Associations between DNA methylation and BMI vary by metabolic health status: a potential link to disparate cardiovascular outcomes

Background: Body mass index (BMI), a well-known risk factor for poor cardiovascular outcomes, is associated with differential DNA methylation (DNAm). Similarly, metabolic health has also been associated with changes in DNAm. It is unclear how overall metabolic health outside of BMI may modify the relationship between BMI and methylation profiles, and what consequences this may have on downstream cardiovascular disease. The purpose of this study was to identify cytosine-phosphate-guanine (CpG) sites at which the association between BMI and DNAm could be modified by overall metabolic health. Results: The discovery study population was derived from three Women’s Health Initiative (WHI) ancillary studies (n = 3977) and two Atherosclerosis Risk in Communities (ARIC) ancillary studies (n = 3520). Findings were validated in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort (n = 1200). Generalized linear models regressed methylation β values on the interaction between BMI and metabolic health Z score (BMI × MHZ) adjusted for BMI, MHZ, cell composition, chip number and location, study characteristics, top three ancestry principal components, smoking, age, ethnicity (WHI), and sex (ARIC). Among the 429,566 sites examined, differential associations between BMI × MHZ and DNAm were identified at 22 CpG sites (FDR q < 0.05), with one site replicated in MESA (cg18989722, in the TRAPPC9 gene). Three of the 22 sites were associated with incident coronary heart disease (CHD) in WHI. For each 0.01 unit increase in DNAm β value, the risk of incident CHD increased by 9% in one site and decreased by 6–10% in two sites over 25 years. Conclusions: Differential associations between DNAm and BMI by MHZ were identified at 22 sites, one of which was validated (cg18989722) and three of which were predictive of incident CHD. These sites are located in several genes related to NF-kappa-B signaling, suggesting a potential role for inflammation between DNA methylation and BMI-associated metabolic health

Clonal hematopoiesis associated with epigenetic aging and clinical outcomes

Clonal hematopoiesis of indeterminate potential (CHIP) is a common precursor state for blood cancers that most frequently occurs due to mutations in the DNA-methylation modifying enzymes DNMT3A or TET2. We used DNA-methylation array and whole-genome sequencing data from four cohorts together comprising 5522 persons to study the association between CHIP, epigenetic clocks, and health outcomes. CHIP was strongly associated with epigenetic age acceleration, defined as the residual after regressing epigenetic clock age on chronological age, in several clocks, ranging from 1.31 years (GrimAge, p &lt; 8.6 × 10−7) to 3.08 years (EEAA, p &lt; 3.7 × 10−18). Mutations in most CHIP genes except DNA-damage response genes were associated with increases in several measures of age acceleration. CHIP carriers with mutations in multiple genes had the largest increases in age acceleration and decrease in estimated telomere length. Finally, we found that ~40% of CHIP carriers had acceleration &gt;0 in both Hannum and GrimAge (referred to as AgeAccelHG+). This group was at high risk of all-cause mortality (hazard ratio 2.90, p &lt; 4.1 × 10−8) and coronary heart disease (CHD) (hazard ratio 3.24, p &lt; 9.3 × 10−6) compared to those who were CHIP−/AgeAccelHG−. In contrast, the other ~60% of CHIP carriers who were AgeAccelHG− were not at increased risk of these outcomes. In summary, CHIP is strongly linked to age acceleration in multiple clocks, and the combination of CHIP and epigenetic aging may be used to identify a population at high risk for adverse outcomes and who may be a target for clinical interventions

Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD

Investigating the socio-economic and livelihoods impacts of African swine fever in Timor-Leste: An application of spatial group model building

Small-scale pig farming is highly important to the economic and social status of households in Timor-Leste. The presence of an African Swine Fever (ASF) outbreak in Timor-Leste was confirmed in 2019, a major concern given that around 70% of agricultural households practice pig farming. This research used a virtual spatial group model building process to construct a concept model to better understand the main feedback loops that determine the socio-economic and livelihood impacts of the ASF outbreak. After discussing the interaction of reinforcing and balancing feedback loops in the concept model, potential leverage points for intervention are suggested that could reduce the impacts of ASF within socio-economic spheres. These include building trust between small-scale farmers and veterinary technicians, strengthening government veterinary services, and the provision of credit conditional on biosecurity investments to help restock the industry. This conceptual model serves as a starting point for further research and the future development of a quantitative system dynamics (SD) model which would allow ex-ante scenario-testing of various policy and technical mitigation strategies of ASF outbreaks in Timor-Leste and beyond. Lessons learned from the blended offline/online approach to training and workshop facilitation are also explored in the paper

BALANCING AUTONOMY AND CAPACITY IN COMMUNITY ORGANIZATIONS: THE DILEMMA OF OFFICIAL RECOGNITION AND SUPPORT FOR NEIGHBORHOOD ASSOCIATIONS

Community organization helps relatively powerless groups improve their political bargaining position by increasing the stability. persistence, and standing of the group… But… community organizations of relatively powerless groups remain constrained by their need to secure resources and develop incentives to attract constituents. For the most part, those may be acquired only through interactions requiring compromises of group independence and goals. Copyright 1983 by The Policy Studies Organization.