Recent exposure to particle radioactivity and biomarkers of oxidative stress and inflammation: The Framingham Heart Study.

Background: Decay products of radioactive materials may attach to ambient fine particles and form radioactive aerosol. Internal ionizing radiation source from inhaled radioactive aerosol may contribute to the fine particulate matter (PM)-inflammation pathway. However, few studies in humans have examined the associations.

Multisystem Trajectories Over the Adult Life Course and Relations to Cardiovascular Disease and Death.

Background: Comprehensive conjoint characterization of long-term trajectories representing several biological systems is lacking.

Methods: We measured serially indicators representing 14 distinct biological systems in up to 3,453 participants attending four Framingham Study examinations: bone mineral density, body mass index (BMI), C-reactive protein, glomerular filtration rate, forced vital capacity (FVC), 1 second forced expiratory volume/FVC ratio (FEV1/FVC), gait speed, grip strength, glycosylated hemoglobin (HbA1c), heart rate, left ventricular mass, Mini-Mental State Examination (MMSE), pulse pressure, and total/high-density lipoprotein cholesterol ratio (TC/HDL).

Results: We observed that correlations among the 14 sex-specific trajectories were modest (r < .

Interpretation of time-to-event outcomes in randomized trials: an online randomized experiment.

Background: Multiple features in the presentation of randomized controlled trial (RCT) results are known to influence comprehension and interpretation. We aimed to compare interpretation of cancer RCTs with time-to-event outcomes when the reported treatment effect measure is the hazard ratio (HR), difference in restricted mean survival times (RMSTD), or both (HR+RMSTD). We also assessed the prevalence of misinterpretation of the HR.

Integrative methylation score to identify epigenetic modifications associated with lipid changes resulting from fenofibrate treatment in families.

Epigenome-wide association studies (EWAS) have traditionally focused on the association test of single epigenetic markers with complex traits. However, it is possible that multiple cytosine-phosphate-guanine (CpG) sites at the same locus could jointly exert their effects on human traits. Therefore, a region-based test that combines multiple markers could be more powerful.

Long- and short-term air pollution exposure and measures of arterial stiffness in the Framingham Heart Study.

Background: Studies of air pollution exposure and arterial stiffness have reported inconsistent results and large studies employing the reference standard of arterial stiffness, carotid-femoral pulse-wave velocity (CFPWV), have not been conducted.

Aim: To study long-term exposure to ambient fine particles (PM), proximity to roadway, and short-term air pollution exposures in relation to multiple measures of arterial stiffness in the Framingham Heart Study.

Methods: We assessed central arterial stiffness using CFPWV, forward pressure wave amplitude, mean arterial pressure and augmentation index.

Meta-analysis of exome array data identifies six novel genetic loci for lung function.

Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV ), forced vital capacity (FVC) and the ratio of FEV to FVC (FEV /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals.

Whole Blood Gene Expression Associated With Clinical Biological Age.

Background: Biologic age may better reflect an individual's rate of aging than chronologic age.

Methods: We conducted a transcriptome-wide association study with biologic age estimated with clinical biomarkers, which included: systolic blood pressure, forced expiratory volume at 1 second (FEV1), total cholesterol, fasting glucose, C-reactive protein, and serum creatinine. We assessed the association between the difference between biologic age and chronologic age (∆age) and gene expression in whole blood measured using the Affymetrix Human Exon 1.

Protein Biomarkers of Cardiovascular Disease and Mortality in the Community.

Background: The discovery of novel and highly predictive biomarkers of cardiovascular disease (CVD) has the potential to improve risk-stratification methods and may be informative regarding biological pathways contributing to disease.

Methods And Results: We used a discovery proteomic platform that targeted high-value proteins for CVD to ascertain 85 circulating protein biomarkers in 3523 Framingham Heart Study participants (mean age, 62 years; 53% women). Using multivariable-adjusted Cox models to account for clinical variables, we found 8 biomarkers associated with incident atherosclerotic CVD, 18 with incident heart failure, 38 with all-cause mortality, and 35 with CVD death (false discovery rate, q<0.

Genome-wide association study of nocturnal blood pressure dipping in hypertensive patients.

Background: Reduced nocturnal fall (non-dipping) of blood pressure (BP) is a predictor of cardiovascular target organ damage. No genome-wide association studies (GWAS) on BP dipping have been previously reported.

Methods: To study genetic variation affecting BP dipping, we conducted a GWAS in Genetics of Drug Responsiveness in Essential Hypertension (GENRES) cohort (n = 204) using the mean night-to-day BP ratio from up to four ambulatory BP recordings conducted on placebo.

Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval.

Background: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability.

Epigenome-Wide Association Study of Soluble Tumor Necrosis Factor Receptor 2 Levels in the Framingham Heart Study.

Transmembrane tumor necrosis factor (TNF) receptors are involved in inflammatory, apoptotic, and proliferative processes. In the bloodstream, soluble TNF receptor II (sTNFR2) can modify the inflammatory response of immune cells and is predictive of cardiovascular disease risk. We hypothesize that sTNFR2 is associated with epigenetic modifications of circulating leukocytes, which may relate to the pathophysiology underlying atherogenic risk.

