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An investigation of coronary heart disease in families. The Framingham offspring study
Abstract
The Framingham Heart Study (FHS) was started in 1948 as a prospective investigation of cardiovascular disease in a cohort of adult men and women. Continuous surveillance of this sample of 5209 subjects has been maintained through biennial physical examinations. In 1971 examinations were begun on the children of the FHS cohort. This study, called the Framingham Offspring Study (FOS), was undertaken to expand upon knowledge of cardiovascular disease, particularly in the area of familial clustering of the disease and its risk factors. This report reviews the sampling design of the FHS and describes the nature of the FOS sample. The FOS families appear to be of typical size and age structure for families with parents born in the late 19th or early 20th century. In addition, there is little evidence that coronary heart disease (CHD) experience and CHD risk factors differ in parents of those who volunteered for this study and the parents of those who did not volunteer.
... Family history (FH) of CAD [FH-CAD] is a risk factor for atherosclerotic CAD [12][13][14][15][16][17], and some reports have demonstrated that FH-CAD may also be a risk factor for VSA, especially in female patients [18][19][20]. However, studies comparing FH-CAD frequency between patients with VSA and those with atherosclerotic CAD while exploring FH-CAD effects on the clinical characteristics and prognosis of patients with VSA remain scarce. ...
... Based on the results of CAG and/or SPT, 656 patients were divided into three groups: atherosclerotic CAD group (n = 362), VSA group (n = 221) and non-VSA group (n = 73) ( Figure 1). Family history (FH) of CAD [FH-CAD] is a risk factor for atherosclerotic CAD [12][13][14][15][16][17], and some reports have demonstrated that FH-CAD may also be a risk factor for VSA, especially in female patients [18][19][20]. However, studies comparing FH-CAD frequency between patients with VSA and those with atherosclerotic CAD while exploring FH-CAD effects on the clinical characteristics and prognosis of patients with VSA remain scarce. ...
... FH-CAD, especially young-onset CAD, is undeniably a risk factor for atherosclerotic CAD [12][13][14][15][16][17]. According to research, 12.2% of patients over the age of 20 had a parent or sibling who had suffered a heart attack or angina pectoris before turning 50 [35]. ...
Background:
Family history (FH) of coronary artery disease (CAD) [FH-CAD] is a well-known risk factor for atherosclerotic CAD. However, FH-CAD frequency in patients with vasospastic angina (VSA) remains unknown, and the clinical characteristics and prognosis of VSA patients with FH-CAD are unclear. Therefore, this study compared FH-CAD frequency between patients with atherosclerotic CAD and those with VSA and examined the clinical characteristics and prognosis of VSA patients with FH-CAD.
Methods:
Coronary angiography and spasm provocation tests (SPT) were used to investigate chest pain of coronary artery origin in patients classified into atherosclerotic CAD (362 cases), VSA (221 cases; positive for SPT) and non-VSA (73 cases; negative for SPT) groups, with FH-CAD being defined. In the VSA group, flow-mediated vasodilation (FMD) and nitroglycerin-independent vasodilation (NID) via brachial artery echocardiography and clinical symptoms in the groups with and without FH-CAD were checked, with Kaplan-Meier curves revealing major adverse cardiovascular events (cardiac death and rehospitalisation for cardiovascular disease) between the two groups.
Results:
The atherosclerotic CAD group had a significantly lower FH-CAD frequency (12%, p = 0.029) than the VSA (19%) and non-VSA groups (19%). FH-CAD was more common in females in the VSA and non-VSA groups than in the atherosclerotic CAD group (p < 0.001). Nonpharmacological treatment for CAD in FH-CAD was more common in the atherosclerotic CAD group (p = 0.017). In the VSA group, FH-CAD tended to be more common in females (p = 0.052). Although no differences in FMD of the brachial artery were observed between the groups, the FH-CAD (+) group had significantly higher NID than the FH-CAD (-) group (p = 0.023). Kaplan-Meier's analysis revealed a similar prognosis between the two groups, and other clinical characteristics did not differ.
Conclusion:
Patients with VSA have a higher FH-CAD frequency than those with atherosclerotic CAD, especially in females. Although FH-CAD may affect vascular function in patients with VSA, its effect on the severity and prognosis of VSA appears to be minimal. FH-CAD and its confirmation may assist in CAD diagnosis, especially in female patients.
... Then, the models are tuned and validated using independent datasets from the Framingham Heart Study (FHS) [15]. Specifically, we use FHS subcohort 1 (n = 797) for tuning and FHS subcohort 2 (n = 798) for validation. ...
... We compared the imputation accuracy between MIMOSA and the models created by Baselmans et al. [2] (hereafter referred to as the Baselmans models) for whole blood using independent samples from the Framingham Heart Study (FHS). The MIMOSA models were trained on summary-level mQTL data from GoDMC [9], which is itself based on a sample size of 27,750 subjects, and tuned using individual-level mQTL data (subcohort 1, n = 797) from the FHS [15]. In total, MIMOSA 3 . ...
... The Baselmans models [2] were trained on individual-level mQTL data from the BIOS Consortium, based on samples from 4,008 subjects. We evaluated the performance of both methods using individual-level data (subcohort 2, n = 798) from the FHS [15]. To make a fair comparison, we examined the number of CpG sites with R 2 > 0.01 in the imputation models for the overlapping CpG site list (i.e., CpG sites with models created by both methods). ...
DNA methylation has been shown to be involved in the etiology of many complex diseases, yet the specific key underlying methylation sites remain largely unknown. One strategy to identify putative causal CpG sites and enhance disease etiology understanding is to conduct methylome-wide association studies (MWASs), in which predicted or measured DNA methylation that is associated with complex diseases can be identified. However, current MWAS models are trained with relatively small reference datasets, limiting the ability to adequately handle CpG sites with low genetic heritability. Here, we introduce a new resource, MWAS Imputing Methylome Obliging Summary-level mQTLs and Associated LD matrices (MIMOSA), a set of models that substantially improve the prediction accuracy of DNA methylation and subsequent MWAS power through the use of a large, summary-level mQTL dataset provided by the Genetics of DNA Methylation Consortium (GoDMC). With the analyses of GWAS summary statistics for 28 complex traits and diseases, we demonstrate that MIMOSA considerably increases the accuracy of DNA methylation prediction in blood, crafts fruitful prediction models for low heritability CpG sites, and determines markedly more CpG site-phenotype associations than preceding methods.
... Since its inception, the study has followed three generations of participants who are invited for follow-up examinations every 2 to 6 years. [15][16][17] The present crosssectional analysis included 5619 non-Hispanic White participants with whole-blood gene expression profiling from the Offspring 16 ...
... Since its inception, the study has followed three generations of participants who are invited for follow-up examinations every 2 to 6 years. [15][16][17] The present crosssectional analysis included 5619 non-Hispanic White participants with whole-blood gene expression profiling from the Offspring 16 ...
Introduction:
We investigated associations of obesity with the expression of Alzheimer's disease (AD)-related genes in a large community-based cohort.
Methods:
The sample consisted of 5619 participants from the Framingham Heart Study. Obesity metrics included body mass index (BMI) and waist-to-hip ratio (WHR). Gene expression was measured for a set of 74 AD-related genes, derived by integrating genome-wide association study results with functional genomics data.
Results:
Obesity metrics were associated with the expression of 21 AD-related genes. The strongest associations were observed with CLU, CD2AP, KLC3, and FCER1G. Unique associations were noted with TSPAN14, SLC24A4 for BMI, and ZSCAN21, BCKDK for WHR. After adjustment for cardiovascular risk factors, 13 associations remained significant for BMI and 8 for WHR. Dichotomous obesity metrics exhibited unique associations with EPHX2 for BMI, and with TSPAN14 for WHR.
Discussion:
Obesity was associated with AD-related gene expression; these findings shed light on the molecular pathways linking obesity to AD.
... DNA methylation and RNA-seq data were collected from 2115 participants in the FHS Offspring (n = 686) and Third Generation (n = 1429) cohorts. Peripheral whole blood samples were collected in the fasting state at the ninth examination cycle from FHS Offspring participants(2011)(2012)(2013)(2014) 24 and at the second examination cycle(2006)(2007)(2008)(2009) 25 from FHS Third Generation participants. All study protocols were approved by the Boston Medical Center Institutional Review Board and performed in accordance with the Declaration of Helsinki and relevant regulations, and all study participants provided their written informed consent.DNA methylation data collection. ...
Expression quantitative trait methylation (eQTM) analysis identifies DNA CpG sites at which methylation is associated with gene expression. The present study describes an eQTM resource of CpG-transcript pairs derived from whole blood DNA methylation and RNA sequencing gene expression data in 2115 Framingham Heart Study participants. We identified 70,047 significant cis CpG-transcript pairs at p < 1E−7 where the top most significant eGenes (i.e., gene transcripts associated with a CpG) were enriched in biological pathways related to cell signaling, and for 1208 clinical traits (enrichment false discovery rate [FDR] ≤ 0.05). We also identified 246,667 significant trans CpG-transcript pairs at p < 1E−14 where the top most significant eGenes were enriched in biological pathways related to activation of the immune response, and for 1191 clinical traits (enrichment FDR ≤ 0.05). Independent and external replication of the top 1000 significant cis and trans CpG-transcript pairs was completed in the Women’s Health Initiative and Jackson Heart Study cohorts. Using significant cis CpG-transcript pairs, we identified significant mediation of the association between CpG sites and cardiometabolic traits through gene expression and identified shared genetic regulation between CpGs and transcripts associated with cardiometabolic traits. In conclusion, we developed a robust and powerful resource of whole blood eQTM CpG-transcript pairs that can help inform future functional studies that seek to understand the molecular basis of disease.
... The copyright holder for this preprint this version posted May 29, 2023. ; https://doi.org/10.1101/2023.05.24.23290487 doi: medRxiv preprint comprehensive demographic and clinical measures such as risk factors for cardiovascular and neurodegenerative diseases 14 . This study analyzed Offspring participants who had metabolite measurements at the 5th examination (n=2526). ...
Background:
Metabolite signatures of long-term alcohol consumption are lacking. To better understand the molecular basis linking alcohol drinking and cardiovascular disease (CVD), we investigated circulating metabolites associated with long-term alcohol consumption and examined whether these metabolites were associated with incident CVD.
