Extracellular microRNAs associated with psychiatric symptoms in the Normative Aging Study.

Earlier studies have revealed microRNAs (miRNAs) as potential biomarkers for neurological conditions, however, such evidence on psychiatric outcomes is limited. We utilized the Normative Aging Study (NAS) cohort to investigate the associations between extracellular miRNAs (ex-miRNA) and psychiatric symptoms among a group of older male adults, along with the targeted genes and biological pathways. We studied 569 participants with miRNA profile primarily measured in extracellular vesicles isolated from plasma, and psychiatric symptoms reported over 1996-2014 with repeated measures.

Extracellular microRNA and cognitive function in a prospective cohort of older men: The Veterans Affairs Normative Aging Study.

Background: Aging-related cognitive decline is an early symptom of Alzheimer's disease and other dementias, and on its own can have substantial consequences on an individual's ability to perform important everyday functions. Despite increasing interest in the potential roles of extracellular microRNAs (miRNAs) in central nervous system (CNS) pathologies, there has been little research on extracellular miRNAs in early stages of cognitive decline. We leverage the longitudinal Normative Aging Study (NAS) cohort to investigate associations between plasma miRNAs and cognitive function among cognitively normal men.

Extracellular Vesicle-Encapsulated microRNAs as Novel Biomarkers of Lung Health.

Early detection of respiratory diseases is critical to facilitate delivery of disease-modifying interventions. Extracellular vesicle-enriched microRNAs (EV-miRNAs) may represent reliable markers of early lung injury. Evaluate associations of plasma EV-miRNAs with lung function.

Predicting risk of lung function impairment and all-cause mortality using a DNA methylation-based classifier of tobacco smoke exposure.

Background: The Epigenetic Smoking Status Estimator (EpiSmokEr) predicts smoking phenotypes based on DNA methylation at 121 CpG sites.

Objective: Evaluate associations of EpiSmokEr-predicted versus self-reported smoking phenotypes with lung function and all-cause mortality in a cohort of older adults.

Methods: The prospective Normative Aging Study collected DNA methylation measurements from 1999 to 2012 with follow-up through 2016.

Pulmonary Function and Blood DNA Methylation: A Multiancestry Epigenome-Wide Association Meta-analysis.

Methylation integrates factors present at birth and modifiable across the lifespan that can influence pulmonary function. Studies are limited in scope and replication. To conduct large-scale epigenome-wide meta-analyses of blood DNA methylation and pulmonary function.

Metabolomic signatures of the short-term exposure to air pollution and temperature.

Background: Short-term exposures to air pollution and temperature have been reported to be associated with inflammation and oxidative stress. However, mechanistic understanding of the affected metabolic pathways is still lacking and literature on the short-term exposure of air-pollution on the metabolome is limited.

Objectives: We aimed to determine changes in the plasma metabolome and associated metabolic pathways related to short-term exposure to outdoor air pollution and temperature.

Ambient PM species and ultrafine particle exposure and their differential metabolomic signatures.

Background: The metabolomic signatures of short- and long-term exposure to PM have been reported and linked to inflammation and oxidative stress. However, little is known about the relative contribution of the specific PM species (hence sources) that drive these metabolomic signatures.

Objectives: We aimed to determine the relative contribution of the different species of PM exposure to the perturbed metabolic pathways related to changes in the plasma metabolome.

Metabolomic signatures of the long-term exposure to air pollution and temperature.

Background: Long-term exposures to air pollution has been reported to be associated with inflammation and oxidative stress. However, the underlying metabolic mechanisms remain poorly understood.

Objectives: We aimed to determine the changes in the blood metabolome and thus the metabolic pathways associated with long-term exposure to outdoor air pollution and ambient temperature.

Biomarkers of aging and lung function in the normative aging study.

Elderly individuals who are never smokers but have the same height and chronological age can have substantial differences in lung function. The underlying biological mechanisms are unclear. To evaluate the associations of different biomarkers of aging (BoA) and lung function, we performed a repeated-measures analysis in the Normative Aging Study using linear mixed-effect models.

Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: a multi-cohort analysis.

Differences in health status by socioeconomic position (SEP) tend to be more evident at older ages, suggesting the involvement of a biological mechanism responsive to the accumulation of deleterious exposures across the lifespan. DNA methylation (DNAm) has been proposed as a biomarker of biological aging that conserves memory of endogenous and exogenous stress during life.We examined the association of education level, as an indicator of SEP, and lifestyle-related variables with four biomarkers of age-dependent DNAm dysregulation: the total number of stochastic epigenetic mutations (SEMs) and three epigenetic clocks (Horvath, Hannum and Levine), in 18 cohorts spanning 12 countries.

Low-Level Cumulative Lead and Resistant Hypertension: A Prospective Study of Men Participating in the Veterans Affairs Normative Aging Study.

Background Bone lead offers a better method over blood lead measurement to discern long-term lead exposure and accumulation. We examined the risk of resistant hypertension based on bone lead levels in a prospective cohort study of NAS (Normative Aging Study). Methods and Results Participants had clinic data on hypertension (systolic blood pressure, diastolic blood pressure, and antihypertension medication), lead (blood, bone-patella, bone-tibia), and demographic and confounding variables.

