The Underlying Biology of Health Disparities

健康差异的根本生物学

• 批准号: 10688821
• 负责人: michele k evans
• 金额: $ 109.79万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10688821
• 关键词: Adult; African American population; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Apolipoproteins; Appearance; Area; Automobile Driving; Basic Science; Behavioral; Biological; Biological Aging; Biological Factors; Biological Process; Biology; Catabolism; Cell Cycle Regulation; Chronic; Chronic Disease; Clinical; Clinical Research; Cognition; Coronavirus; DNA Methylation; DNA Repair; Diet; Discrimination; Disease; Disease susceptibility; Dissection; Elderly; Environmental Risk Factor; Epidemiology; Epigenetic Process; Etiology; Female; Gene Expression; Genes; Genetic; Genetic Transcription; Genomic Segment; Genomics; Goals; Health; Health Disparities Research; Health Status; Health and Retirement Study; Impaired cognition; Individual; Inflammation; Inflammatory; Interdisciplinary Study; Investigation; Knowledge; Laboratories; Lead; Life; Life Expectancy; Link; Lobular Neoplasia; Longevity; Measures; Mediating; Mediation; Mediator of activation protein; Medical; Methylation; Minority; Modeling; Modification; Molecular; Morbidity - disease rate; Musculoskeletal Physiology; Neighborhoods; Neuropsychological Tests; Not Hispanic or Latino; Outcome; Oxidative Stress; Participant; Pathogenesis; Pathway Analysis; Pathway interactions; Pattern; Peripheral Blood Mononuclear Cell; Phenotype; Physiological; Play; Population; Predisposition; Psychosocial Factor; Race; Research; Risk; Role; Rotation; Sampling; Scientist; Severities; Site; Socioeconomic Factors; Structural Racism; Syndrome; Testing; Time; Tissue-Specific Gene Expression; Translational Research; Visual; Woman; Work; age related; base; brain health; cognitive performance; cognitive testing; cohort; comparison group; depressive symptoms; dietary; disability; epidemiology study; frailty; health disparity; health outcome disparity; healthy aging; high risk; indexing; intercellular communication; literacy; low socioeconomic status; male; methylation biomarker; middle age; mortality; novel; nutrition; perceived discrimination; population based; prevent; racial diversity; sex; social culture; social health determinants; socioeconomics; telomere; therapeutic target; transcriptome; transcriptome sequencing

We have continued our work examining the biology of health disparities because it is through biological mechanisms that social determinants of health result in disparate health outcomes. Selected notable findings from this year include studies involving DNA methylation in the APOE genomic region, differential gene expression and frailty, and the relationship between discrimination and epigenetic accelerated aging. Others have shown that Apolipoprotein (APOE) 4 allele is a strong risk factor for Alzheimer's disease (AD) and cognitive decline. Epigenetic modifications such as DNA methylation (DNAm) play a central role in cognition. We sought to identify DNAm sites in the APOE genomic region associated with cognitive performance in a racially diverse middle-aged cohort (n = 411). Cognitive performance was measured by 11 standard neuropsychological tests. Two CpG sites were associated with the Card Rotation and Benton Visual Retention cognitive tests. The methylation level of the CpG site cg00397545 was associated with Card Rotation Test score (p = 0.000177) and a novel CpG site cg10178308 was associated with Benton Visual Retention Test score (p = 0.000084). Significant associations were observed among the dietary inflammatory index, which reflects the inflammatory potential of the diet, cognitive performance, and the methylation level of several CpG sites. Our results indicate that DNAm in the APOE genomic area is correlated with cognitive performance and may presage cognitive decline. Our work in frailty continues to be multifaceted. Frailty is a clinical syndrome described as reduced physiological reserve and increased vulnerability. Typically examined in older adults, recent work shows frailty occurs in middle-aged individuals and is associated with increased mortality. Previous investigation of global transcriptome changes in a middle-aged cohort from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study demonstrated inflammatory genes and pathways were significantly altered by frailty status and race. Transcriptome differences in frailty by sex remain unclear. We sought to discover novel genes and pathways associated with sex and frailty in a diverse middle-aged cohort using RNA-Sequencing. Differential gene expression and pathway analyses were performed in peripheral blood mononuclear cells for 1) frail females (FRAF, n = 4) vs non-frail females (NORF, n = 4), 2) frail males (FRAM, n = 4) vs non-frail males (NORM, n = 4), 3) FRAM vs FRAF, and 4) NORM vs NORF. We evaluated exclusive significant genes and pathways, as well as overlaps, between the comparison groups. Over 80% of the significant genes exclusive to FRAF vs NORF, FRAM vs NORM, and FRAM vs FRAF, respectively, were novel and associated with various biological functions. Pathways exclusive to FRAF vs NORF were associated with reduced inflammation, while FRAM vs NORM exclusive pathways were related to aberrant musculoskeletal physiology. Pathways exclusive to FRAM vs FRAF were associated with reduced cell cycle regulation and activated catabolism and Coronavirus pathogenesis. Our results indicate sex-specific transcriptional changes occur in middle-aged frailty, enhancing knowledge on frailty progression and potential therapeutic targets to prevent frailty. Our discrimination suite of studies continues to examine at the molecular and epidemiologic level mechanisms and mediators of its influence on health. Perceived discrimination may be associated with accelerated aging later in life, with depressive symptoms acting as potential mediator. We examined a nationally representative sample of older adults Health and Retirement Study 2010-2016, Age: 50-100 y in 2016, N = 2,806, 55.6% female, 82.3% Non-Hispanic White (NHW) to evaluate associations of perceived discrimination measures Experience of discrimination or EOD; and Reasons for Perceived discrimination or RPD) and depressive symptoms (DEP) with 13 DNAm-based measures of epigenetic aging. Group-based trajectory and four-way mediation analyses were used. Overall, and mostly among female and NHW participants, greater RPD in 2010-2012 had a significant adverse total effect on epigenetic aging 2016: DNAm GrimAge, DunedinPoAm38 (MPOA), Levine (PhenoAge) and Horvath 2, with 20-50% of this effect being explained by a pure indirect effect through DEP in 2014-2016. Among females, sustained elevated DEP (2010-2016) was associated with greater LIN DNAm age ( SE: +1.506 0.559, p = 0.009, reduced model), patterns observed for elevated DEP (high vs. low) for GrimAge and MPOA DNAm markers. Overall and in White adults, the relationship of the Levine clock with perceived discrimination in general (both EOD and RPD) was mediated through elevated DEP. Sustained elevations in DEP and RPD were associated with select biological aging measures, consistently among women and White adults, with DEP acting as mediator in several RPD-EPICLOCK associations.