Methods:
Cumulative average alcohol consumption (g/day) was derived from the total consumption of beer, wine and liquor on average of 19 years in 2,428 Framingham Heart Study Offspring participants (mean age 56 years, 52% women). We used linear mixed models to investigate the associations of alcohol consumption with 211 log-transformed plasma metabolites, adjusting for age, sex, batch, smoking, diet, physical activity, BMI, and familial relationship. Cox models were used to test the association of alcohol-related metabolite scores with fatal and nonfatal incident CVD (myocardial infarction, coronary heart disease, stroke, and heart failure).
Results:
We identified 60 metabolites associated with cumulative average alcohol consumption (p<0.05/211≈0.00024). For example, one g/day increase of alcohol consumption was associated with higher levels of cholesteryl esters (e.g., CE 16:1, beta=0.023±0.002, p=6.3e-45) and phosphatidylcholine (e.g., PC 32:1, beta=0.021±0.002, p=3.1e-38). Survival analysis identified that 10 alcohol-associated metabolites were also associated with a differential CVD risk after adjusting for age, sex, and batch. Further, we built two alcohol consumption weighted metabolite scores using these 10 metabolites and showed that, with adjustment age, sex, batch, and common CVD risk factors, the two scores had comparable but opposite associations with incident CVD, hazard ratio 1.11(95% CI=[1.02, 1.21],p=0.02) vs 0.88 (95% CI=[0.78, 0.98], p=0.02).
Summary:
We identified 60 long-term alcohol consumption-associated metabolites. The association analysis with incident CVD suggests a complex metabolic basis between alcohol consumption and CVD.
... Particularly, only a few studies begin at an early-life stage and sustain long-term. Although child-mother pairs are usually recruited for birth cohort studies 38-40 , and grown-up children from existing cohorts may be recruited in other new cohorts [41][42][43] , rarely are cohorts that include integrated and completed three-generation data 14 . ...
Background
Epidemiologic research has increasingly acknowledged the importance of developmental origins of health and disease and suggests that prior exposures can be transferred across generations. Understanding the intergenerational inheritance has profound implications for developing public health interventions to prevent diseases. Multigenerational cohorts are crucial to verify the above-mentioned issues among human subjects. We carried out this scoping review aims to map existing literature to summarize multigenerational cohort studies' characteristics, issues, and implications and hence provide evidence to the developmental origins of health and disease hypothesis and intergenerational inheritance.
Methods
This study followed Arksey and O’Malley’s five-stage scoping review framework. We adopted a three-step search strategy to identify multigenerational cohorts comprehensively, searching PubMed, EMBASE, and Web of Science databases from the inception of each dataset to June 20th, 2022, to retrieve relevant articles. We aim to include all the existing multigenerational cohorts. Data of included cohorts were extracted using a standardized tool, to form a descriptive analysis and a thematic summary.
Results
After screening, 28 unique multigenerational cohort studies were identified. We classified all studies into four types: population-based cohort extended three generation cohort, birth cohort extended three generation cohort, three generation cohort, and integrated birth and three generation cohort. Most cohorts (n = 15, 53%) were categorized as birth cohort extended three-generation studies. The sample size of included cohorts varied from 41 to 167,729. The study duration ranged from two years to 31 years. Most cohorts had comprehensive data collection schemes. Almost all cohorts had common exposures, including socioeconomic factors, lifestyle, and grandparents’ and parents’ health and risk behaviors over the life course. These studies usually investigated intergenerational inheritance of diseases as the outcomes, most frequently, obesity, child health, and cardiovascular diseases.
Conclusions
Most multigenerational studies aim to disentangle genetic, lifestyle and environmental contributions to the developmental origins of health and disease across generations. We call for more research on large multigenerational well-characterized cohorts, up to four or even more generations, and more studies from low-and middle-income countries.
... Cohort studies should consider adding offspring ancillary studies to examine physical activity across lifecourse stages, such as the Avon Longitudinal Study of Parents and Children 154 and the Framingham Offspring Study. 155 With the advent of the quantified self, an exponential growth in the amount of quantified, longitudinal physical activity data opens opportunities to resolve several unanswered questions. 156 A central question revolves around 24-hour patterns of physical activity (eg, sleep, sedentary behavior) and how they may modify the association of physical activity with CVD. ...
Despite improvements in cardiovascular care in recent decades, cardiovascular disease (CVD) remains a leading cause of death worldwide. At its core, CVD is a largely preventable disease with diligent risk factor management and early detection. As highlighted in the American Heart Association's Life's Essential 8, physical activity plays a central role in CVD prevention at an individual and population level. Despite pervasive knowledge of the numerous cardiovascular and noncardiovascular health benefits of physical activity, physical activity has steadily decreased over time and unfavorable changes in physical activity occur throughout people's lives. Here, we use a lifecourse framework to examine the evidence reporting on the association of physical activity with CVD. From in utero to older adults, we review and discuss the evidence detailing how physical activity may prevent incident CVD and mitigate CVD-related morbidity and death across all life stages.
... The FHS is a community-based prospective cohort study. Starting in 1948, the FHS recruited 5209 participants residing in Framingham, Massachusetts who were primarily white American adults of European ancestry as the Original cohort [38], followed by the Offspring cohort (n=5129) which was recruited in 1971, consisting of the children of the Original cohort and spouses of the Offspring [39,40]. The Offspring cohort participants have been examined every 4-8 years since enrollment. ...
Understanding the composition of circulating immune cells with aging and the underlying biologic mechanisms driving aging may provide molecular targets to slow the aging process and reduce age-related disease. Utilizing cryopreserved cells from 996 Framingham Heart Study (FHS) Offspring Cohort participants aged 40 and older (mean 62 years, 48% female), we report on 116 immune cell phenotypes including monocytes, T-, B-, and NK cells and their subtypes, across age groups, sex, cytomegalovirus (CMV) exposure groups, smoking and other cardiovascular risk factors. The major cellular differences with CMV exposure were higher Granzyme B+ cells, effector cells, and effector-memory re-expressing CD45RA (TEMRA) cells for both CD4+ and CD8+. Older age was associated with lower CD3+ T cells, lower naïve cells and naïve/memory ratios for CD4+ and CD8+. We identified many immune cell differences by sex, with males showing lower naïve cells and higher effector and effector memory cells. Current smokers showed lower pro-inflammatory CD8 cells, higher CD8 regulatory type cells and altered B cell subsets. No significant associations were seen with BMI and other cardiovascular risk factors. Our cross-sectional observations of immune cell phenotypes provide a reference to further the understanding of the complexity of immune cells in blood, an easily accessible tissue.
... Between 1971 and 1974, children of the Original Cohort were enrolled in a separate Offspring Cohort. Details of the study design, implementation and criteria for diagnosis have been previously published 31,32 . This study is approved by the Institutional Review Board (Ethics and Research Governance Online (ERGO), University of Southampton: 54,198) and the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (ID 8194). ...
Studies investigating the association between acetylsalicylic acid (ASA) use and spontaneous subarachnoid haemorrhage (SAH) in the general population have produced conflicting results. The aim of this study is to clarify the relationship between SAH and ASA. We included all participants who reported on ASA use during interim examinations of the Framingham Heart Study Cohorts. Using Cox proportional-hazards regression modelling, we estimated the hazard ratio (HR) associated with ASA use. 7692 participants were included in this study. There were 30 cases of SAH during follow up, with an estimated incidence of 10.0 per 100,000 person- years (CI 6.90–14.15). Univariate analysis showed no association between regular ASA use and SAH (HR, 0.33 [0.08–1.41]; p = 0.14). This was similar when accounting for smoking (HR, 0.35 [0.08–1.51]; p = 0.16). Using a large longitudinal dataset from the Framingham Heart Study, we observed some evidence suggesting fewer SAH in those participants taking regular ASA. However, multivariate statistical analysis showed no significant association between ASA use and SAH. Due to the low incidence of SAH in the general population, the absolute number of SAH events was low and it remains uncertain if a significant effect would become apparent with more follow up.
... The FHS is a population-based cohort that began in 1948 by enrolling 5209 individuals to investigate CVD and familial risk factors [21]. In addition, from 1971-1975, 5124 offspring of the original participants in the FHS were enrolled to investigate the roles of family history and genetics in the development of CVD [22]. ...
Background:
Polyphenolic antioxidants derived from plant foods may reduce oxidative stress and frailty, but the effect of the polyphenol subclass of dietary flavonoids and their subclasses on frailty is uncertain.
Objectives:
To determine the association between dietary flavonoids, their subclasses, quercetin (a specific flavonol), and frailty onset in adults.
Methods:
This prospective cohort study included individuals from the Framingham Heart Study with no frailty at baseline. Intake of total flavonoids, subclasses of flavonoids (flavonols, flavan-3-ols, flavonones, flavones, anthocyanins, and polymeric flavonoids), and quercetin were estimated via semi-quantitative FFQ along with frailty (Fried phenotype), and covariates at baseline (1998-2001). Frailty was re-evaluated in 2011-2014. Logistic regression estimated OR and 95% CIs for each flavonoid variable and frailty onset.
Results:
Mean age was 58.4 y (SD ± 8.3, n = 1701; 55.5% women). The mean total flavonoid intake was 309 mg/d (SD ± 266). After 12.4 (SD ± 0.8) y, 224 (13.2%) individuals developed frailty. Although total flavonoid intake was not statistically associated with frailty onset (adjusted OR: 1.00; 95% CI: 0.99-1.01), each 10 mg/d of flavonols intake was linked with 20% lower odds of frailty onset (OR: 0.80; 95% CI: 0.67-0.96). Other subclasses showed no association (P values range: 0.12-0.99), but every 10 mg/d of quercetin intake was associated with 35% lower odds of frailty onset (OR: 0.65; 95% CI: 0.48-0.88).
Conclusions:
Although no association was observed between total flavonoid intake and frailty onset in adults, a higher intake of flavonols was associated with lower odds of frailty onset, with a particularly strong association for quercetin. This hypothesis-generating study highlights the importance of assessing specific subclasses of flavonoids and the potential of dietary flavonols and quercetin as a strategy to prevent the development of frailty.
