The Underlying Biology of Health Disparities

健康差异的根本生物学

• 批准号: 10001281
• 负责人: michele k evans
• 金额: $ 127.65万
• 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/10001281
• 关键词: Acceleration; Adult; Affect; African American; Age; Aging; American; Appearance; Basic Science; Behavioral; Biological; Biology; Blood; Chronic; Chronic Disease; Chronology; Clinical Research; DNA; DNA Damage; DNA Methylation; DNA Repair; Data; Disease; Disease susceptibility; Dissection; Early Intervention; Environmental Risk Factor; Epigenetic Process; FCGR3B gene; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Glucose Transporter; Goals; Growth and Development function; H19 gene; Health; Human; Immune signaling; Immunity; Individual; Inflammation; Interdisciplinary Study; Laboratories; Lead; Life Expectancy; Link; Longevity; Measures; Medical; Messenger RNA; Methylation; Minority; Mitochondria; Molecular; Neighborhoods; Outcome; Oxidative Stress; Pathway interactions; Peripheral Blood Mononuclear Cell; Phenotype; Physiology; Play; Population; Positioning Attribute; Poverty; Proteins; RNA; Race; Research; Risk; Risk Factors; Role; Scientist; Severities; Stress; Syndrome; Tissue-Specific Gene Expression; Translational Research; Untranslated RNA; Virus Diseases; Woman; Work; age related; bead chip; cohort; cytokine; differential expression; disability; experience; frailty; genome-wide; health disparity; healthy aging; high risk; insight; low socioeconomic status; male; men; methylation pattern; middle age; mortality; mortality statistics; neutrophil; next generation; novel; population based; premature; programs; racism; receptor; response; sex; social; social genomics; stressor; transcription factor; transcriptome sequencing; validation studies

We have continued our work examining the biology of health disparities because it is through biological mechanisms that social determinates of health result in disparate health outcomes. Notable results from this year include studies involving frailty, social genomics and epigenetic age acceleration. Frailty is an aging-associated syndrome resulting from diminished capacity to respond to stressors and is a significant risk factor for disability and mortality. Although frailty is usually studied in old age, it is present in mid-life. Given the increases in mortality statistics among middle-aged Americans, understanding molecular drivers of frailty in a younger, diverse cohort may facilitate identifying pathways for early intervention. We analyzed frailty-associated, genome-wide transcriptional changes in middle-aged blacks and whites. Next generation RNA sequencing was completed using total RNA from peripheral blood mononuclear cells (n = 16). We analyzed differential gene expression patterns and completed a parametric analysis of gene set enrichment (PAGE). Differential gene expression was validated using RT-qPCR (n = 52). We identified 5,082 genes differentially expressed with frailty. Frailty altered gene expression patterns and biological pathways differently in blacks and whites, including pathways related to inflammation and immunity. The validation study showed a significant two-way interaction between frailty, race, and expression of the cytokine IL1B and the transcription factor EGR1. The glucose transporter, SLC2A6, the neutrophil receptor, FCGR3B, and the accessory protein, C17orf56, were decreased with frailty. These results suggest that there may be demographic dependent, divergent biological pathways underlying frailty in middle-aged adults. Emerging evidence indicates that noncoding RNAs play regulatory roles in aging and disease. The functional roles of long noncoding RNAs (lncRNAs) in physiology and disease are not completely understood. Little is known about lncRNAs in the context of human aging and socio-environmental conditions. Microarray profiling of lncRNAs and mRNAs from peripheral blood mononuclear cells from young and old white (n=16) and African American (AA) males (n=16) living above or below poverty from the Healthy Aging in Neighborhoods of Diversity across the Life Span study revealed changes in both lncRNAs and mRNAs with age and poverty status in white males, but not in AA males. We validated lncRNA changes in an expanded cohort (n=40); CTD-3247F14.2, GAS5, H19, TERC and MEG3 changed significantly with age, whereas AK022914, GAS5, KB-1047C11.2, MEG3 and XLOC_003262 changed with poverty. Mitochondrial function and response to DNA damage and stress were pathways enriched in younger individuals. Response to stress, viral infection, and immune signals were pathways enriched in individuals living above poverty. These data show that both human age and a marker of social adversity influence lncRNA expression, which may provide insight about molecular pathways underlying aging and social factors that affect disparities in aging and disease. African Americans (AAs) experience premature chronic health outcomes and longevity disparities consistent with an accelerated aging phenotype. DNA methylation (DNAm) levels at specific CpG positions are hallmarks of aging evidenced by the presence of age-associated differentially methylated CpG positions (aDMPs) that are the basis for the epigenetic clock for measuring biological age acceleration. Since DNAm has not been widely studied among non-European populations, we examined the association between DNAm and chronological age in AAs and whites, and the association between race, poverty and sex and epigenetic age acceleration. We measured genome-wide DNA methylation (866,836 CpGs) using the Illumina MethylationEPIC BeadChip in blood DNA extracted from 487 middle-aged AA (N=244) and white (N=243), men (N=248) and women (N=239). The mean (sd) age was 48.4 (8.8) in AA and 49.0 (8.7) in whites (p=0.48). We identified 4,930 significantly associated aDMPs in AAs and 469 in whites. Of these, 75.6% and 53.1% were novel, largely driven by the increased number of measured CpGs in the EPIC array, in AA and whites, respectively. AAs had more age-associated DNAm changes than whites in genes implicated in age-related diseases and cellular pathways involved in growth and development. We assessed three epigenetic age acceleration measures (universal, intrinsic and extrinsic). AAs had a significantly slower extrinsic aging compared to whites. Furthermore, compared to AA women, both AA and white men had faster aging in the universal age acceleration measure (+2.04 and +1.24 years, respectively, p<0.05). AAs have more wide-spread methylation changes than whites. Race and sex interact to underlie biological age acceleration suggesting altered DNA methylation patterns may be important in age-associated health disparities.

