DNA methylation near MAD1L1, KDM2B, and SOCS3 mediates the effect of socioeconomic status on elevated body mass index in African American adults.

Obesity and poverty disproportionally affect African American persons. Epigenetic mechanisms could partially explain the association between socioeconomic disadvantage and body mass index (BMI). We examined the extent to which epigenetic mechanisms mediate the effect of socioeconomic status (SES) on BMI. Using data from African American adults from the Atherosclerosis Risk in Communities (ARIC) Study (n = 2664, mean age = 57 years), education, income, and occupation were used to create a composite SES score at visit 1 (1987-1989). We conducted two methylation-wide association analyses to identify associations between SES (visit 1), BMI and cytosine-phosphate-guanine (CpG) sites measured at a subsequent visit (1990-1995). We then utilized structural equation modeling (SEM) to test whether identified sites mediated the association between earlier SES and BMI in sex-stratified models adjusted for demographic and risk factor covariates. Independent replication and meta-analyses were conducted using the Jackson Heart Study (JHS, n = 874, mean age 51 years, 2000-2004). Three CpG sites near MAD1L1, KDM2B, and SOCS3 (cg05095590, cg1370865, and cg18181703) were suggestively associated (P-value < 1.3×10-5) in ARIC and at array-wide significance (P-value < 1.3×10-7) in a combined meta-analysis of ARIC with JHS. SEM of these three sites revealed significant indirect effects in females (P-value < 5.8×10-3), each mediating 7%-20% of the total effect of SES on BMI. Nominally significant indirect effects were observed for two sites near MAD1L1 and KDM2B in males (P-value < 3.4×10-2), mediating -17 and -22% of the SES-BMI effect. These results provide further evidence that epigenetic modifications may be a potential pathway through which SES may "get under the skin" and contribute to downstream health disparities.

A data harmonization project of three large prospective cardiovascular health-focused cohorts.

Few prospective studies examine multilevel resilience resources and psychosocial factors in relation to cardiovascular health and disease. Recent research indicates that resilience resources are associated with a reduction in the incidence of cardiovascular disease-related events, but few studies have examined this relationship across different racial/ethnic populations or in large cohorts. Harmonization may address these limitations because it allows data from several cohorts to be analyzed together, potentially increasing sample size and in turn power overall and in minority populations. This paper describes the process involved in combining three cardiovascular health-focused cohorts: Jackson Heart Study, Multi-Ethnic Study of Atherosclerosis, and Mediators of Atherosclerosis in South Asians Living in America Study. Using a systematic process, we identified appropriate data harmonization techniques to use in harmonizing variables across cohorts. Variables included exposures (e.g., resilience resources), outcomes (e.g., American Heart Association's Life's Simple 7), and covariates (e.g., race and ethnicity). Post harmonization examinations included psychometric analyses of the harmonized variables. A total of 13,284 participants were included in the final harmonized dataset. This project provides opportunities for future research in resilience resources and informs future studies that need to harmonize data. Results based on the harmonized dataset could inform interventions and policies.

Cardiovascular Risk Associated With Social Determinants of Health at Individual and Area Levels.

Importance: The benefit of adding social determinants of health (SDOH) when estimating atherosclerotic cardiovascular disease (ASCVD) risk is unclear. Objective: To examine the association of SDOH at both individual and area levels with ASCVD risks, and to assess if adding individual- and area-level SDOH to the pooled cohort equations (PCEs) or the Predicting Risk of CVD Events (PREVENT) equations improves the accuracy of risk estimates. Design, Setting, and Participants: This cohort study included participants data from 4 large US cohort studies. Eligible participants were aged 40 to 79 years without a history of ASCVD. Baseline data were collected from 1995 to 2007; median (IQR) follow-up was 13.0 (9.3-15.0) years. Data were analyzed from September 2023 to February 2024. Exposures: Individual- and area-level education, income, and employment status. Main outcomes and measures: ASCVD was defined as the composite outcome of nonfatal myocardial infarction, death from coronary heart disease, and fatal or nonfatal stroke. Results: A total of 26 316 participants were included (mean [SD] age, 61.0 [9.1] years; 15 494 women [58.9%]; 11 365 Black [43.2%], 703 Chinese American [2.7%], 1278 Hispanic [4.9%], and 12 970 White [49.3%]); 11 764 individuals (44.7%) had at least 1 adverse individual-level SDOH and 10 908 (41.5%) had at least 1 adverse area-level SDOH. A total of 2673 ASCVD events occurred during follow-up. SDOH were associated with increased risk of ASCVD at both the individual and area levels, including for low education (individual: hazard ratio [HR], 1.39 [95% CI, 1.25-1.55]; area: HR, 1.31 [95% CI, 1.20-1.42]), low income (individual: 1.35 [95% CI, 1.25-1.47]; area: HR, 1.28 [95% CI, 1.17-1.40]), and unemployment (individual: HR, 1.61 [95% CI, 1.24-2.10]; area: HR, 1.25 [95% CI, 1.14-1.37]). Adding area-level SDOH alone to the PCEs did not change model discrimination but modestly improved calibration. Furthermore, adding both individual- and area-level SDOH to the PCEs led to a modest improvement in both discrimination and calibration in non-Hispanic Black individuals (change in C index, 0.0051 [95% CI, 0.0011 to 0.0126]; change in scaled integrated Brier score [IBS], 0.396% [95% CI, 0.221% to 0.802%]), and improvement in calibration in White individuals (change in scaled IBS, 0.274% [95% CI, 0.095% to 0.665%]). Adding individual-level SDOH to the PREVENT plus area-level social deprivation index (SDI) equations did not improve discrimination but modestly improved calibration in White participants (change in scaled IBS, 0.182% [95% CI, 0.040% to 0.496%]), Black participants (0.187% [95% CI, 0.039% to 0.501%]), and women (0.289% [95% CI, 0.115% to 0.574%]). Conclusions and Relevance: In this cohort study, both individual- and area-level SDOH were associated with ASCVD risk; adding both individual- and area-level SDOH to the PCEs modestly improved discrimination and calibration for estimating ASCVD risk for Black individuals, and adding individual-level SDOH to PREVENT plus SDI also modestly improved calibration. These findings suggest that both individual- and area-level SDOH may be considered in future development of ASCVD risk assessment tools, particularly among Black individuals.

