局和 健康差距，这可能有助于制定有效的干预措施来缩小健康差距 差距。最后，考虑到共同的致病机制，这些发现对其他 自身免疫性疾病。