Analysis of repeated leukocyte DNA methylation assessments reveals persistent epigenetic alterations after an incident myocardial infarction.

Background: Most research into myocardial infarctions (MIs) have focused on preventative efforts. For survivors, the occurrence of an MI represents a major clinical event that can have long-lasting consequences. There has been little to no research into the molecular changes that can occur as a result of an incident MI.

Metastable DNA methylation sites associated with longitudinal lung function decline and aging in humans: an epigenome-wide study in the NAS and KORA cohorts.

DNA methylation is an epigenetic regulator of gene transcription, which has been found to be both metastable and variable within human cohort studies. Currently, few studies have been done to identify metastable DNA methylation biomarkers associated with longitudinal lung function decline in humans. The identification of such biomarkers is important for screening vulnerable populations.

Bone Lead Levels and Risk of Incident Primary Open-Angle Glaucoma: The VA Normative Aging Study.

Background: Oxidative stress may play an important role in the etiology of primary open-angle glaucoma (POAG). The association between risk of POAG and lead exposure, which is an environmental source of oxidative stress, has not been fully investigated yet.

Objective: Our objective was to determine the association between bone lead—a biomarker of cumulative lead dose (tibia lead) or an endogenous source of stored lead (patella lead)—and incident POAG.

Lung function association with outdoor temperature and relative humidity and its interaction with air pollution in the elderly.

While the effects of weather variability on cardio-respiratory mortality are well described, research examining the effects on morbidity, especially for vulnerable populations, is warranted. We investigated the associations between lung function and outdoor temperature (T in Celsius degrees (°C)) and relative humidity (RH), in a cohort of elderly men, the Normative Aging Study. Our study included 1103 participants whose forced vital capacity (FVC), forced expiratory volume in one second (FEV), and weather exposures were assessed one to five times during the period 1995-2011 (i.

Improving estimation and prediction in linear regression incorporating external information from an established reduced model.

We consider a situation where there is rich historical data available for the coefficients and their standard errors in a linear regression model describing the association between a continuous outcome variable Y and a set of predicting factors X, from a large study. We would like to use this summary information for improving inference in an expanded model of interest, Y given X,B. The additional variable B is a new biomarker, measured on a small number of subjects in a new dataset.

Empirical comparison of reduced representation bisulfite sequencing and Infinium BeadChip reproducibility and coverage of DNA methylation in humans.

We empirically examined the strengths and weaknesses of two human genome-wide DNA methylation platforms: rapid multiplexed reduced representation bisulfite sequencing and Illumina's Infinium BeadChip. Rapid multiplexed reduced representation bisulfite sequencing required less input DNA, offered more flexibility in coverage, and interrogated more CpG loci at a higher regional density. The Infinium covered slightly more protein coding, cancer-associated and mitochondrial-related genes, both platforms covered all known imprinting clusters, and rapid multiplexed reduced representation bisulfite sequencing covered more microRNA genes than the HumanMethylation450, but fewer than the MethylationEPIC.

DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry.

Testing for the indirect effect under the null for genome-wide mediation analyses.

Mediation analysis helps researchers assess whether part or all of an exposure's effect on an outcome is due to an intermediate variable. The indirect effect can help in designing interventions on the mediator as opposed to the exposure and better understanding the outcome's mechanisms. Mediation analysis has seen increased use in genome-wide epidemiological studies to test for an exposure of interest being mediated through a genomic measure such as gene expression or DNA methylation (DNAm).

The Inflammatory Potential of Dietary Manganese in a Cohort of Elderly Men.

Manganese is an essential nutrient that may play a role in the production of inflammatory biomarkers. We examined associations between estimated dietary manganese intake from food/beverages and supplements with circulating biomarkers of inflammation. We further explored whether estimated dietary manganese intake affects DNA methylation of selected genes involved in the production of these biomarkers.

Exposure enriched outcome dependent designs for longitudinal studies of gene-environment interaction.

Joint effects of genetic and environmental factors have been increasingly recognized in the development of many complex human diseases. Despite the popularity of case-control and case-only designs, longitudinal cohort studies that can capture time-varying outcome and exposure information have long been recommended for gene-environment (G × E) interactions. To date, literature on sampling designs for longitudinal studies of G × E interaction is quite limited.

Ultra-high dimensional variable selection with application to normative aging study: DNA methylation and metabolic syndrome.

Background: Metabolic syndrome has become a major public health challenge worldwide. The association between metabolic syndrome and DNA methylation is of great research interest.

Results: We constructed a binomial model to investigate the association between a metabolic syndrome index and DNA methylation in the Normative Aging Study.

Fine-scale spatial and temporal variation in temperature and arrhythmia episodes in the VA Normative Aging Study.

Unlabelled: Many studies have demonstrated that cold and hot temperatures are associated with increased deaths and hospitalization rates; new findings indicate also an association with more specific cardiac risk factors. Most of these existing studies have relied on few weather stations to characterize exposures; few have used residence-specific estimates of temperature, or examined the exposure-response function. We investigated the association of arrhythmia episodes with spatial and temporal variation in temperature.