Association of Childhood Socioeconomic Status with Leukocyte Telomere Length Among African Americans and the Mediating Role of Behavioral and Psychosocial Factors: Results from the GENE-FORECAST Study.

PURPOSE: We examined if childhood socioeconomic status (SES) was related to adult leucocyte telomere length (TL) using the data of 361 African American (AA) participants from the GENE-FORECAST Study. We also assessed the mediating role of behavioral and psychosocial factors in the association between childhood SES and adult TL. METHODS: Childhood SES was assessed individually by using participant's mother's education and occupation, father's education and occupation, parental home ownership, and family structure. TL was assessed using the quantitative polymerase chain reaction method. Information on potential confounders and mediators were collected. The associations of childhood SES with TL were assessed using multivariable linear regression models. We used path analysis to quantify and test the share of these associations that was statistically explained by each of the mediators (participant's educational attainment, smoking status, physical activity, dietary habit, perceived stress, and depressive symptoms). RESULTS: Mother's education was associated with longer average TL (ß: 0.021; 95% CI: 0.001, 0.04, p=0.038) in confounder adjusted models. Once mediators were introduced in the model, the estimates were reduced and remained marginally significant (ß: 0.017; 95% CI: -0.003, 0.038, p=0.061). According to path model, approximately 19% of the effect of mother's education on TL (ß: 0.004; 95% CI: -0.001, 0.01, p < 0.10) was mediated through participant's own education level. No significant mediation effect was observed for any other mediators. CONCLUSIONS: These data provide evidence that participant's mother's education was positively linked to adult TL in AA population. Participant's own educational level partially explained this association.

Ethnic differences in subclinical vascular function in South Asians, Whites, and African Americans in the United States.

BACKGROUND: South Asians are a high-risk ethnic group for cardiovascular disease despite having lower levels of conventional cardiovascular risk factors such as obesity and smoking. Ethnic differences in pulse wave reflections, arterial stiffness, and subclinical atherosclerosis as measured using augmentation index (AIX), pulse wave velocity (PWV), and carotid intima-media thickness (CIMT) may reflect some of this excess risk. METHODS: We conducted a cross-sectional analysis of pooled data from three community-based sources in Atlanta, Georgia, USA. Data on 530 South Asians collected from local health fairs was compared with data on 507 White and 192 African Americans from the Emory Predictive Health Initiative and 351 White and 382 African Americans from the Morehouse and Emory Team up to Eliminate Health Disparities Study. RESULTS: Linear regression models adjusted for age, sex, smoking, MAP, fasting glucose, TC, HDL-C, creatinine, and body mass index were used to assess the relationship between ethnicity and vascular function measures. In fully adjusted models, South Asians had higher heart rate corrected AIX as compared with Whites and African Americans (by 5.47%, p < 0.01 and 3.50%, p < 0.01; respectively), but lower PWV (by 0.51 m/s, p < 0.01 and 0.72 m/s, p < 0.01; respectively) and lower CIMT (by 0.02 mm p = 0.03 and 0.04 mm p < 0.01; respectively). CONCLUSIONS: Systemic pulse wave reflections, independent of other risk factors, are higher in South Asians as compared with Whites and African Americans. Future research is needed to determine whether higher AIX explains the increased cardiovascular risk among South Asians.

ARMC 5 Variants and Risk of Hypertension in Blacks: MH- GRID Study.