... The study initially enrolled participants living in the town of Framingham, Massachusetts, who were free of overt symptoms of CVD, heart attack, or stroke at enrollment. In 1971, the study started the FHS offspring cohort to enroll a second generation of the original participants' adult children and their spouses (n = 5124) to conduct similar examinations [58]. Participants from the FHS offspring cohort were eligible for our study if they attended both the seventh and eighth examination cycles and consented to having their molecular data used for the study. ...
Claims surrounding exceptional longevity are sometimes disputed or dismissed for lack of credible evidence. Here, we present three DNA methylation-based age estimators (epigenetic clocks) for verifying age claims of centenarians. The three centenarian clocks were developed based on n = 7039 blood and saliva samples from individuals older than 40, including n = 184 samples from centenarians, 122 samples from semi-supercentenarians (aged 105 +), and 25 samples from supercentenarians (aged 110 +). The oldest individual was 115 years old. Our most accurate centenarian clock resulted from applying a neural network model to a training set composed of individuals older than 40. An epigenome-wide association study of age in different age groups revealed that age effects in young individuals (age < 40) are correlated (r = 0.55) with age effects in old individuals (age > 90). We present a chromatin state analysis of age effects in centenarians. The centenarian clocks are expected to be useful for validating claims surrounding exceptional old age.
... The "AtheroSclerotic Cardiovascular Disease (ASCVD) Risk Estimator" estimates the risk of ASCVD in the next 10 years. The estimator was developed using data from large, diverse cohorts, including the ARIC [84], Cardiovascular Health [85], and the Coronary Artery Risk Development in Young Adults (CARDIA) [86], as well as with the Framingham Original and Offspring Study cohorts [87]. The ASCVD estimator accompanied the "2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk" [88,89] and the "2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults" [90]. ...
Despite major advances in pharmacotherapy and interventional procedures, coronary artery disease (CAD) remains a principal cause of morbidity and mortality worldwide. Invasive coronary imaging along with the computation of hemodynamic forces, primarily endothelial shear stress and plaque structural stress, have enabled a comprehensive identification of atherosclerotic plaque components, providing a unique insight into the understanding of plaque vulnerability and progression, which may help guide patient treatment. However, the invasive-only approach to CAD has failed to show high predictive value. Meanwhile, it is becoming increasingly evident that along with the “vulnerable plaque”, the presence of a “vulnerable patient” state is also necessary to precipitate an acute coronary thrombotic event. Non-invasive imaging techniques have also evolved, providing new opportunities for the identification of high-risk plaques, the study of atherosclerosis in asymptomatic individuals, and general population screening. Additionally, risk stratification scores, circulating biomarkers, immunology, and genetics also complete the armamentarium of a broader “vulnerable plaque and patient” concept approach. In the current review article, the invasive and non-invasive modalities used for the detection of high-risk plaques in patients with CAD are summarized and critically appraised. The challenges of the vulnerable plaque concept are also discussed, highlighting the need to shift towards a more interdisciplinary approach that can identify the “vulnerable plaque” in a “vulnerable patient”.
... To test the bAge predictor, data from an additional 4134 individuals (with a total of 1653 deaths) from four external cohorts (six datasets) were considered. These included the baseline samples of both the LBC1921 and LBC1936 cohorts, as well as the Framingham Heart Study (FHS) [27][28][29] and the Women's Health Initiative (WHI) [30,31] Broad Agency Award 23 (B23) study for Black, White, and Hispanic individuals (Table 2). ...
Background
Epigenetic clocks can track both chronological age (cAge) and biological age (bAge). The latter is typically defined by physiological biomarkers and risk of adverse health outcomes, including all-cause mortality. As cohort sample sizes increase, estimates of cAge and bAge become more precise. Here, we aim to develop accurate epigenetic predictors of cAge and bAge, whilst improving our understanding of their epigenomic architecture.
Methods
First, we perform large-scale (N = 18,413) epigenome-wide association studies (EWAS) of chronological age and all-cause mortality. Next, to create a cAge predictor, we use methylation data from 24,674 participants from the Generation Scotland study, the Lothian Birth Cohorts (LBC) of 1921 and 1936, and 8 other cohorts with publicly available data. In addition, we train a predictor of time to all-cause mortality as a proxy for bAge using the Generation Scotland cohort (1214 observed deaths). For this purpose, we use epigenetic surrogates (EpiScores) for 109 plasma proteins and the 8 component parts of GrimAge, one of the current best epigenetic predictors of survival. We test this bAge predictor in four external cohorts (LBC1921, LBC1936, the Framingham Heart Study and the Women’s Health Initiative study).
Results
Through the inclusion of linear and non-linear age-CpG associations from the EWAS, feature pre-selection in advance of elastic net regression, and a leave-one-cohort-out (LOCO) cross-validation framework, we obtain cAge prediction with a median absolute error equal to 2.3 years. Our bAge predictor was found to slightly outperform GrimAge in terms of the strength of its association to survival (HRGrimAge = 1.47 [1.40, 1.54] with p = 1.08 × 10⁻⁵², and HRbAge = 1.52 [1.44, 1.59] with p = 2.20 × 10⁻⁶⁰). Finally, we introduce MethylBrowsR, an online tool to visualise epigenome-wide CpG-age associations.
Conclusions
The integration of multiple large datasets, EpiScores, non-linear DNAm effects, and new approaches to feature selection has facilitated improvements to the blood-based epigenetic prediction of biological and chronological age.
... The Framingham Heart Study The Framingham Heart Study, launched in 1948, is a communitybased longitudinal population study that recruited participants who self-identified as being of European descent and lived in Framingham, MA (Dawber et al., 1951). In 1971, the original FHS participants' children and spouses were recruited to establish the Framingham Offspring Study (FHS) (Kannel et al., 1979). Participants of FHS were interviewed and clinically examined about every 4-8 years after that. ...
Background: Many epigenetic loci have been associated with plasma triglyceride (TG) levels, but epigenetic connections between those loci and dietary exposures are largely unknown. This study aimed to characterize the epigenetic links between diet, lifestyle, and TG.
Methods: We first conducted an epigenome-wide association study (EWAS) for TG in the Framingham Heart Study Offspring population (FHS, n = 2,264). We then examined relationships between dietary and lifestyle-related variables, collected four times in 13 years, and differential DNA methylation sites (DMSs) associated with the last TG measures. Third, we conducted a mediation analysis to evaluate the causal relationships between diet-related variables and TG. Finally, we replicated three steps to validate identified DMSs associated with alcohol and carbohydrate intake in the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) study ( n = 993).
Results: In the FHS, the EWAS revealed 28 TG-associated DMSs at 19 gene regions. We identified 102 unique associations between these DMSs and one or more dietary and lifestyle-related variables. Alcohol and carbohydrate intake showed the most significant and consistent associations with 11 TG-associated DMSs. Mediation analyses demonstrated that alcohol and carbohydrate intake independently affect TG via DMSs as mediators. Higher alcohol intake was associated with lower methylation at seven DMSs and higher TG. In contrast, increased carbohydrate intake was associated with higher DNA methylation at two DMSs ( CPT1A and SLC7A11 ) and lower TG. Validation in the GOLDN further supports the findings.
Conclusion: Our findings imply that TG-associated DMSs reflect dietary intakes, particularly alcoholic drinks, which could affect the current cardiometabolic risk via epigenetic changes. This study illustrates a new method to map epigenetic signatures of environmental factors for disease risk. Identification of epigenetic markers of dietary intake can provide insight into an individual’s risk of cardiovascular disease and support the application of precision nutrition.
Clinical Trial Registration: www.ClinicalTrials.gov , the Framingham Heart Study (FHS), NCT00005121; the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN), NCT01023750.
... The Framingham Offspring Study began in 1971 with the enrollment of 5124 offspring of the original Framingham Heart Study cohort [24]. Generally, participants have been examined approximately every four years for the development of CVD and other health outcomes. ...
The association between egg consumption and cardiometabolic risk factors such as high blood pressure (HBP) and impaired fasting glucose (IFG) or type 2 diabetes (T2D) is still under debate. This study examines the association between egg consumption and these outcomes among 2349 30–64 year-old adults in the prospective Framingham Offspring Study. Diet was assessed using three-day dietary records. Potential confounders retained in the final models included age, sex, body mass index, and other dietary factors. The analysis of covariance and Cox proportional hazard’s models were used to assess the relevant continuous (i.e., FG, SBP, DBP) and categorical (i.e., T2D, HBP) outcomes. Consuming ≥5 eggs per week was associated with lower mean FG (p = 0.0004) and SBP (p = 0.0284) after four years of follow-up. Higher egg intakes led to lower risks of developing IFG or T2D (HR: 0.72; 95% CI: 0.51–1.03) and high blood pressure (HBP) (HR: 0.68; 0.50–0.93). The beneficial effects of egg consumption were stronger in combination with other healthy dietary patterns. This study found that regular egg consumption as part of a healthy diet had long-term beneficial effects on blood pressure and glucose metabolism and lowered the long-term risks of high blood pressure and diabetes.
... female) from the Offspring cohort (Gen 2) with data on genome wide single nucleotide polymorphisms (SNPs) and circulating CD34+CD133+ cells measured at examination8 (2005-2007) who were followed subsequently for incident AD dementia. Relevant details about this cohort have been previously described.58 159 of them developed incident AD through the period ending in 2019 (SupplementFigure 1). ...
Cerebrovascular damage coexists with Alzheimers disease (AD) pathology and increases AD risk. However, it is unclear whether endothelial progenitor cells reduce AD risk via cerebrovascular repair. By using the Framingham Heart Study (FHS) offspring cohort, which includes data on different progenitor cells, the incidence of AD dementia, peripheral and cerebrovascular pathologies, and genetic data (n = 1,566), we found that elevated numbers of circulating endothelial progenitor cells with CD34+CD133+ co-expressions had a dose-dependent association with decreased AD risk (HR = 0.67, 95% CI: 0.46-0.96, p = 0.03) after adjusting for age, sex, years of education, and APOE4. With stratification, this relationship was only significant among those individuals who had vascular pathologies, especially hypertension (HTN) and cerebral microbleeds (CMB), but not among those individuals who had neither peripheral nor central vascular pathologies. We applied a genome-wide association study (GWAS) and found that the number of CD34+CD133+ cells impacted AD risk depending on the homozygous genotypes of two genes: KIRREL3 rs580382 CC carriers (HR = 0.31, 95% CI: 0.17-0.57, p<0.001), KIRREL3 rs4144611 TT carriers (HR = 0.29, 95% CI: 0.15-0.57, p<0.001), and EXOC6B rs61619102 CC carriers (HR = 0.49, 95% CI: 0.31-0.75, p<0.001) after adjusting for confounders. In contrast, the relationship did not exist in their counterpart genotypes, e.g. KIRREL3 TT/CT or GG/GT carriers and EXOC6B GG/GC carriers. Our findings suggest that circulating CD34+CD133+ endothelial progenitor cells can be therapeutic in reducing AD risk in the presence of cerebrovascular pathology, especially in KIRREL3 and EXOC6B genotype carriers.