Lifetime risk of atrial fibrillation according to optimal, borderline, or elevated levels of risk factors: cohort study based on longitudinal data from the Framingham Heart Study.

Objective: To examine the association between risk factor burdens-categorized as optimal, borderline, or elevated-and the lifetime risk of atrial fibrillation.

Design: Community based cohort study.

Setting: Longitudinal data from the Framingham Heart Study.

A Meta-Analysis of Genome-Wide Association Studies of Growth Differentiation Factor-15 Concentration in Blood.

Blood levels of growth differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1 (MIC-1), have been associated with various pathological processes and diseases, including cardiovascular disease and cancer. Prior studies suggest genetic factors play a role in regulating blood MIC-1/GDF-15 concentration. In the current study, we conducted the largest genome-wide association study (GWAS) to date using a sample of ∼5,400 community-based Caucasian participants, to determine the genetic variants associated with MIC-1/GDF-15 blood concentration.

ADP Platelet Hyperreactivity Predicts Cardiovascular Disease in the FHS (Framingham Heart Study).

Background: Platelet function is associated with adverse events in patients with cardiovascular disease (CVD).

Methods And Results: We examined associations of baseline platelet function with incident CVD events in the community-based FHS (Framingham Heart Study). Participants free of prevalent CVD and without recent aspirin treatment with available data in the Framingham Offspring cohort (1991-1995) and Omni cohort (1994-1998) were included.

Familial clustering of hypertensive target organ damage in the community.

Objectives: Prior studies suggest that hypertensive target organ damage (TOD) is a heritable trait. However, the risk that parental TOD confers on propensity for TOD in their offspring, and how hypertensive TOD clusters in the context of parental versus offspring hypertension status remain unclear.

Methods: We studied 3238 Framingham Heart Study participants (mean age 39 ± 8 years, 53% women) with available parental data on TOD.

Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness.

Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1).

Longitudinal Associations of Pericardial and Intrathoracic Fat With Progression of Coronary Artery Calcium (from the Framingham Heart Study).

Cross-sectional studies have shown that pericardial fat is associated with atherosclerotic burden above and beyond generalized and central adiposity. Whether pericardial fat is longitudinally associated with coronary artery calcium (CAC) has not been firmly established. We examined the associations between cardiac ectopic fat including pericardial and intrathoracic fat with CAC progression and incidence in a community-based study setting.

Association Between Leukocyte Telomere Length and the Risk of Incident Atrial Fibrillation: The Framingham Heart Study.

Background: Advancing age is a prominent risk factor for atrial fibrillation (AF). Shorter telomere length is a biomarker of biological aging, but the link between shorter telomere length and increased risk of AF remains unclear. We examined the association between shorter leukocyte telomere length (LTL) and incident AF.

Transcriptome-wide association study of inflammatory biologic age.

Chronic low grade inflammation is a fundamental mechanism of aging. We estimated biologic age using nine biomarkers from diverse inflammatory pathways and we hypothesized that genes associated with inflammatory biological age would provide insights into human aging. In Framingham Offspring Study participants at examination 8 (2005 to 2008), we used the Klemera-Doubal method to estimate inflammatory biologic age and we computed the difference (∆Age) between biologic age and chronologic age.

Association of built environment characteristics with adiposity and glycaemic measures.

Objective: This study examined the cross-sectional and longitudinal relationships of built environment characteristics with adiposity and glycaemic measures.

Method: Longitudinal study sample consisted of 4,010 Framingham Heart Study Offspring (baseline: 1998-2001; follow-up: 2005-2008) and Generation Three (baseline: 2002-2005; follow-up: 2008-2011) participants (54.8% women, baseline mean age 48.

Sex Differences and Similarities in Atrial Fibrillation Epidemiology, Risk Factors, and Mortality in Community Cohorts: Results From the BiomarCaRE Consortium (Biomarker for Cardiovascular Risk Assessment in Europe).

Background: Atrial fibrillation (AF) is a common cardiac disease in aging populations with high comorbidity and mortality. Sex differences in AF epidemiology are insufficiently understood.

Methods: In N=79 793 individuals without AF diagnosis at baseline (median age, 49.

Diminished Expression Is Associated With Increased Risk of Atrial Fibrillation and Shortening of the Cardiac Action Potential.

Background: Atrial fibrillation (AF) affects over 33 million individuals worldwide. Genome-wide association studies have identified at least 30 AF loci, but the mechanisms through which individual variants lead to altered disease risk have remained unclear for the majority of these loci. At the 1q24 locus, we hypothesized that the transcription factor could be a strong candidate gene as it is expressed in the pulmonary veins, a source of AF in many individuals.

Whole blood gene expression and white matter Hyperintensities.

Background: White matter hyperintensities (WMH) are an important biomarker of cumulative vascular brain injury and have been associated with cognitive decline and an increased risk of dementia, stroke, depression, and gait impairments. The pathogenesis of white matter lesions however, remains uncertain. The characterization of gene expression profiles associated with WMH might help uncover molecular mechanisms underlying WMH.