我们继续开展研究健康差异的生物学工作，因为健康的社会决定因素正是通过生物机制导致不同的健康结果。 今年精选的值得注意的发现包括涉及 APOE 基因组区域 DNA 甲基化、差异基因表达和虚弱以及歧视和表观遗传加速衰老之间关系的研究。 其他研究表明，载脂蛋白 (APOE) 4 等位基因是阿尔茨海默病 (AD) 和认知能力下降的重要危险因素。 DNA 甲基化 (DNAm) 等表观遗传修饰在认知中发挥着核心作用。我们试图确定 APOE 基因组区域中与种族多样化中年队列 (n = 411) 认知表现相关的 DNAm 位点。认知表现通过 11 项标准神经心理学测试进行测量。两个 CpG 位点与卡片旋转和本顿视觉保留认知测试相关。 CpG 位点 cg00397545 的甲基化水平与卡片旋转测试分数相关 (p = 0.000177)，而新的 CpG 位点 cg10178308 与本顿视觉保留测试分数相关 (p = 0.000084)。饮食炎症指数之间观察到显着相关性，该指数反映了饮食的炎症潜力、认知能力和几个 CpG 位点的甲基化水平。我们的结果表明 APOE 基因组区域中的 DNAm 与认知能力相关，并可能预示认知能力下降。 我们在脆弱方面的工作仍然是多方面的。虚弱是一种临床综合征，被描述为生理储备减少和脆弱性增加。通常在老年人中进行检查，最近的研究表明，中年人会出现虚弱，并且与死亡率增加有关。先前对来自跨生命周期多样性社区健康老龄化（HANDLS）研究的中年队列的全球转录组变化的调查表明，炎症基因和通路因虚弱状态和种族而显着改变。不同性别的虚弱程度的转录组差异仍不清楚。我们试图利用 RNA 测序在不同的中年人群中发现与性和虚弱相关的新基因和途径。对以下对象的外周血单核细胞进行差异基因表达和通路分析：1) 虚弱女性 (FRAF，n = 4) 与非虚弱女性 (NORF，n = 4)，2) 虚弱男性 (FRAM，n = 4) 与非虚弱男性 (NORM，n = 4)，3) FRAM 与 FRAF，以及 4) NORM 与 NORF。我们评估了比较组之间独特的重要基因和途径以及重叠。 FRAF 与 NORF、FRAM 与 NORM 以及 FRAM 与 FRAF 分别独有的显着基因中超过 80% 是新颖的并且与各种生物学功能相关。 FRAF 与 NORF 独有的途径与炎症减轻相关，而 FRAM 与 NORM 独有的途径与异常的肌肉骨骼生理学相关。 FRAM 与 FRAF 独有的途径与细胞周期调节减弱、分解代谢激活和冠状病毒发病机制相关。我们的结果表明，性别特异性转录变化发生在中年虚弱中，增强了对虚弱进展和预防虚弱的潜在治疗靶点的认识。 我们的歧视系列研究继续在分子和流行病学水平上检查其对健康影响的机制和中介因素。感知到的歧视可能与晚年加速衰老有关，其中抑郁症状是潜在的中介因素。我们检查了 2010-2016 年老年人健康与退休研究的全国代表性样本，年龄：2016 年 50-100 岁，N = 2,806，55.6% 女性，82.3% 非西班牙裔白人 (NHW)，以评估感知歧视措施与歧视或 EOD 经历之间的关联；感知歧视的原因 (RPD) 和抑郁症状 (DEP)，以及 13 种基于 DNAm 的表观遗传衰老指标。使用基于组的轨迹和四向中介分析。总体而言，主要是在女性和 NHW 参与者中，2010-2012 年较大的 RPD 对 2016 年表观遗传衰老产生了显着的不利总体影响：DNAm GrimAge、DunedinPoAm38 (MPOA)、Levine (PhenoAge) 和 Horvath 2，其中 20-50% 的这种影响可以通过 2014-2016 年 DEP 的纯粹间接影响来解释。在女性中，持续升高的 DEP（2010-2016 年）与较高的 LIN DNAm 年龄相关（SE：+1.506 0.559，p = 0.009，简化模型），观察到 GrimAge 和 MPOA DNAm 标记的 DEP 升高（高与低）模式。总体而言，在白人成年人中，莱文时钟与一般感知歧视（EOD 和 RPD）的关系是通过 DEP 升高来调节的。 DEP 和 RPD 的持续升高与特定的生物衰老指标相关，在女性和白人成年人中一致，DEP 在多个 RPD-EPICLOCK 关联中充当中介。