... The current study focused on Offspring cohort (Generation 2) white participants who have data on GWAS and serum CRP measurement and have been rigorously evaluated for cognitive decline and dementia since 1979. Other details of this cohort have been previously described [20]. In brief, the cohort included 5124 white participants at the first health examination (1971)(1972)(1973)(1974)(1975). ...
Abstract Apolipoprotein ε4 (APOE ε4) is the most significant genetic risk factor for late-onset Alzheimer’s disease (AD). Elevated blood C-reactive protein (CRP) further increases the risk of AD for people carrying the APOE ε4 allele. We hypothesized that CRP, as a key inflammatory element, could modulate the impact of other genetic variants on AD risk. We selected ten single nucleotide polymorphisms (SNPs) in reported AD risk loci encoding proteins related to inflammation. We then tested the interaction effects between these SNPs and blood CRP levels on AD incidence using the Cox proportional hazards model in UK Biobank (n = 279,176 white participants with 803 incident AD cases). The five top SNPs were tested for their interaction with different CRP cutoffs for AD incidence in the Framingham Heart Study (FHS) Generation 2 cohort (n = 3009, incident AD = 156). We found that for higher concentrations of serum CRP, the AD risk increased for SNP genotypes in 3 AD-associated genes (SPI1, CD33, and CLU). Using the Cox model in stratified genotype analysis, the hazard ratios (HRs) for the association between a higher CRP level (≥10 vs.
... The FHS Original cohort (n = 5209) was established in 1948 to investigate risk factors for cardiovascular disease 25 . In the early 1970s, the children of the Original cohort participants and their spouses were enrolled into the Offspring cohort (n = 5124) 26 . A study sample (n = 2676 participants) was drawn from the FHS Offspring cohort who attended exam eight (2005)(2006)(2007)(2008), total n = 3021 exam attendees) with archived blood specimens available for eicosanoid profiling. ...
Chronic inflammation is a continuous low-grade activation of the systemic immune response. Whereas downstream inflammatory markers are associated with atrial fibrillation (AF), upstream inflammatory effectors including eicosanoids are less studied. To examine the association between eicosanoids and incident AF. We used a liquid chromatography-mass spectrometry for the non-targeted measurement of 161 eicosanoids and eicosanoid-related metabolites in the Framingham Heart Study. The association of each eicosanoid and incident AF was assessed using Cox proportional hazards models and adjusted for AF risk factors, including age, sex, height, weight, systolic/diastolic blood pressure, current smoking, antihypertensive medication, diabetes, history of myocardial infarction and heart failure. False discovery rate (FDR) was used to adjust for multiple testing. Eicosanoids with FDR < 0.05 were considered significant. In total, 2676 AF-free individuals (mean age 66 ± 9 years, 56% females) were followed for mean 10.8 ± 3.4 years; 351 participants developed incident AF. Six eicosanoids were associated with incident AF after adjusting for multiple testing (FDR < 0.05). A joint score was built from the top eicosanoids weighted by their effect sizes, which was associated with incident AF (HR = 2.72, CI = 1.71–4.31, P = 2.1 × 10–5). In conclusion, six eicosanoids were associated with incident AF after adjusting for clinical risk factors for AF.
... FHS (including Original cohort, Offspring cohort, Third Generation cohort, New Offspring Spouse cohort, and two minority ethnic cohorts) was initiated in the town of Framingham, Massachusetts, in 1948 to detect risk factors for cardiovascular diseases [11]. Thereinto, the Offspring cohort was established in 1971, and it involved 5,124 individuals, including the children of individuals from the Original cohort together with their spouses [12]. To date, nine rounds of physical examinations have been completed, with the frequency of approximately every four years [13]. ...
Background
Triglyceride-glucose (TyG) index is a reliable surrogate marker of insulin resistance (IR), whereas IR has been implicated in Alzheimer’s disease (AD) pathophysiology. However, the relationship between the TyG index and AD remains unclear. Herein, we aimed to evaluate the associations of both baseline level and long-term trajectories of the TyG index with the risk of AD.
Methods
This prospective study included 2,170 participants free of AD from the Framingham Heart Study Offspring cohort. The TyG index was calculated as Ln[fasting triglyceride (mg/dL)×fasting glucose (mg/dL)/2]. Data for the TyG index from three examinations were used to identify the long-term trajectories of the TyG index by latent class growth mixture modeling analysis. The Cox and logistic regression models were applied to evaluate the associations of the baseline level and long-term trajectories of the TyG index with AD.
Results
During a median follow-up of 13.8 years, 163 (7.5%) participants developed AD. Each unit increment of baseline TyG index was associated with a 39% increased risk of AD (adjusted hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.02–1.88). When compared with the reference (TyG index ≤ 8.28), we observed a significantly elevated risk of AD in the group with TyG index of 8.68–9.09 (adjusted HR 1.69, 95% CI 1.03–2.77). In addition, three long-term trajectories of the TyG index were identified (low-stable [95.3%], intermediate-remitting [2.1%], and high-decreasing [2.6%] trajectory group). There was no significant difference in AD risk among the three groups.
Conclusions
Our findings first showed that a higher baseline TyG index was associated with an increased incidence of AD. The TyG index might be used as a simple surrogate marker for the early detection of AD.
... The study sample included consenting participants from the FHS Offspring, Third Generation, and Omni cohorts. In 1971, the FHS recruited the offspring of participants in the Original FHS cohort as well as the spouses of offspring to form the FHS Offspring cohort37 . The children of the Offspring cohort participants were recruited to the Third Generation cohort beginning in 200238 . ...
DNA methylation commonly occurs at cytosine-phosphate-guanine sites (CpGs) that can serve as biomarkers for many diseases. We analyzed whole genome sequencing data to identify DNA methylation quantitative trait loci (mQTLs) in 4126 Framingham Heart Study participants. Our mQTL mapping identified 94,362,817 cis-mQTLvariant-CpG pairs (for 210,156 unique autosomal CpGs) at P < 1e−7 and 33,572,145 trans-mQTL variant-CpG pairs (for 213,606 unique autosomal CpGs) at P < 1e−14. Using cis-mQTL variants for 1258 CpGs associated with seven cardiovascular disease (CVD) risk factors, we found 104 unique CpGs that colocalized with at least one CVD trait. For example, cg11554650 (PPP1R18) colocalized with type 2 diabetes, and was driven by a single nucleotide polymorphism (rs2516396). We performed Mendelian randomization (MR) analysis and demonstrated 58 putatively causal relations of CVD risk factor-associated CpGs to one or more risk factors (e.g., cg05337441 [APOB] with LDL; MR P = 1.2e−99, and 17 causal associations with coronary artery disease (e.g. cg08129017 [SREBF1] with coronary artery disease; MR P = 5e−13). We also showed that three CpGs, e.g., cg14893161 (PM20D1), are putatively causally associated with COVID-19 severity. To assist in future analyses of the role of DNA methylation in disease pathogenesis, we have posted a comprehensive summary data set in the National Heart, Lung, and Blood Institute’s BioData Catalyst.
... This study focused on offspring cohort (Generation 2) participants with available data on genome-wide genotyping and serum MCP-1 measurements and have been rigorously evaluated for cognitive functioning and dementia since 1979. 22 After excluding individuals with dementia at baseline, this study used genetic data and the MCP-1 levels measured in Exam 7 (baseline) and data on the AD/dementia incidence with followup until 2019 ( Figure S1). Participants were evaluated for AD and other dementia diagnoses as previously described. ...
Introduction: C-Reactive protein (CRP) and monocyte chemoattractant protein-
1 (MCP-1) are both implicated in the peripheral proinflammatory cascade and
blood‒brain barrier (BBB) disruption. Since the blood CRP level increases Alzheimer’s
disease (AD) risk depending on the apolipoprotein E (APOE) genotype,wehypothesized
that the blood MCP-1 level exerts different effects on the AD risk depending on the
genotypes.
Methods: Using multiple regression analyses, data from the Framingham Heart Study
(n = 2884) and Alzheimer’s Disease Neuroimaging Initiative study (n = 231) were
analyzed.
Results: An elevated blood MCP-1 level was associated with AD risk in major histocompatibility
complex,Class II,DRbeta 1 (HLA-DRB1) rs9271192-AC/CC(hazard ratio
[HR] = 3.07, 95% confidence interval [CI] = 1.50–6.28, p = 0.002) and in APOE ε4
carriers (HR = 3.22, 95% CI = 1.59–6.53, p = 0.001). In contrast, among HLA-DRB1 rs9271192-AA and APOE ε4 noncarriers, blood MCP-1 levels were not associated with
these phenotypes.
Discussion: Since HLA-DRB1 and APOE are expressed in the BBB, blood MCP-1
released in the peripheral inflammatory cascade may function as a mediator of the
effects of HLA-DRB1 rs9271192-AC/CC and APOE ε4 genotypes on AD pathogenesis
in the brain via the BBB pathways.
... Participant follow-up has occurred at approximately four yearly intervals to the present, as previously described. 16 There was an initial high dropout between Exam 1 and Exam 2, but no further recruitment took place. Participants did not necessarily attend all exams and may have attended Exam 3 without attending Exam 2 for example. ...
Background
Low body mass index (BMI) is associated with COPD, but temporal relationships between airflow obstruction (AO) development and emphysematous change are unclear. We investigated longitudinal changes in BMI, AO, and lung density throughout adulthood using data from the Framingham Offspring Cohort (FOC).