Deep Diving Into the Cardiovascular Health Paradox: A Journey Towards Personalized Prevention.

Objectives: The Life's Simple 7 score (LS7) promotes cardiovascular health (CVH). Despite this, some with optimal LS7 develop cardiovascular disease (CVD), while others with poor CVH do not, termed the "CVH paradox." This paper explores pathways explaining this paradox. Methods: We examined methodological aspects: 1) misclassification bias in self-reported lifestyle factors (smoking, physical activity, diet); 2) cumulative exposure to risk factors over a lifetime, impacting the CVH paradox. Punctual risk factor assessments are suboptimal for predicting outcomes. We proposed personalized prevention using "novel" elements to refine CVH assessment: 1) subclinical vascular disease markers, 2) metabolic biomarkers in blood and urine, 3) emerging risk factors, 4) polygenic risk scores (PRS), 5) epigenetics, and 6) the exposome. Results: Addressing the CVH paradox requires a multifaceted approach, reducing misclassification bias, considering cumulative risk exposure, and incorporating novel personalized prevention elements. Conclusion: A holistic, individualized approach to CVH assessment and CVD prevention can better reduce cardiovascular outcomes and improve population health. Collaboration among researchers, healthcare providers, policymakers, and communities is essential for effective implementation and realization of these strategies.

Contributors to Early Mortality in African Americans, the Jackson Heart Study.

Introduction: In recent years, premature "deaths of despair" (ie, due to alcohol, drug use, and suicide) among middle-aged White Americans have received increased attention in the popular press, yet there has been less discussion on what explains premature deaths among young African Americans. In this study, we examined factors related to deaths of despair (alcohol use, drug use, smoking) and contextual factors (perceived discrimination, socioeconomic status, neighborhood conditions) as predictors of premature deaths before the age of 65 years among African Americans. Methods: The Jackson Heart Study (JHS) is a longitudinal cohort study of African Americans in the Jackson, Mississippi, metropolitan statistical area. We included participants younger than 65 years at baseline (n=4000). Participant enrollment began in 2000 and data for these analyses were collected through 2019. To examine predictors of mortality, we calculated multivariable adjusted hazard ratios (HRs; 95% CI), using Cox proportional hazard models adjusted for age, sex, ideal cardiovascular health metrics, drug use, alcohol intake, functional status, cancer, chronic kidney disease, asthma, waist circumference, depression, income, education, health insurance status, perceived neighborhood safety, and exposure to lifetime discrimination. Results: There were 230 deaths in our cohort, which spanned from 2001-2019. After adjusting for all covariates, males (HR, 1.50; 95% CI, 1.11-2.03), participants who used drugs (HR, 1.53; 95% CI, 1.13-2.08), had a heavy alcohol drinking episode (HR, 1.71; 95% CI, 1.22-2.41), reported 0-1 ideal cardiovascular health metrics (HR, 1.78; 95% CI, 1.06-3.02), had cancer (HR, 2.38; 95% CI, 1.41-4.01), had poor functional status (HR, 1.68; 95% CI, 1.19-2.37), or with annual family income less than $25,000 (HR, 1.63; 95% CI, 1.02-2.62) were more likely to die before 65 years of age. Conclusions: In our large cohort of African American men and women, clinical predictors of premature death included poor cardiovascular health and cancer, and social predictors included low income, drug use, heavy alcohol use, and being a current smoker. Clinical and social interventions are warranted to prevent premature mortality in African Americans.