Background We recently found that ARMC 5 variants may be associated with primary aldosteronism in blacks. We investigated a cohort from the MH - GRID (Minority Health Genomics and Translational Research Bio-Repository Database) and tested the association between ARMC 5 variants and blood pressure in black s. Methods and Results Whole exome sequencing data of 1377 black s were analyzed. Target single-variant and gene-based association analyses of hypertension were performed for ARMC 5, and replicated in a subset of 3015 individuals of African descent from the UK Biobank cohort. Sixteen rare variants were significantly associated with hypertension ( P=0.0402) in the gene-based (optimized sequenced kernel association test) analysis; the 16 and one other, rs116201073, together, showed a strong association ( P=0.0003) with blood pressure in this data set. The presence of the rs116201073 variant was associated with lower blood pressure. We then used human embryonic kidney 293 and adrenocortical H295R cells transfected with an ARMC 5 construct containing rs116201073 (c.*920T>C). The latter was common in both the discovery ( MH - GRID ) and replication ( UK Biobank) data and reached statistical significance ( P=0.044 [odds ratio, 0.7] and P=0.007 [odds ratio, 0.76], respectively). The allele carrying rs116201073 increased levels of ARMC5 mRNA , consistent with its protective effect in the epidemiological data. Conclusions ARMC 5 shows an association with hypertension in black s when rare variants within the gene are considered. We also identified a protective variant of the ARMC 5 gene with an effect on ARMC 5 expression confirmed in vitro. These results extend our previous report of ARMC 5's possible involvement in the determination of blood pressure in blacks.

Neighborhood social cohesion is associated with lower levels of interleukin-6 in African American women.

INTRODUCTION: Social cohesion is a positive neighborhood characteristic defined by feelings of connectedness and solidarity within a community. Studies have found significant associations between social cohesion and cardiovascular disease (CVD) risk factors and outcomes. Inflammation is one potential physiological pathway linking social cohesion to CVD development, but few studies have evaluated the relationship between social cohesion and inflammatory biomarkers. Prior research has also established that race and gender can modify the effects of neighborhood features, including social cohesion, on CVD risk factors and outcomes. This study aimed to examine the association between social cohesion and the inflammatory biomarkers interleukin-6 (IL-6) and C-reactive protein (CRP) in a cohort of African American and White women and men. MATERIALS AND METHODS: Data from the Morehouse and Emory Team Up to Eliminate Health Disparities (META-Health) Study were used to assess the association between social cohesion and inflammation among African American (n = 203) and White (n = 176) adults from the Atlanta metropolitan area. Social cohesion was measured using the social cohesion subscale from the Neighborhood Health Questionnaire. Inflammatory biomarkers were measured from plasma frozen at -70 °C. Multivariable linear regression analyses were conducted, controlling for demographic, clinical, behavioral, and psychosocial factors sequentially. Interaction by race and gender was also examined. RESULTS: In models adjusted for age, race, gender, and education, social cohesion was significantly associated with lower levels of IL-6 (ß = -0.06, p = 0.03). There was a significant race × social cohesion interaction (p = 0.04), and a marginally significant gender × race × social cohesion interaction (p = 0.09). In race-stratified models controlling for age, gender, and education, social cohesion was associated with lower IL-6 levels in African Americans (ß = -0.11, p = 0.01), but not Whites (ß = 0.01, p = 0.91). In fully adjusted race- and gender-stratified models, social cohesion was associated with lower levels of IL-6 in African American women only (ß = -0.15, p = 0.003). CRP was not associated with social cohesion in fully adjusted models. CONCLUSION: The association between social cohesion and lower levels of IL-6 is modified by gender and race, with the strongest association emerging for African American women. Although the pathways through which social cohesion impacts inflammation remain unclear, it is possible that for African American women social cohesion manifests through neighborhood networks.

Generating evidence to inform an update of asthma clinical practice guidelines: Perspectives from the National Heart, Lung, and Blood Institute.

Asthma is the most prevalent chronic respiratory disease worldwide. Its increasing prevalence and evidence of suboptimal control require renewed efforts in the development and widespread implementation of clinical practice guidelines for prevention, treatment, and control. Given the rapidly changing landscape and evolving best practices for guideline development, the National Heart, Lung, and Blood Institute made a commitment to support rigorous systematic evidence reviews that frontline health care providers and stakeholders could use to create new or update existing guidelines. This article describes the protocols, key questions, methodology, and analytic framework to support the update of the 2007 National Asthma Education and Prevention Program Expert Panel Report 3 (EPR-3) on the diagnosis and management of asthma in adults and children. It also describes the expert panel's practical experience in managing asthmatic patients across the age and severity spectrum. The article explains the process for ensuring that the expert panel's deliberations are conducted in accordance with the Institute of Medicine's standards and recommendations for guideline development. The outcome of this ambitious effort will be an update of the EPR-3 asthma guidelines and publication of the key recommendations in the Journal of Allergy and Clinical Immunology. Importantly, several novel approaches will be explored and incorporated as appropriate to accelerate adoption and sustained implementation of the guidelines.