Methods
BMI trajectories were modelled throughout adulthood in 4587 FOC participants from Exam 2 (mean age = 44), through Exam 9 (mean age = 71), in AO participants and non-AO participants (AO n = 1036), determined by spirometry, using fractional polynomial growth curves. This process was repeated for low lung density (LLD) and non LLD participants (LLD n = 225) determined by Computed Tomography. Spirometry decline was compared separately between tertiles of BMI in those aged <40 years and associations between fat and lean mass (measured using Dual Energy X-ray Absorptiometry, DEXA) and development of AO and LLD were also assessed. Additional analyses were performed with adjustment for smoking volume.
Results
The BMI trajectory from 30 years of age was visually lower in the AO group than both non-AO smokers (non-<AO-S) and non-AO non-smokers (non-AO-N). Similarly, BMI trajectories were visually lower in participants with LLD throughout adulthood compared to normal lung density smokers and non-smokers. Differences remained after adjustment for smoking volume. The lowest BMI tertile in ages <40 years was associated with the steepest subsequent decline in FEV 1 /FVC ratio in both sexes.
Conclusion
Mean BMI is lower throughout adulthood in AO and LLD participants. Lower BMI is associated with a steeper decline in the ratio of FEV 1 /FVC. These findings suggest body mass may precede and potentially have a role in the development of COPD lung pathophysiology.
... The FOS cohort completes a series of questionnaires and laboratory and cardiovascular tests and undergoes a physical examination every 4 years. The details of the sampling methods and design of the study have been previously published (Kannel et al., 1979). All study participants provided informed consent, and protocols were approved by the IRB at Boston University Medical Center (Boston, MA). ...
The biological mechanisms underlying decline in physical function with age remain unclear. We examined the plasma proteomic profile associated with longitudinal changes in physical function measured by gait speed and grip strength in community-dwelling adults. We applied an aptamer-based platform to assay 1154 plasma proteins on 2854 participants (60% women, aged 76 years) in the Cardiovascular Health Study (CHS) in 1992-1993 and 1130 participants (55% women, aged 54 years) in the Framingham Offspring Study (FOS) in 1991-1995. Gait speed and grip strength were measured annually for 7 years in CHS and at cycles 7 (1998-2001) and 8 (2005-2008) in FOS. The associations of individual protein levels (log-transformed and standardized) with longitudinal changes in gait speed and grip strength in two populations were examined separately by linear mixed-effects models. Meta-analyses were implemented using random-effects models and corrected for multiple testing. We found that plasma levels of 14 and 18 proteins were associated with changes in gait speed and grip strength, respectively (corrected p < 0.05). The proteins most strongly associated with gait speed decline were GDF-15 (Meta-analytic p = 1.58 × 10-15 ), pleiotrophin (1.23 × 10-9 ), and TIMP-1 (5.97 × 10-8 ). For grip strength decline, the strongest associations were for carbonic anhydrase III (1.09 × 10-7 ), CDON (2.38 × 10-7 ), and SMOC1 (7.47 × 10-7 ). Several statistically significant proteins are involved in the inflammatory responses or antagonism of activin by follistatin pathway. These novel proteomic biomarkers and pathways should be further explored as future mechanisms and targets for age-related functional decline.
Background: Magnetic resonance imaging (MRI) visible perivascular spaces (PVS) are associated with the risk of incident dementia but their association with the early stages of cognitive impairment remains equivocal. Objective: We examined the association between MRI visible PVS and the risk of incident mild cognitive impairment (MCI) in the community-based Framingham Heart Study (FHS). Methods: FHS participants aged at least 50 years free of stroke, cognitive impairment, and dementia at the time of MRI were included. PVS were rated according to severity in the basal ganglia and centrum semiovale (CSO) using established criteria. Cox regression analyses were used to relate PVS to incident MCI adjusted for demographic and cardiovascular variables. Results: The mean age of the sample (1,314 participants) at MRI was 68 years (SD, 9; 54% women). There were 263 cases of incident MCI over a median 7.4 years follow-up (max, 19.8 years). MCI risk increased with higher PVS severity in the CSO. Relative to persons with the lowest severity rating, persons with the highest severity rating in the CSO had a higher risk of incident MCI (hazard ratio [HR] = 2.55; 95% confidence interval [CI], 1.48–4.37; p = 0.0007). In secondary analysis, this association seemed stronger in women. Risk of incident MCI was nominally higher for participants with the highest severity grade of PVS in the basal ganglia, though not statistically significant relative to the lowest grade (HR = 2.19; 95% CI, 0.78–6.14; p = 0.14). Conclusions: PVS burden in the CSO may be a risk marker for early cognitive impairment.
Background
Loss of muscle mass is a known feature of sarcopenia and predicts poor clinical outcomes. Although muscle metrics can be derived from routine computed tomography (CT) images, sex-specific reference values at multiple vertebral levels over a wide age range are lacking.
Objective
The aim of this study was to provide reference values for skeletal muscle mass and attenuation on thoracic and abdominal CT scans in the community-based Framingham Heart Study cohort to aid in the identification of sarcopenia.
Materials and Methods
This secondary analysis of a prospective trial describes muscle metrics by age and sex for participants from the Framingham Heart Study without prior history of cancer who underwent at least 1 CT scan between 2002 and 2011. Using 2 previously validated machine learning algorithms followed by human quality assurance, skeletal muscle was analyzed on a single axial CT image per level at the 5th, 8th, 10th thoracic, and 3rd lumbar vertebral body (T5, T8, T10, L3). Cross-sectional muscle area (cm ² ), mean skeletal muscle radioattenuation (SMRA, in Hounsfield units), skeletal muscle index (SMI, in cm ² /m ² ), and skeletal muscle gauge (SMRA·SMI) were calculated. Measurements were summarized by age group (<45, 45–54, 55–64, 65–74, ≥75 years), sex, and vertebral level. Models enabling the calculation of age-, sex-, and vertebral-level–specific reference values were created and embedded into an open access online Web application.
Results
The cohort consisted of 3804 participants (1917 [50.4%] males; mean age, 55.6 ± 11.8 years; range, 33–92 years) and 7162 CT scans. Muscle metrics qualitatively decreased with increasing age and female sex.
Conclusions
This study established age- and sex-specific reference values for CT-based muscle metrics at thoracic and lumbar vertebral levels. These values may be used in future research investigating the role of muscle mass and attenuation in health and disease, and to identify sarcopenia.
Background:
Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements.
Purpose:
To clarify factors associated with variations in sex hormone concentrations.
Data sources:
Systematic literature searches (to July 2019).
Study selection:
Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry.
Data extraction:
Individual participant data (IPD) (9 studies; n = 21 074) and aggregate data (2 studies; n = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted.
Data synthesis:
Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years.
Limitation:
Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data.
Conclusion:
Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer.
Primary funding source:
Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).
Introduction:
Cardiometabolic risk factors and epigenetic patterns, increased in physically inactive individuals, are associated with an accelerated brain aging process.
Objective:
To determine whether cardiometabolic risk factors and epigenetic patterns mediate the association of physical inactivity with unfavorable brain morphology.
Methods:
We included dementia and stroke free participants from the Framingham Heart Study Third Generation and Offspring cohorts who had accelerometery and brain MRI data (n = 2,507, 53.9% women, mean age 53.9 years). We examined mediation by the 2017-revised Framingham Stroke Risk Profile (FSRP, using weights for age, cardiovascular disease, atrial fibrillation, diabetes and smoking status, antihypertension medications, and systolic blood pressure) and the homeostatic model of insulin resistance (HOMA-IR) in models of the association of physical inactivity with brain aging, adjusting for age, age-squared, sex, accelerometer wear time, cohort, time from exam-to-MRI, and season. We similarly assessed mediation by an epigenetic age-prediction algorithm, GrimAge, in a smaller sample of participants who had DNA methylation data (n = 1,418).
Results:
FSRP and HOMA-IR explained 8.3-20.5% of associations of higher moderate-to-vigorous physical activity (MVPA), higher steps, and lower sedentary time with higher brain volume. Additionally, FSRP and GrimAge explained 10.3-22.0% of associations of physical inactivity with lower white matter diffusivity and FSRP explained 19.7% of the association of MVPA with lower free water accumulation.
Conclusion:
Our results suggest that cardiometabolic risk factors and epigenetic patterns partially mediate the associations of physical inactivity with lower brain volume, higher white matter diffusivity, and aggregation of free water in the extracellular compartments of the brain.
Background and aims:
Despite interest in the use of polygenic risk scores (PRS) for predicting coronary heart disease (CHD) risk, the clinical utility of PRS compared to conventional risk factors has not been demonstrated. We compared the performance of PRS with that of high-sensitivity C-reactive protein (hsCRP) in two well-established cohorts.
Methods:
The study population included individuals of European ancestry free of baseline CHD from ARIC (N = 13,113) and the Framingham Offspring Study (FHS) (N = 2,696). The primary predictors included a validated PRS consisting of >6.6 million single nucleotide polymorphisms and hsCRP. The outcome was incident CHD, defined as non-fatal or fatal myocardial infarction. We compared the performance of both predictors after adjusting for the Pooled Cohort Equations in multivariable-adjusted Cox regression models. We assessed discrimination and reclassification using c-statistics and net reclassification improvement.
Results:
Incident CHD occurred in 565 ARIC and 153 FHS participants. In multivariable-adjusted models, both PRS and hsCRP were associated with incident CHD (p < 0.05 in both cohorts). In models incorporating both predictors, strengths of association were similar. For instance, in ARIC, the hazard ratio per SD increment was 1.38 (95% CI, 1.27-1.50, p = 2.94 × 10-14) for PRS and 1.41 (1.30-1.55, p = 3.10 × 10-15) for hsCRP. Neither predictor significantly increased model discrimination or net reclassification when compared with models containing the Pooled Cohort Equations alone.
Conclusions:
In two independent cohorts, PRS performed similarly to hsCRP for the prediction of CHD risk. These findings suggest PRS does not have unique clinical utility beyond this widely-available, inexpensive measure of risk in unselected middle-aged populations.
