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.

我们继续研究健康差异的生物学，因为健康的社会决定因素正是通过生物学机制导致不同的健康结果。 今年的一些值得注意的发现包括涉及APOE基因组区域DNA甲基化、差异基因表达和脆弱性以及歧视与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）和认知能力下降的一个强危险因素。表观遗传修饰如DNA甲基化（DNAm）在认知中起着核心作用。我们试图在一个种族多样的中年队列（n = 411）中确定与认知能力相关的APOE基因组区域中的DNAm位点。认知能力通过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持认知测试相关。CpG位点cg 00397545的甲基化水平与卡片旋转测试得分相关（p = 0.000177），新的CpG位点cg 10178308与本顿视觉保持测试得分相关（p = 0.000084）。饮食炎症指数（反映饮食的炎症潜力）、认知表现和几个CpG位点的甲基化水平之间存在显着关联。我们的研究结果表明，在APOE基因组区域的DNAm与认知能力，并可能预示着认知能力下降。 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，表现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，中年人的脆弱性与死亡率增加有关。之前对来自健康老龄化社区多样性跨寿命（HANDLS）研究的中年队列中的全球转录组变化的研究表明，炎症基因和途径因虚弱状态和种族而显着改变。转录组的性别脆弱差异仍不清楚。我们试图使用RNA测序在一个多样化的中年队列中发现与性别和虚弱相关的新基因和途径。在外周血单核细胞中进行差异基因表达和途径分析，用于1）虚弱女性（FRAF，n = 4）与非虚弱女性（NORF，n = 4），2）虚弱男性（弗拉姆，n = 4）与非虚弱男性（NORM，n = 4），3）弗拉姆与FRAF，和4）NORM与NORF。我们评估了比较组之间唯一的重要基因和途径，以及重叠。FRAF与NORF、弗拉姆与NORM、弗拉姆与FRAF的特异性基因中，分别有超过80%是新基因，与多种生物学功能相关。FRAF与NORF的专用通路与炎症减少相关，而弗拉姆与NORM专用通路与异常的肌肉骨骼生理学相关。弗拉姆与FRAF的专用途径与细胞周期调节减少和活化的catalysts和冠状病毒发病机制相关。我们的研究结果表明，性别特异性的转录变化发生在中年虚弱，增强对虚弱进展和潜在的治疗靶点，以防止虚弱的知识。 我们的歧视研究系列继续在分子和流行病学水平上研究其对健康影响的机制和介导因素。感知到的歧视可能与生命后期的加速衰老有关，抑郁症状是潜在的中介。我们检查了2010-2016年老年人健康和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%非西班牙裔白色（NHW），以评估感知歧视措施或EOD的经验的关联;和感知歧视或RPD的原因）和抑郁症状（DEP）与13个基于DNA的表观遗传衰老指标。采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年更大的RPD对表观遗传衰老2016年有显著的不利总影响：DNAm GrimAge，DunedinPoAm 38（MPOA），Levine（PhenoAge）和Horvath 2，2014-2016年通过DEP的纯间接影响解释了这种影响的20-50%。在女性中，持续升高的DEP（2010-2016）与较大的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标记物的DEP升高模式（高vs.低）。总体而言，在白色成年人中，Levine时钟与一般感知歧视（EOD和RPD）的关系是通过DEP升高介导的。DEP和RPD的持续升高与选择的生物衰老指标相关，在女性和白色成年人中一致，DEP在几个RPD-EPIClectomy协会中起中介作用。