我们继续研究健康差异的生物学，因为它是通过生物学机制来确定健康的生物学机制。 今年的值得注意的结果包括涉及脆弱，社会基因组学和表观遗传年龄加速的研究。 脆弱是一种衰老相关的综合症，这是由于对压力源反应的能力降低而导致的，并且是残疾和死亡率的重要危险因素。尽管通常在老年中研究脆弱，但它存在于中年。鉴于中年美国人的死亡率统计数据的增加，了解年轻的队列中脆弱的分子驱动因素可能有助于确定早期干预的途径。我们分析了中年黑人和白人中脆弱的，全基因组的转录变化。使用外周血单核细胞中的总RNA完成下一代RNA测序（n = 16）。我们分析了差异基因表达模式，并完成了基因集富集的参数分析（PAGE）。使用RT-QPCR验证差异基因表达（n = 52）。我们确定了5,082个基因，这些基因用脆弱的差异表达。在黑人和白人中，脆弱的基因表达模式和生物途径不同，包括与炎症和免疫有关的途径。验证研究表明，细胞因子IL1B和转录因子EGR1之间的脆弱，种族和表达之间存在显着的双向相互作用。葡萄糖转运蛋白SLC2A6，中性粒细胞受体FCGR3B和辅助蛋白C17ORF56随着脆弱而降低。这些结果表明，中年成年人可能存在依赖人口统计学的生物学途径不同。 新兴的证据表明，未编码的RNA在衰老和疾病中起调节作用。尚未完全了解长期非编码RNA（LNCRNA）在生理和疾病中的功能作用。关于人类衰老和社会环境条件的LNCRNA知之甚少。 LNCRNA和MRNA的微阵列分析来自年轻人和老年白人（n = 16）和非裔美国人（AA）男性（n = 16）的单核细胞（n = 16）（n = 16）（n = 16），贫困中的贫困中的贫困中，来自LNCRNAS和MIRNA的多样性中的健康衰老中的贫困阶层和贫穷的变化都揭示了与白人贫民的变化，但在白人Males中，但在白人群中，但在白人群体中，但在白人中却不在白人中，但在白人中，但在白人中，但在白人中却没有在白人中，但在白人中，但在白人中却没有在白人中，但在白人群体中却没有在白人中，但在白人群体中，但在白人中均具有贫困研究。我们验证了扩展队列中的lncRNA变化（n = 40）； CTD-3247F14.2，GAS5，H19，TERC和MEG3随着年龄的增长而发生巨大变化，而AK022914，GAS5，KB-1047C11.2，MEG3和XLOC_003262随着贫困而发生了变化。线粒体功能和对DNA损伤的反应和应力富含年轻人。对压力，病毒感染和免疫信号的反应富含在贫困上方的个体中。这些数据表明，人类年龄和社会逆境的标志都会影响lncRNA的表达，这可能会提供有关衰老和社会因素的分子途径的见解，这些途径影响了衰老和疾病的差异。 非裔美国人（AAS）经历了与加速衰老表型一致的早期慢性健康成果和寿命差异。在特定CpG位置处的DNA甲基化（DNAM）水平是存在与年龄相关的差异甲基化的CpG位置（ADMP）所证明的衰老的标志，这是测量生物年龄加速的表观遗传时钟的基础。由于DNAM在非欧洲人群中没有得到广泛的研究，因此我们研究了DNAM与AAS和白人的年代年龄之间的关联，以及种族，贫困与性别与表观遗传年龄加速之间的关联。我们使用487个中年AA（n = 244）和白色（n = 243），男性（n = 248）和女性（n = 239）中提取的血液DNA中测量了全基因组DNA甲基化（866,836 CPG），并使用487个中年AA（n = 243）提取的血液DNA中的Illumina甲基化表皮珠。在AA中的平均年龄为48.4（8.8），白人为49.0（8.7）（p = 0.48）。我们在AAS中确定了4,930个显着相关的ADMP和469名白人。其中75.6％和53.1％是新颖的，在很大程度上是由于史诗阵列中测得的CpG数量增加，分别是AA和白人。与与年龄有关的疾病和与生长与发育有关的年龄相关疾病和细胞途径涉及的基因中，AA的年龄相关的DNAM变化比白人更大。我们评估了三项表观遗传年龄的加速度度量（通用，内在和外在）。与白人相比，AAS的外在衰老明显较慢。此外，与AA女性相比，AA和白人男性在通用年龄加速度措施中的老化速度更快（分别为+2.04和+1.24岁，P <0.05）。与白人相比，AA具有更广泛的甲基化变化。种族和性别与生物年龄加速的基础相互作用表明改变DNA甲基化模式可能在与年龄相关的健康差异中很重要。