Sleep electroencephalogram (EEG) signals likely encode brain health information that may identify individuals at high risk for age-related brain diseases. Here, we evaluate the correlation of a previously proposed brain age biomarker, the “brain age index” (BAI), with cognitive test scores and use machine learning to develop and validate a series of new sleep EEG-based indices, termed “sleep cognitive indices” (SCIs), that are directly optimized to correlate with specific cognitive scores. Three overarching cognitive processes were examined: total, fluid (a measure of cognitive processes involved in reasoning-based problem solving and susceptible to aging and neuropathology), and crystallized cognition (a measure of cognitive processes involved in applying acquired knowledge toward problem-solving). We show that SCI decoded information about total cognition (Pearson’s r = 0.37) and fluid cognition (Pearson’s r = 0.56), while BAI correlated only with crystallized cognition (Pearson’s r = − 0.25). Overall, these sleep EEG-derived biomarkers may provide accessible and clinically meaningful indicators of neurocognitive health.
Mendelian randomization is a technique used to examine the causal effect of a modifiable exposure on a trait using an observational study by utilizing genetic variants. The use of many instruments can help to improve the estimation precision but may suffer bias when the instruments are weakly associated with the exposure. To overcome the difficulty of high-dimensionality, we propose a model average estimator which involves using different subsets of instruments (single nucleotide polymorphisms, SNPs) to predict the exposure in the first stage, followed by weighting the submodels' predictions using penalization by common penalty functions such as least absolute shrinkage and selection operator (LASSO), smoothly clipped absolute deviation (SCAD) and minimax concave penalty (MCP). The model averaged predictions are then used as a genetically predicted exposure to obtain the estimation of the causal effect on the response in the second stage. The novelty of our model average estimator also lies in that it allows the number of submodels and the submodels' sizes to grow with the sample size. The practical performance of the estimator is examined in a series of numerical studies. We apply the proposed method on a real genetic dataset investigating the relationship between stature and blood pressure.
Background
The American Heart Association's framework “ideal cardiovascular health” (CVH) focuses on modifiable risk factors to reduce cardiovascular disease (CVD). Metabolomics provides important pathobiological insights into risk factors and CVD development. We hypothesized that metabolomic signatures associate with CVH status, and that metabolites, at least partially, mediate the association of CVH score with atrial fibrillation (AF) and heart failure (HF).
Methods and Results
We studied 3056 adults in the FHS (Framingham Heart Study) cohort to evaluate CVH score and incident outcomes of AF and HF. Metabolomics data were available in 2059 participants; mediation analysis was performed to evaluate the mediation of metabolites in the association of CVH score and incident AF and HF. In the smaller cohort (mean age, 54 years; 53% women), CVH score was associated with 144 metabolites, with 64 metabolites shared across key cardiometabolic components (body mass index, blood pressure, and fasting blood glucose) of the CVH score. In mediation analyses, 3 metabolites (glycerol, cholesterol ester 16:1, and phosphatidylcholine 32:1) mediated the association of CVH score with incident AF. Seven metabolites (glycerol, isocitrate, asparagine, glutamine, indole‐3‐proprionate, phosphatidylcholine C36:4, and lysophosphatidylcholine 18:2), partly mediated the association between CVH score and incident HF in multivariable‐adjusted models.
Conclusions
Most metabolites that associated with CVH score were shared the most among 3 cardiometabolic components. Three main pathways: (1) alanine, glutamine, and glutamate metabolism; (2) citric acid cycle metabolism; and (3) glycerolipid metabolism mediated CVH score with HF. Metabolomics provides insights into how ideal CVH status contributes to the development of AF and HF.
Background
The 2022 American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Failure Society of America (HFSA) clinical practice guideline proposed an updated definition for heart failure (HF) stages.
Objectives
This study aimed to compare prevalence and prognosis of HF stages according to classification/definition originally described in 2013 and 2022 ACC/AHA/HFSA definitions.
Methods
Study participants from 3 longitudinal cohorts (the MESA [Multi-Ethnic Study of Atherosclerosis], CHS [Cardiovascular Health Study], and the FHS [Framingham Heart Study]), were categorized into 4 HF stages according to the 2013 and 2022 criteria. Cox proportional hazards regression was used to assess predictors of progression to symptomatic HF and adverse clinical outcomes associated with each HF stage.
Results
Among 11,618 study participants, according to the 2022 staging, 1,943 (16.7%) were healthy, 4,348 (37.4%) were in stage A (at risk), 5,019 (43.2%) were in stage B (pre-HF), and 308 (2.7%) were in stage C/D (symptomatic HF). Compared to the classification/definition originally described in 2013, the 2022 ACC/AHA/HFSA approach resulted in a higher proportion of individuals with stage B HF (increase from 15.9% to 43.2%); this shift disproportionately involved women as well as Hispanic and Black individuals. Despite the 2022 criteria designating a greater proportion of individuals as stage B, the relative risk of progression to symptomatic HF remained similar (HR: 10.61; 95% CI: 9.00-12.51; P < 0.001).
Conclusions
New standards for HF staging resulted in a substantial shift of community-based individuals from stage A to stage B. Those with stage B HF in the new system were at high risk for progression to symptomatic HF.
Background:
Dietary intake of antioxidants such as vitamins C and E protect against oxidative stress, and may also be associated with altered DNA methylation patterns.
Methods:
We meta-analysed epigenome-wide association study (EWAS) results from 11,866 participants across eight population-based cohorts to evaluate the association between self-reported dietary and supplemental intake of vitamins C and E with DNA methylation. EWAS were adjusted for age, sex, BMI, caloric intake, blood cell type proportion, smoking status, alcohol consumption, and technical covariates. Significant results of the meta-analysis were subsequently evaluated in gene set enrichment analysis (GSEA) and expression quantitative trait methylation (eQTM) analysis.
Results:
In meta-analysis, methylation at 4,656 CpG sites was significantly associated with vitamin C intake at FDR ≤ 0.05. The most significant CpG sites associated with vitamin C (at FDR ≤ 0.01) were enriched for pathways associated with systems development and cell signalling in GSEA, and were associated with downstream expression of genes enriched in the immune response in eQTM analysis. Furthermore, methylation at 160 CpG sites was significantly associated with vitamin E intake at FDR ≤ 0.05, but GSEA and eQTM analysis of the top most significant CpG sites associated with vitamin E did not identify significant enrichment of any biological pathways investigated.
Conclusions:
We identified significant associations of many CpG sites with vitamin C and E intake, and our results suggest that vitamin C intake may be associated with systems development and the immune response.
Background:
Dysfunction in blood vessel dynamics may contribute to changes in muscle measures. Therefore, we examined associations of vascular health measures with grip strength and gait speed in adults from the Framingham Heart Study.
Methods:
The cross-sectional study (1998-2001) included participants with 1 measure of grip strength (kg, dynamometer) or gait speed (4-m walk, m/s) and at least 1 measure of aortic stiffness (carotid-femoral pulse wave velocity, brachial pulse pressure, and brachial flow pulsatility index) or brachial artery structure and function (resting flow velocity, resting brachial artery diameter, flow-mediated dilation %, hyperemic brachial blood flow velocity, and mean arterial pressure [MAP]) assessed by tonometry and brachial artery ultrasound. The longitudinal study included participants with ≥1 follow-up measurement of gait speed or grip strength. Multivariable linear regression estimated the association of 1 standard deviation (SD) higher level of each vascular measure with annualized percent change in grip strength and gait speed, adjusting for covariates.
Results:
In cross-sectional analyses (n = 2 498, age 61 ± 10 years; 56% women), higher resting brachial artery diameter (β ± standard error [SE] per 1 SD: 0.59 ± 0.24, p = .01) and MAP (β ± SE: 0.39 ± 0.17, p = .02) were associated with higher grip strength. Higher brachial pulse pressure (β ± SE: -0.02 ± 0.01, p = .07) was marginally associated with slower gait speed. In longitudinal analyses (n = 2 157), higher brachial pulse pressure (β ± SE: -0.19 ± 0.07, p = .005), was associated with slowing of gait speed but not with grip strength.
Conclusions:
Higher brachial artery pulse pressure (measure of aortic stiffness) was associated with loss of physical function over ~11 years, although we found no evidence that microvascular function contributed to the relation.
Background
The objective was to determine if abdominal fat is related to poor muscle health.
Methods
This cross-sectional study included 428 males and 534 females with appendicular lean mass (ALM, kg) from dual-energy X-ray absorptiometry (DXA), grip strength (kg), and upper extremity muscle “quality” (grip strength/arm lean mass) measured (1996–2001) in the Framingham Offspring Study. Sex-specific linear regressions associated adiposity measures [waist circumference (WC, cm) and visceral adipose tissue (VAT, cm³), and subcutaneous adipose tissue (SAT, cm³)] as Z-scores with each measure of muscle, adjusting for covariates. Models were further stratified by body mass index (BMI, < 30, ≥ 30 kg/m²).
Results
Mean (± SD) age was 60 ± 9 years and BMI was 28.9 ± 4.6 kg/m² (men) and 27.7 ± 5.8 kg/m², (women). In men, the BMI-stratified analyses showed higher WC was associated with higher ALM (P < 0.0001 each) but with lower muscle quality (P < 0.02) in both BMI groups. Higher SAT was also associated with higher ALM (P = 0.0002) and lower muscle quality (P = 0.0002) in men with BMI < 30, but not in obese men. In women, higher WC, SAT, and VAT were each associated with higher ALM but lower muscle quality, particularly in obese women. Higher SAT (P = 0.05) and VAT (P = 0.04) were associated with higher quadriceps strength in women with BMI < 30 kg/m² but not in obese women.
Conclusions
Higher abdominal fat may be associated with greater lean mass but poorer muscle quality, particularly in obese women. This suggests that adipose tissue may have endocrine influences on muscle, which should be confirmed in longitudinal studies.
