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。 虚弱是一种与衰老相关的综合征，由应对压力的能力下降引起，是残疾和死亡的重要风险因素。虽然虚弱通常是在老年研究，但它存在于中年。鉴于中年美国人死亡率统计数据的增加，了解年轻，多样化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与虚弱相关的全基因组转录变化。使用来自外周血单核细胞的总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（PAGE）的参数分析。使用RT-qPCR验证差异基因表达（n = 52）。我们确定了5,082个与虚弱相关的差异表达基因。虚弱改变了黑人和白人不同的基因表达模式和生物学途径，包括与炎症和免疫相关的途径。验证研究表明，虚弱，种族和细胞因子IL 1B和转录因子EGR 1的表达之间存在显着的双向相互作用。葡萄糖转运蛋白SLC 2A 6、中性粒细胞受体FCGR 3B和辅助蛋白C17 orf 56随着虚弱而减少。这些结果表明，可能有人口依赖性，不同的生物学途径的基础上脆弱的中年人。 新的证据表明，非编码RNA在衰老和疾病中起着调节作用。长链非编码RNA（lncRNA）在生理和疾病中的功能作用尚未完全了解。人们对lncRNA在人类衰老和社会环境条件下的作用知之甚少。来自年轻和老年白色男性（n=16）和非洲裔美国人（AA）男性（n=16）的外周血单核细胞的lncRNA和mRNA的微阵列分析显示，在白色男性中，lncRNA和mRNA随着年龄和贫困状态而变化，但在AA男性中没有。我们在扩展队列（n=40）中验证了lncRNA的变化; CTD-3247F14.2、GAS 5、H19、TERC和MEG 3随年龄显著变化，而AK 022914、GAS 5、KB-1047C11.2、MEG 3和XLOC_003262随贫困而变化。线粒体功能和对DNA损伤和应激的反应是年轻个体中富集的途径。对压力、病毒感染和免疫信号的反应是生活在贫困之上的人所丰富的途径。这些数据表明，人类年龄和社会逆境的标志物都会影响lncRNA的表达，这可能会提供有关衰老和影响衰老和疾病差异的社会因素的分子途径的见解。 非裔美国人（AA）经历过早的慢性健康结果和寿命差异与加速老化表型一致。特定CpG位置处的DNA甲基化（DNAm）水平是衰老的标志，其通过年龄相关的差异甲基化CpG位置（aDMPs）的存在来证明，所述差异甲基化CpG位置（aDMPs）是用于测量生物学年龄加速的表观遗传时钟的基础。由于DNAm在非欧洲人群中尚未得到广泛研究，我们研究了AAs和白人中DNAm与实际年龄之间的关联，以及种族，贫困和性别与表观遗传年龄加速之间的关联。我们使用Illumina MethylationEPIC BeadChip测量了从487名中年AA（N=244）和白色（N=243），男性（N = 248）和女性（N =239）提取的血液DNA中的全基因组DNA甲基化（866，836个CpG）。AA和白人的平均（sd）年龄分别为48.4（8.8）和49.0（8.7）（p=0.48）。我们确定了4，930个显著相关的aDMPs在AA和469白人。其中，75.6%和53.1%是新的，主要是由于在AA和白人中EPIC阵列中测量的CpG数量增加。在与年龄相关的疾病和参与生长和发育的细胞通路相关的基因中，AA比白人有更多与年龄相关的DNAm变化。我们评估了三个表观遗传年龄加速措施（普遍，内在和外在）。与白人相比，AA的外在衰老明显较慢。此外，与AA女性相比，AA和白色男性在通用年龄加速测量中的衰老速度更快（分别为+2.04和+1.24岁，p<0.05）。AA比白人有更广泛的甲基化变化。种族和性别相互作用，以生物学年龄加速的基础上，改变DNA甲基化模式可能是重要的年龄相关的健康差异。