The Underlying Biology of Health Disparities

National Institute On Aging

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Abstract

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. Notable results from this year include studies involving social genomics, gene expression in hypertension and cell-free circulating mitochondrial DNA in extracellular vesicles. Socioeconomic status (SES), living in poverty, and other social determinants of health contribute to health disparities in the United States. African American (AA) men living below poverty in Baltimore City have a higher incidence of mortality when compared to either white males or AA females living below poverty. Previous studies in our laboratory and elsewhere suggest that environmental conditions are associated with differential gene expression (DGE) patterns in peripheral blood mononuclear cells (PBMCs). DGE have also been associated with hypertension and cardiovascular disease (CVD) and correlate with race and sex. However, no studies have investigated how poverty status associates with DGE between male and female AAs and whites living in Baltimore City. We examined DGE in 52 AA and white participants of the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) cohort, who were living above or below 125% of the 2004 federal poverty line at time of sample collection. We performed a microarray to assess DGE patterns in PBMCs from these participants. AA males and females living in poverty had the most genes differentially-expressed compared with above poverty controls. Gene ontology (GO) analysis identified unique and overlapping pathways related to the endosome, single-stranded RNA binding, long-chain fatty-acyl-CoA biosynthesis, toll-like receptor signaling, and others within AA males and females living in poverty and compared with their above poverty controls. We performed RT-qPCR to validate top differentially-expressed genes in AA males. We found that KLF6, DUSP2, RBM34, and CD19 are expressed at significantly lower levels in AA males in poverty and KCTD12 is higher compared to above poverty controls. This study serves as an additional link to better understand the gene expression response in peripheral blood mononuclear cells in those living in poverty. The prevalence of hypertension among African Americans (AAs) in the US is among the highest of any demographic and affects over two-thirds of AA women. Previous data from our laboratory suggest substantial differential gene expression (DGE) of mRNAs and microRNAs (miRNAs) exists within peripheral blood mononuclear cells (PBMCs) isolated from AA and white women with or without hypertension. We hypothesized that DGE by race may contribute to racial differences in hypertension. In a reanalysis of our previous dataset, we found that the Wiskott-Aldrich syndrome protein Verprolin-homologous protein 2 (WASF2 (also known as WAVE2)) is differentially expressed in AA women with hypertension, along with several other members of the actin cytoskeleton signaling pathway that plays a role in cell shape and branching of actin filaments. We performed an in silico miRNA target prediction analysis that suggested miRNA miR-1253 regulates WASF2. Transfection of miR-1253 mimics into human umbilical vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs) significantly repressed WASF2 mRNA and protein levels (p < 0.05), and a luciferase reporter assay confirmed that miR-1253 regulates the WASF2 3' UTR (p < 0.01). miR-1253 overexpression in HUVECs significantly increased HUVEC lamellipodia formation (p < 0.01), suggesting the miR-1253-WASF2 interaction may play a role in cell shape and actin cytoskeleton function. Together, we have identified novel roles for miR-1253 and WASF2 in a hypertension-related disparities context. This may ultimately lead to the discovery of additional actin-related genes which are important in the vascular-related complications of hypertension and influence the disproportionate susceptibility to hypertension among AAs in general and AA women in particular. The mitochondrial free radical theory of aging suggests that accumulating oxidative damage to mitochondria and mitochondrial DNA (mtDNA) plays a central role in aging. Circulating cell-free mtDNA (ccf-mtDNA) isolated from blood may be a biomarker of disease. Extracellular vesicles (EVs) are small (30-400 nm), lipid-bound vesicles capable of shuttling proteins, nucleic acids, and lipids as part of intercellular communication systems. Here, we report that a portion of ccf-mtDNA in plasma is encapsulated in EVs. To address whether EV mtDNA levels change with human age, we analyzed mtDNA in EVs from individuals aged 30-64 years cross-sectionally and longitudinally. EV mtDNA levels decreased with age. Furthermore, the maximal mitochondrial respiration of cultured cells was differentially affected by EVs from old and young donors. Our results suggest that plasma mtDNA is present in EVs, that the level of EV-derived mtDNA is associated with age, and that EVs affect mitochondrial energetics in an EV age-dependent manner.