Background
Alzheimer’s disease (AD) is the leading cause of dementia in older adults, but most people are not diagnosed until significant neuronal loss has likely occurred along with a decline in cognition. Non-invasive and cost-effective digital biomarkers for AD have the potential to improve early detection.Objective
We examined the validity of DCTclock™ (a digitized clock drawing task) as an AD susceptibility biomarker.DesignWe used two primary independent variables, Apolipoprotein E (APOE) ε4 allele carrier status and polygenic risk score (PRS). We examined APOE and PRS associations with DCTclock™ composite scores as dependent measures.SettingWe used existing data from the Framingham Heart Study (FHS), a community-based study with the largest dataset of digital clock drawing data to date.ParticipantsThe sample consisted of 2,398 older adults ages 60–94 with DCTclock™ data (mean age of 72.3, 55% female and 92% White).MeasurementsPRS was calculated using 38 variants identified in a recent large genome-wide association study (GWAS) and meta-analysis of late-onset AD (LOAD).ResultsResults showed that DCTclock™ performance decreased with advancing age, lower education, and the presence of one or more copies of APOE ε4. Lower DCTclock™ Total Score as well as lower composite scores for Information Processing Speed (both command & copy conditions) and Drawing Efficiency (command condition) were significantly associated with higher PRS levels and more copies of APOE ε4. APOE and PRS associations displayed similar effect sizes in both men and women.Conclusions
Our results indicate that higher AD genetic risk is associated with poorer DCTclock™ performance in older adults without dementia. This is the first study to demonstrate significant differences in clock drawing performance on the basis of APOE status or PRS.
Objective:
To evaluate the value of serial C-reactive protein (CRP) measurements in predicting the risk of cardiovascular disease (CVD), cancer, and mortality.
Methods:
The analysis was performed using data from two prospective, population-based observational cohorts: the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study and the Framingham Heart Study (FHS). A total of 9253 participants had CRP measurements available at two examinations (PREVEND: 1997-1998 and 2001-2002; FHS Offspring cohort: 1995-1998 and 1998-2001). All CRP measurements were natural log-transformed before analyses. Cardiovascular disease included fatal and nonfatal cardiovascular, cerebrovascular and peripheral vascular events, and heart failure. Cancer included all malignancies except nonmelanoma skin cancers.
Results:
The mean age of the study population at baseline was 52.4±12.1 years and 51.2% (n=4733) were women. Advanced age, female sex, smoking, body mass index, and total cholesterol were associated with greater increases in CRP levels over time (Pall<.001 in the multivariable model). Baseline CRP, as well as increase in CRP over time (ΔCRP), were associated with incident CVD (hazard ratio [HR]: 1.29 per 1-SD increase; 95% confidence interval [CI]: 1.29 to 1.47, and HR per 1-SD increase: 1.19; 95% CI: 1.09 to 1.29 respectively). Similar findings were observed for incident cancer (baseline CRP, HR: 1.17; 95% CI: 1.09 to 1.26; ΔCRP, HR: 1.08; 95% CI: 1.01 to 1.15) and mortality (baseline CRP, HR: 1.29; 95% CI: 1.21 to 1.37; ΔCRP, HR: 1.10; 95% CI: 1.05 to 1.16).
Conclusion:
Initial as well as subsequent increases in CRP levels predict future CVD, cancer, and mortality in the general population.
C-reactive protein (CRP) impacts apolipoprotein E4 (ApoE4) allele to increase Alzheimer's disease (AD) risk. However, it is unclear how the ApoE protein and its binding to LRP1 are involved. We found that ApoE2 carriers had the highest but ApoE4 carriers had the lowest concentrations of blood ApoE in both humans and mice; blood ApoE concentration was negatively associated with AD risk. Elevation of peripheral monomeric CRP (mCRP) reduced the expression of ApoE in ApoE2 mice, while it decreased ApoE-LRP1 binding in the brains of ApoE4 mice that was characterized by Proximity Ligation Assay. Both serum ApoE and brain ApoE-LRP1 binding were positively associated with the expression of pericytes that disappeared after mCRP treatment, and negatively associated with brain tauopathy and neuroinflammation in the presence of mCRP. In ApoE-/- mice, mCRP reduced the brain expression levels of synaptophysin and PSD95 and the positive relationship between ApoE-LRP1 binding and synaptophysin or PSD95 expression disappeared. Our study suggests that blood ApoE protects against AD pathogenesis by binding to LRP1 during peripheral chronic inflammation.
Background Recent data suggest that dementia incidence is declining. We investigated whether similar secular trends consisting of increasing size of brain structures and improving memory performance could be simultaneously occurring as a possible explanation. Method The Framingham Heart Study is a 3 generation, longitudinal study that includes cognitive assessment and medical surveillance. This study cohort consisted of 4,506 unique, non-demented, stroke free, individuals with brain MRI, cognitive assessment, and demographic information spanning dates of birth from 1902 to 1985. Outcomes consisted of height, MRI, and memory measures. Covariates included age at MRI, sex, decade of birth, and all interactions. Models with neuropsychological outcomes also included educational achievement as a covariate. Results Height and intracranial (TCV), hippocampus and cortical gray matter volumes were significantly larger, and memory performance significantly better, with advancing decades of birth after adjusting for age, sex, and interactions. Sensitivity analysis using progressively restricted age-ranges to reduce the association between age and decade of birth, confirmed the findings. Mediation analysis showed that hippocampal volume mediated approximately 5-7% of the effect of decade of birth on logical memory performance. Discussion These findings indicate improvement in brain health and memory performance with advancing decades of birth. Although brain structures are under substantial genetic influence, we conclude that improved early life environmental influences over ensuing decades likely explain these results. We hypothesize that these secular improvements are consistent with declining dementia incidence in this cohort potentially through a mechanism of increased brain reserve.
Introduction:
We examined for associations between potentially modifiable risk factors across the adult life course and incident dementia.
Methods:
Participants from the Framingham Heart Study were included (n = 4015). Potential modifiable risk factors included education, alcohol intake, smoking, body mass index (BMI), physical activity, social network, diabetes, and hypertension. Cox models were used to examine associations between each factor and incident dementia, stratified by early adult life (33-44 years), midlife (45-65 years), and late life (66-80 years).
Results:
Increased dementia risk was associated with diabetes (hazard ratio [HR] = 1.62; 95% confidence interval [CI] = 1.07-2.46) and physical inactivity (HR = 1.57; 95% CI = 1.12-2.20) in midlife, and with obesity (HR = 1.76; 95% CI = 1.08-2.87) in late life. Having multiple potential modifiable risk factors in midlife and late life was associated with greater risk.
Discussion:
Potentially modifiable risk factors individually have limited impact on dementia risk in this population across the adult life course, although in combination they may have a synergistic effect.
Highlights:
Diabetes and physical inactivity in midlife is associated with increased dementia risk. Obesity in late life is associated with increased dementia risk. Having more potentially modifiable risk factors in midlife and late life is associated with greater dementia risk.
Introduction:
Greater parity has been associated with cardiovascular disease risk, though effects on cardiac remodeling and heart failure risk remain unclear.
Methods:
We examined the association of number of live births and echocardiographic measures of cardiac structure and function in participants of the Framingham Heart Study (FHS) using multivariable linear regression. We next examined the association of parity with incident heart failure with preserved (HFpEF) or reduced (HFrEF) ejection fraction using a Fine-Gray subdistribution hazards model in a pooled analysis of n=12,635 participants of FHS, the Cardiovascular Health Study, the Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular Endstage Disease. Secondary analyses included major CVD, MI, and stroke.
Results:
Among n=3931 FHS participants (mean age 48 ± 13 years), higher number of live births was associated with worse LV fractional shortening (multivariable β -1.11 (0.31), p= 0.0005 in ≥ 5 live births vs nulliparous women) and worse cardiac mechanics including global circumferential strain and longitudinal and radial dyssynchrony (p< 0.01 for all comparing ≥ 5 live births vs nulliparity). When examining HF subtypes, women with ≥5 live births were at higher risk of developing future HFrEF compared with nulliparous women (HR 1.93, 95% CI 1.19-3.12, p=0.008); by contrast, a lower risk of HFpEF was observed (HR 0.58, 95% CI 0.37-0.91, p=0.02).
Conclusions:
Greater number of live births are associated with worse cardiac structure and function. While there was no association with overall HF, a higher number of live births was associated with greater risk for incident HFrEF.
Background:
As suboptimal diet quality remains the leading modifiable contributor to chronic disease risk, it is important to better understand the individual-level drivers of food choices. Recently, a genetic component of food choices was proposed based on variants (SNPs) in genes related to taste perception (taste-related SNPs).
Objectives:
This study aimed to determine the cumulative contribution of taste-related SNPs for basic tastes (bitter, sweet, umami, salt, and sour), summarized as "polygenic taste scores," to food group intakes among adults.
Methods:
Cross-sectional analyses were performed on 6230 Framingham Heart Study participants (mean age ± SD: 50 ± 14 y; 54% female). Polygenic taste scores were derived for tastes with ≥2 related SNPs identified in prior genome-wide association studies, and food group intakes (servings per week [sev/wk]) were tabulated from food frequency questionnaires. Associations were determined via linear mixed-effects models, using false discovery rates and bootstrap resampling to determine statistical significance.
Results:
Thirty-three taste-related SNPs (9 bitter, 19 sweet, 2 umami, 2 sour, 1 salt) were identified and used to derive polygenic taste scores for bitter, sweet, umami, and sour. Per additional allele for higher bitter perception, whole grain intakes were lower by 0.17 (95% CI: -0.28, -0.06) sev/wk, and for higher umami perception, total and red/orange vegetable intakes were lower by 0.73 (95% CI: -1.12, -0.34) and 0.25 (95% CI: -0.40, -0.10) sev/wk, respectively. Subsequent analyses at the SNP level identified four novel SNP-diet associations-two bitter-related SNPs with whole grains (rs10960174 and rs6782149) and one umami-related SNP with total and red/orange vegetables (rs7691456)-which may have been driving the identified associations.
Conclusions:
Taste-related genes for bitter and umami were differentially associated with food choices that may impact diet quality. Hence, a benefit could be derived from leveraging knowledge of taste-related genes when developing personalized risk reduction dietary guidance.
Study objective
Aortic arch geometry changes with age, including an increase in aortic arch width (AAW). High AAW is a predictor of incident adverse cardiovascular disease (CVD) events, but its distribution and determinants are unknown. We hypothesized that traditional CVD risk factors, in addition to age, are associated with increased AAW in community-dwelling adults.