Rationale and design of a placebo controlled randomized trial to assess short term, high-dose oral cholecalciferol on select laboratory and genomic responses in African Americans with hypovitaminosis D.

Cardiovascular Disease (CVD) and related disorders remain a leading cause of health disparities and premature death for African Americans. Hypovitaminosis D is disproportionately prevalent in African Americans and has been linked to CVD and CVD risk factors including hypertension, diabetes and obesity. Thus, hypovitaminosis D may represent a common pathway influencing CV risk factors in a select subgroup of persons. The purpose of this paper is to report the study design of a prospective eight week prospective double-blind randomized, placebo-controlled trial (n = 330 allocated 2:1 to intervention vs. control) to assess the effect of placebo vs. high-dose oral cholecalciferol (100,000 IU vitamin D3 at baseline and week 2) on 6-week change of select biologic cardiometabolic risk factors (including parathyroid hormone to assess biologic activity, pro-inflammatory/pro-thrombotic/fibrotic markers, insulin sensitivity and vitamin D metabolites) and their relationship to vitamin D administration and modification by vitamin D receptor polymorphisms in overweight, hypertensive African Americans with hypovitaminosis D. Findings from this trial will present insights into potential causal links between vitamin D repletion and mechanistic pathways of CV disease, including established and novel genomic markers.

Circulating MiR-374a-5p is a potential modulator of the inflammatory process in obesity.

Obese individuals without expected metabolic co-morbidities are referred to as metabolically healthy obese (MHO). The molecular mechanisms underlying this phenotype remain elusive. MicroRNAs may be involved in the MHO phenotype. To test this hypothesis, we screened 179 serum miRNAs in 20 African-American women (10 MHOs and 10 metabolically abnormal obese individuals -MAO). We identified 8 differentially expressed miRNAs (DEMs) with validation in an independent sample of 64 MHO and 34 MAO. Of the eight DEMs in the screening phase (p ≤ 0.05), miR-374a-5p remained significant (p = 0.04) with directional consistency in the validation sample. Ingenuity Pathway analysis revealed that miR-374a-5p putatively targeted 37 mRNAs (e.g. chemokines and transcription factors) which are members of canonical pathways involved in inflammation (IL-17A signaling) and lipid metabolism. Analysis restricted to adipocytes, the main source of circulating miRNAs in obesity, identified 3 mRNAs (CCL2, STEAP2, EN1) as the main target of miR-374a-5p. Evaluation of the 3 mRNAs in an independent sample showed that CCL2 was significantly downregulated (p = 0.0005). In summary, MiR-374a-5p is upregulated in MHO compared to MAO individuals and appears to show association with downregulation of pro-inflammatory markers that are linked to insulin resistance. Given the correlative nature of our findings, functional studies are needed.

Whole-genome transcriptomic insights into protective molecular mechanisms in metabolically healthy obese African Americans.

Several clinical guidelines have been proposed to distinguish metabolically healthy obesity (MHO) from other subgroups of obesity but the molecular mechanisms by which MHO individuals remain metabolically healthy despite having a high fat mass are yet to be elucidated. We conducted the first whole blood transcriptomic study designed to identify specific sets of genes that might shed novel insights into the molecular mechanisms that protect or delay the occurrence of obesity-related co-morbidities in MHO. The study included 29 African-American obese individuals, 8 MHO and 21 metabolically abnormal obese (MAO). Unbiased transcriptome-wide network analysis was carried out to identify molecular modules of co-expressed genes that are collectively associated with MHO. Network analysis identified a group of 23 co-expressed genes, including ribosomal protein genes (RPs), which were significantly downregulated in MHO subjects. The three pathways enriched in the group of co-expressed genes are EIF2 signaling, regulation of eIF4 and p70S6K signaling, and mTOR signaling. The expression of ten of the RPs collectively predicted MHO status with an area under the curve of 0.81. Triglycerides/HDL (TG/HDL) ratio, an index of insulin resistance, was the best predictor of the expression of genes in the MHO group. The higher TG/HDL values observed in the MAO subjects may underlie the activation of endoplasmic reticulum (ER) and related-stress pathways that lead to a chronic inflammatory state. In summary, these findings suggest that controlling ER stress and/or ribosomal stress by downregulating RPs or controlling TG/HDL ratio may represent effective strategies to prevent or delay the occurrence of metabolic disorders in obese individuals.

