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. 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.