The Underlying Biology of Health Disparities

我们继续研究健康差距的生物学方面的工作，因为正是通过生物学机制，健康的社会决定因素导致了不同的健康结果。今年的显著成果包括涉及脆弱性、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，是由于对应激源的反应能力减弱而导致的，是导致残疾和死亡的重要风险因素。虽然脆弱通常是在老年时被研究的，但它在中年时也存在。鉴于美国中年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的脆弱相关的全基因组转录变化。采用外周血单个核细胞总RNA(n=16)进行下一代RNA测序。我们分析了差异基因表达模式，并完成了基因集丰富的参数分析(PAGE)。用RT-qPCR验证差异基因表达(n=52)。我们鉴定了5,082个与脆弱性差异表达的基因。在黑人和白人中，脆弱改变了不同的基因表达模式和生物途径，包括与炎症和免疫相关的途径。验证研究表明，脆弱性、RACE和细胞因子IL1B和转录因子Egr1的表达之间存在显著的双向交互作用。葡萄糖转运蛋白SLC2A6、中性粒细胞受体FCGR3B和辅助蛋白C17orf56随着衰弱而降低。这些结果表明，中年人的虚弱可能存在与人口统计相关的、不同的生物学途径。 新的证据表明，非编码RNA在衰老和疾病中发挥着调节作用。长非编码RNA(LncRNAs)在生理和疾病中的功能还不完全清楚。在人类老龄化和社会环境条件的背景下，人们对InncRNA知之甚少。对来自年轻和老年白人(n=16)和非裔美国人(AA)男性(n=16)的外周血单核细胞中的lncRNAs和mRNAs的微阵列图谱分析表明，在白人男性中，lncRNAs和mRNAs随着年龄和贫困状况的变化而变化，但在aa男性中没有变化。在扩大的队列中验证了LncRNA的变化(n=40)，CTD-3247F14.2、GAS5、H19、TERC和MEG3随年龄变化显著，而AK022914、GAS5、KB-1047C11.2、MEG3和XLOC_003262则随贫困而变化。线粒体功能以及对DNA损伤和压力的反应是年轻个体丰富的途径。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丰富的途径。这些数据表明，人类的年龄和一个社会逆境的标志都会影响lncRNA的表达，这可能有助于深入了解导致衰老的分子途径，以及影响衰老和疾病差异的社会因素。 非裔美国人(AA)经历了过早的慢性健康结局和与加速老化表型相一致的寿命差距。特定CpG位置的DNA甲基化(DNaM)水平是衰老的标志，与年龄相关的差异甲基化CpG位置(ADMP)的存在证明了这一点，这些位置是测量生物年龄加速的表观遗传学时钟的基础。由于dNaM在非欧洲人群中还没有被广泛研究，我们研究了dNaM与AAS和白人的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。我们使用发光甲基化EPIC微珠芯片检测了487名中年AA(N=244)、白人(N=243)、男性(N=248)和女性(N=239)血液DNA的全基因组DNA甲基化(866,836 cpgs)。AA和白人的平均年龄(SD)分别为48.4岁(8.8岁)和49.0岁(8.7岁)(p=0.48)。我们在AA和白人中发现了4930个显著相关的aDMP和469个。其中，75.6%和53.1%是新的，主要是由于EPIC阵列中测得的CPG数量的增加，分别在AA和白人中。在与年龄相关的疾病和与生长发育有关的细胞通路中，AAS比白人有更多与年龄相关的dNaM变化。我们评估了三种表观遗传年龄加速措施(普遍的、内在的和外在的)。与白人相比，AAS的外在衰老明显较慢。此外，与AA女性相比，AA和白人男性在普遍年龄加速指标中的衰老速度都更快(分别为+2.04岁和+1.24岁，p&lt；0.05)。AAS比白人有更广泛的甲基化变化。种族和性别的相互作用是生物年龄加速的基础，这表明DNA甲基化模式的改变在与年龄相关的健康差异中可能是重要的。

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.