Comparisons of the Framingham and Pooled Cohort Equation Risk Scores for Detecting Subclinical Vascular Disease in Blacks Versus Whites.

The pooled cohort Atherosclerotic Cardiovascular Disease (ASCVD) risk calculator is designed to improve cardiovascular risk estimation compared with the Framingham Risk Score, particularly in blacks. Although the ASCVD risk score better predicts mortality and incident cardiovascular disease in blacks, less is known about its performance for subclinical vascular disease measures, including arterial stiffness and carotid intima-media thickness. We sought to determine if the ASCVD risk score better identifies subclinical vascular disease in blacks compared with the Framingham risk score. We calculated both the Framingham and ASCVD cohort risk scores in 1,231 subjects (mean age 53 years, 59% female, 37% black) without known cardiovascular disease and measured the extent of arterial stiffness, as determined by pulse wave velocity (PWV), central pulse pressure (CPP), and central augmentation index (CAIx), and subclinical atherosclerosis, as determined by carotid-IMT (C-IMT). Compared with whites, blacks had higher CAIx (23.9 ± 10.2 vs 22.1 ± 9.6%, p = 0.004), CPP (36.4 ± 10.5 vs 34.9 ± 9.8 mmHg, p = 0.014), PWV (7.6 ± 1.5 vs 7.3 ± 1.3 m/s, p = 0.004), and C-IMT (0.67 ± 0.10 vs 0.65 ± 0.10 mm, p = 0.005). In a multivariable analysis including race and Framingham risk score, race remained an independent predictor of all measures of subclinical vascular disease; however, models with race and the ASCVD risk score showed that race was not an independent predictor of subclinical vascular disease. In conclusion, greater subclinical vascular disease in blacks was not estimated by the Framingham risk score. The new ASCVD risk score provided a better estimate of racial differences in vascular function and structure.

Influence of socioeconomic status on the whole blood transcriptome in African Americans.

BACKGROUND: The correlation between low socioeconomic status (SES) and poor health outcome or higher risk of disease has been consistently reported by many epidemiological studies across various race/ancestry groups. However, the biological mechanisms linking low SES to disease and/or disease risk factors are not well understood and remain relatively under-studied. The analysis of the blood transcriptome is a promising window for elucidating how social and environmental factors influence the molecular networks governing health and disease. To further define the mechanistic pathways between social determinants and health, this study examined the impact of SES on the blood transcriptome in a sample of African-Americans. METHODS: An integrative approach leveraging three complementary methods (Weighted Gene Co-expression Network Analysis, Random Forest and Differential Expression) was adopted to identify the most predictive and robust transcriptome pathways associated with SES. We analyzed the expression of 15079 genes (RNA-seq) from whole blood across 36 samples. RESULTS: The results revealed a cluster of 141 co-expressed genes over-expressed in the low SES group. Three pro-inflammatory pathways (IL-8 Signaling, NF-κB Signaling and Dendritic Cell Maturation) are activated in this module and over-expressed in low SES. Random Forest analysis revealed 55 of the 141 genes that, collectively, predict SES with an area under the curve of 0.85. One third of the 141 genes are significantly over-expressed in the low SES group. CONCLUSION: Lower SES has consistently been linked to many social and environmental conditions acting as stressors and known to be correlated with vulnerability to chronic illnesses (e.g. asthma, diabetes) associated with a chronic inflammatory state. Our unbiased analysis of the blood transcriptome in African-Americans revealed evidence of a robust molecular signature of increased inflammation associated with low SES. The results provide a plausible link between the social factors and chronic inflammation.