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.

我们一直在研究研究健康差异的生物学，因为正是通过生物学机制，社会决定因素导致健康结果不同。 今年的选定发现包括涉及APOE基因组区域DNA甲基化的研究，差异基因表达和脆弱，以及歧视与表观遗传加速衰老之间的关系。 其他人则表明，载脂蛋白（APOE）4等位基因是阿尔茨海默氏病（AD）和认知能力下降的强大危险因素。表观遗传修饰（例如DNA甲基化（DNAM））在认知中起着核心作用。我们试图在种族多样化的中年队列中识别与认知性能相关的APOE基因组区域中的DNAM位点（n = 411）。认知表现通过11种标准神经心理学测试来衡量。两个CpG位点与卡旋转和本顿视觉保留认知测试有关。 CPG位点CG00397545的甲基化水平与卡旋转测试得分相关（P = 0.000177），而新型的CPG位点CG10178308与Benton Visual保留测试得分相关（P = 0.000084）。在饮食炎症指数中观察到了显着的关联，这反映了饮食，认知性能和几个CPG部位的甲基化水平的炎症潜力。我们的结果表明，APOE基因组区域中的DNAM与认知表现相关，并可能预示认知能力下降。 我们在脆弱的工作继续进行多方面。脆弱是一种临床综合征，描述为减少生理储备和增加脆弱性。通常在老年人中检查的，最近的工作表明，中年个体发生脆弱，与死亡率增加有关。先前对整个寿命多样性社区（Handls）研究的中年人群中全球转录组变化的调查表明，炎症基因和途径因弱势地位和种族而显着改变。性别脆弱的转录组差异尚不清楚。我们试图在多样化的中年队列中发现与性别和脆弱相关的新型基因和途径。在外周血单核细胞中进行差异基因表达和途径分析，1）脆弱的女性（FRAF，n = 4）与非果雌性（NORF，n = 4），2）脆弱的雄性（Frail，n = 4）与非frail Males（norm，n = 4），n = 4），3），3）Fram vs fraf vs fraf和4）和4）narm. 4）narm. 4）。我们评估了比较组之间的独家重要基因和途径以及重叠。分别是FRAF与Norf，Fram VS Norm和Fram vs Fraf的主要基因的80％以上是新颖的，并且与各种生物学功能有关。 FRAF与Norf的途径与炎症减少有关，而FRAM与规范的独家途径与异常的肌肉骨骼生理学有关。 FRAM与FRAF的途径与细胞周期调节减少以及活化的分解代谢和冠状病毒发病机理有关。我们的结果表明，在中年脆弱的情况下发生性别特异性的转录变化，增强了对脆弱进展的知识以及预防脆弱的潜在治疗靶标。 我们的研究套件继续研究其对健康的影响的分子和流行病学水平机制和介体。感知的歧视可能与以后的生活加速衰老有关，抑郁症状是潜在的介体。我们研究了2010-2016-2016年老年人健康和退休研究的全国代表性样本，2016年50-100 y，n = 2,806，55.6％的女性，82.3％的非西班牙裔白人（NHW），以评估歧视歧视或EOD的歧视经验的关联；及其感知歧视或RPD的原因和抑郁症状（DEP），并具有13个基于DNAM的表观遗传衰老的措施。使用了基于组的轨迹和四向中介分析。总体而言，大多数在女性和NHW参与者中，2010 - 2012年更大的RPD对2016年表观遗传衰老产生了严重的不利影响：Dnam Grimage，Dunedindinpoam38（MPOA）（MPOA），Levine（phenoage）和Horvath 2，此效果的20-50％通过纯粹的独立效应来解释20-50％的效果。在女性中，持续升高的DEP（2010-2016）与更大的Lin Dnam时代有关（SE：+1.506 0.559，p = 0.009，模型降低），对于高高的DEP（高与低）观察到的模式（对于磨损而高）和MPOA DNAM标记。总体而言，在白人成年人中，通过升高的DEP介导了湖泊时钟与通常的歧视（EOD和RPD）的关系。 DEP和RPD的持续升高与妇女和白人成年人之间一致的精选生物老化措施有关，DEP在几个RPD- epiclock协会中充当介体。