Study design
Framingham Offspring and Third Generation cohort participants (N = 3026, 52 % men) underwent thoracic multidetector computed tomography (MDCT). A referent group (733M, 738W) free of clinical CVD, hypertension, dyslipidemia, smoking, and diabetes was used to generate sex and 10-year age-group specific upper 90th percentile (P90) cut-points for AAW. AAW was measured as the distance between the cross-sectional centroids of the ascending and descending thoracic aorta. Multivariable logistic regression models were used to identify clinical correlates of high AAW (≥referent P90) in the overall study group.
Results
Among referent participants, AAW increased with greater age-group, p for trend <0.0001 in each sex. Overall and within each age group, AAW was greater in men than women, p < 0.0001 all comparisons. Across all participants, high AAW was associated with greater age (odds ratio, OR = 1.34/10 years; 95 % confidence interval 1.20–1.50), body surface area (OR = 1.97/SD; 1.62–2.40), diastolic blood pressure (OR = 1.59/10 mm Hg; 1.40–1.81), pack-years smoked (OR = 1.07; 1.02–1.13), and prevalent CVD (OR = 1.64; 1.08–2.49).
Conclusion
AAW increases with greater age, body size, diastolic blood pressure and burden of smoking. High AAW (≥referent P90) is also associated with prevalent (clinically apparent) CVD. AAW is often seen on and easily measured from tomographic thoracic images and has prognostic value.
Background:
Molecular mechanisms underlying the benefits of healthy dietary patterns are poorly understood. Identifying protein biomarkers of dietary patterns can contribute to characterizing biological pathways influenced by food intake.
Objectives:
This study aimed to identify protein biomarkers associated with four indexes of healthy dietary patterns: Healthy Eating Index-2015 (HEI-2015); Alternative Healthy Eating Index-2010 (AHEI-2010); DASH diet; and alternate Mediterranean Diet (aMED).
Methods:
Analyses were conducted on 10,490 Black and White men and women aged 49-73 y from the ARIC study at visit 3 (1993-1995). Dietary intake data were collected using a food frequency questionnaire, and plasma proteins were quantified using an aptamer-based proteomics assay. Multivariable linear regression models were used to examine the association between 4955 proteins and dietary patterns. We performed pathway overrepresentation analysis for diet-related proteins. An independent study population from the Framingham Heart Study was used for replication analyses.
Results:
In the multivariable-adjusted models, 282 out of 4955 proteins (5.7%) were significantly associated with at least one dietary pattern (HEI-2015: 137; AHEI-2010: 72; DASH: 254; aMED: 35; P value < 0.05/4955 = 1.01 × 10-5). There were 148 proteins that were associated with only one dietary pattern (HEI-2015: 22; AHEI-2010: 5; DASH: 121; aMED: 0), and 20 proteins were associated with all four dietary patterns. Five unique biological pathways were significantly enriched by diet-related proteins. Seven out of 20 proteins associated with all dietary patterns in the ARIC study were available for replication analyses, and 6 out of these 7 proteins were consistent in direction and significantly associated with at least 1 dietary pattern in the Framingham Heart Study (HEI-2015: 2; AHEI-2010: 4; DASH: 6; aMED: 4; P value < 0.05/7 = 7.14 × 10-3).
Conclusions:
A large-scale proteomic analysis identified plasma protein biomarkers that are representative of healthy dietary patterns among middle-aged and older US adult population. These protein biomarkers may be useful objective indicators of healthy dietary patterns.
Background
Stiffness of the proximal aorta may play a critical role in adverse left ventricular (LV)–vascular interactions and associated LV diastolic dysfunction. In a community‐based sample, we sought to determine the association between proximal aortic stiffness measured by cardiovascular magnetic resonance (CMR) and several clinical measures of LV diastolic mechanics.
Methods and Results
Framingham Heart Study Offspring adults (n=1502 participants, mean 67±9 years, 54% women) with available 1.5T CMR and transthoracic echocardiographic measures were included. Measures included proximal descending aortic strain and aortic arch pulse wave velocity by CMR (2002–2006) and diastolic function (mitral Doppler E and A wave velocity, E wave area, and LV tissue Doppler e' velocity) by echocardiography (2005–2008). Multivariable linear regression analysis was used to relate CMR aortic stiffness measures to measures of echocardiographic LV diastolic function. All continuous variables were standardized. In multivariable‐adjusted regression analyses, aortic strain was inversely associated with E wave deceleration time (estimated β=−0.10±0.032, P=0.001), whereas aortic arch pulse wave velocity was inversely associated with E/A ratio (estimated β=−0.094±0.027, P=0.0006), E wave area (estimated β=−0.070±0.027, P=0.010), and e' (estimated β=−0.061±0.027, P=0.022), all indicating associations of higher aortic stiffness by CMR with less favorable LV diastolic function. Compared with men, women had a larger inverse relationship between pulse wave velocity and E/A ratio (interaction β=−0.085±0.031, P=0.0064). There was no significant effect modification by age or a U‐shaped (quadratic) relation between aortic stiffness and LV diastolic function measures.
Conclusions
Higher proximal aortic stiffness is associated with less favorable LV diastolic function. Future studies may clarify temporal relations of aortic stiffness with varying patterns and progression of LV diastolic dysfunction.
We previously described a DNA methylation (DNAm) based biomarker of human mortality risk DNAm GrimAge. Here we describe version 2 of GrimAge (trained on individuals aged between 40 and 92) which leverages two new DNAm based estimators of (log transformed) plasma proteins: high sensitivity C-reactive protein (logCRP) and hemoglobin A1C (logA1C). We evaluate GrimAge2 in 13,399 blood samples across nine study cohorts. After adjustment for age and sex, GrimAge2 outperforms GrimAge in predicting mortality across multiple racial/ethnic groups (meta P=3.6x10⁻¹⁶⁷ versus P=2.6x10⁻¹⁴⁴) and in terms of associations with age related conditions such as coronary heart disease, lung function measurement FEV1 (correlation= -0.31, P=1.1x10⁻¹³⁶), computed tomography based measurements of fatty liver disease. We present evidence that GrimAge version 2 also applies to younger individuals and to saliva samples where it tracks markers of metabolic syndrome.
DNAm logCRP is positively correlated with morbidity count (P=1.3x10⁻⁵⁴). DNAm logA1C is highly associated with type 2 diabetes (P=5.8x10⁻¹⁵⁵). DNAm PAI-1 outperforms the other age-adjusted DNAm biomarkers including GrimAge2 in correlating with triglyceride (cor=0.34, P=9.6x10⁻²⁶⁷) and visceral fat (cor=0.41, P=4.7x10⁻⁴¹).
Overall, we demonstrate that GrimAge version 2 is an attractive epigenetic biomarker of human mortality and morbidity risk.
BACKGROUND
Heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) are distinct clinical entities, yet there is scant evidence for associations of proteomic signatures with future development of HFpEF versus HFrEF.
METHODS
We evaluated the association of 71 protein biomarkers with incident HFpEF versus HFrEF (left ventricular ejection fraction ≥ versus <50%) among Framingham Heart Study participants using multivariable Cox models.
RESULTS
Among 7038 participants (mean age 49 years; 54% women), 5 biomarkers were associated with increased risk of incident HFpEF (false discovery rate q<0.05): NT-proBNP (N-terminal pro-B-type natriuretic peptide; hazard ratio [HR]‚ 2.13; 95% CI‚ 1.52–2.99; P <0.001), growth differentiation factor-15 (HR‚ 1.67; 95% CI‚ 1.32–2.12; P <0.001), adrenomedullin (HR‚ 1.58; 95% CI‚ 1.23–2.04; P <0.001), uncarboxylated matrix Gla protein (HR‚ 1.55; 95% CI 1.23–1.95; P <0.001), and C-reactive protein (HR‚ 1.46; 95% CI‚ 1.17–1.83; P =0.001). Fourteen biomarkers were associated with incident HFrEF (multivariable P <0.001, q<0.05 for all). Of these, 3 biomarkers were associated with both HF subtypes (NT-proBNP, growth differentiation factor-15, and C-reactive protein). When compared directly, myeloperoxidase, resistin, and paraoxanase-1 were more strongly associated with HFrEF than HFpEF.
CONCLUSIONS
We identified 5 protein biomarkers of new-onset HFpEF representing pathways of inflammation, cardiac stress, and vascular stiffness, which partly overlapped with HFrEF. We found 14 biomarkers associated with new-onset HFrEF, with some distinct associations including myeloperoxidase, resistin, and paraoxanase-1. Taken together, these findings provide insights into similarities and differences in the development of HF subtypes.
Registration
URL: https://clinicaltrials.gov/ct2/show/NCT00005121 ; Unique identifier: NCT0005121.
Rationale and objectives
Atherosclerosis of the aorta is associated with increased risk of cardiovascular mortality and vascular events. We aim to describe the prevalence and distribution of non-calcified atherosclerotic plaque in the descending aorta as quantified by noncontrast cardiovascular magnetic resonance (CMR) in a community-dwelling cohort of adults.
Materials and methods
We used CMR to quantify noncalcified aortic plaque in 1726 participants (aged 65 ± 9 years, 46.7% men) from the Cohort Study Offspring cohort. ECG-gated, fat-suppressed, T2-weighted, black blood turbo spin echo sequence was used to acquire 36 transverse slices covering the descending aorta from just below the arch to the aortoiliac bifurcation. Plaque was defined as discrete luminal protrusions ≥1 mm; these were manually traced, then summed to determine total descending aortic plaque (DAP) and segmental thoracic and abdominal aortic plaque (TAP, AAP). Participants were stratified by sex and age group (<55, 55–64, 65–74, ≥75y). A healthy referent group (without clinical cardiovascular disease, smoking, diabetes, impaired renal function; (N = 768, 43.8% men) was used to determine upper 90th percentile cutpoints for DAP and AAP which were then applied to the overall study cohort.
Results
Prevalence of DAP was similar between men (47.3%) and women (48.9%), p = 0.50, as was AAP prevalence (men: 44.5%, women: 46.7%, p = 0.16); TAP was less prevalent in both sexes (men: 8.9%, women: 7.1%, p = 0.15). Both prevalence and burden of DAP, AAP and TAP increased with advancing age.
Conclusion
Noncalcified plaque prevalence, visualized on CMR, in community-dwelling adults is similar between the sexes, and both prevalence and burden of aortic plaque increase with greater age.
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