Objectives The aim of this study was to determine whether ectopic fat depots are prospectively associated with cardiovascular disease, cancer, and all-cause mortality. Background The morbidity ...associated with excess body weight varies among individuals of similar body mass index. Ectopic fat depots may underlie this risk differential. However, prospective studies of directly measured fat are limited. Methods Participants from the Framingham Heart Study (n = 3,086; 49% women; mean age of 50.2 years) underwent assessment of fat depots (visceral adipose tissue, pericardial adipose tissue, and periaortic adipose tissue) using multidetector computed tomography and were followed up longitudinally for a median of 5.0 years. Cox proportional hazards regression models were used to examine the association of each fat depot (per 1 SD increment) with the risk of incident cardiovascular disease, cancer, and all-cause mortality after adjustment for standard risk factors, including body mass index. Results Overall, there were 90 cardiovascular events, 141 cancer events, and 71 deaths. After multivariable adjustment, visceral adipose tissue was associated with cardiovascular disease (hazard ratio: 1.44; 95% confidence interval: 1.08 to 1.92; p = 0.01) and cancer (hazard ratio: 1.43; 95% confidence interval: 1.12 to 1.84; p = 0.005). Addition of visceral adipose tissue to a multivariable model that included body mass index modestly improved cardiovascular risk prediction (net reclassification improvement of 16.3%). None of the fat depots were associated with all-cause mortality. Conclusions Visceral adiposity is associated with incident cardiovascular disease and cancer after adjustment for clinical risk factors and generalized adiposity. These findings support the growing appreciation of a pathogenic role of ectopic fat.
BACKGROUND—Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) vary in volume and quality. We evaluated whether fat volume or attenuation (indirect measure of quality) predicts ...metabolic risk factor changes.
METHODS AND RESULTS—Framingham Heart Study Multi-detector Computed Tomography Substudy participants (n=1730, 45% women) were followed up over a mean of 6.2 years. Baseline VAT and SAT volume (in cm) and attenuation (in Hounsfield units) were assessed. Outcomes included blood pressure, lipids, and glucose. We constructed multivariable regression models predicting change from baseline to follow-up. Baseline VAT was associated with metabolic risk factors at follow-up. Per 500-cm increase in baseline VAT, glucose was 2.34 mg/dL higher (95% confidence interval, 1.71–2.97) and high-density lipoprotein was 1.62 mg/dL lower (95% confidence interval, 0.97–2.28) in women (P<0.0001 for both). These findings remained significant after adjustment for body mass index. Results for SAT were similar although less striking. Lower (more negative) fat attenuation was associated with more adverse metabolic profiles at follow-up. For example, per 5-unit decrease in baseline VAT Hounsfield units, log triglycerides increased by 0.08 mg/dL (95% confidence interval, 0.05–0.12; P=0.005), which remained significant after adjustment for baseline VAT. Among men, VAT and SAT Hounsfield units were associated with changes in cardiovascular disease risk factors but were mostly attenuated after baseline volume adjustment.
CONCLUSIONS—VAT volume and SAT volume are associated with incident metabolic risk factors beyond overall adiposity. Decreases in fat attenuation are also associated with incident risk factors. These findings suggest that both volume and quality of VAT and SAT contribute to metabolic risk.
Type 2 diabetes is a common disorder and an important risk factor for cardiovascular disease. The Framingham Heart Study is a population-based epidemiologic study that has contributed to our ...knowledge of cardiovascular disease and its risk factors. This review will focus on the contemporary contributions of the Framingham Heart Study to the field of diabetes epidemiology, including data on diabetes trends, genetics, and future advances in population-based studies.
The probability of success of developing medicines to treat human disease can be improved by leveraging human genetics. Different types of genetic data and techniques, including genome-wide ...association, whole-exome sequencing, and whole-genome sequencing, can be used to gain insight into human disease. Layering different types of genetic evidence from Mendelian disease, coding variants, and common variation can bolster support for a genetic target. Human knockouts offer the potential to perform reverse genetic screens in humans to identify physiologically relevant targets. Other components of a good genetic target include protective loss-of-function mutations, some degree of known biology, tractability, and a clean on-target safety profile. In addition to using human genetics to inspire new drug programs, phenome-wide association studies can be used to identify alternative indications or repurposing opportunities. This information can be combined into a 5-step approach for selecting a genetic target for validation, which is presented in detail in this review. Finally, current challenges in leveraging human genetics are highlighted, including the difficulties translating certain types of genetic data, relatively small number of bona fide disease-associated coding rare variants, and current sample sizes of large well-curated biobanks linked to comprehensive genetic information.
Chronic kidney disease (CKD) is defined by reduced estimated glomerular filtration rate (eGFR). Previous genetic studies have implicated regulatory mechanisms contributing to CKD. Here we present ...epigenome-wide association studies of eGFR and CKD using whole-blood DNA methylation of 2264 ARIC Study and 2595 Framingham Heart Study participants to identify epigenetic signatures of kidney function. Of 19 CpG sites significantly associated (P < 1e-07) with eGFR/CKD and replicated, five also associate with renal fibrosis in biopsies from CKD patients and show concordant DNA methylation changes in kidney cortex. Lead CpGs at PTPN6/PHB2, ANKRD11, and TNRC18 map to active enhancers in kidney cortex. At PTPN6/PHB2 cg19942083, methylation in kidney cortex associates with lower renal PTPN6 expression, higher eGFR, and less renal fibrosis. The regions containing the 243 eGFR-associated (P < 1e-05) CpGs are significantly enriched for transcription factor binding sites of EBF1, EP300, and CEBPB (P < 5e-6). Our findings highlight kidney function associated epigenetic variation.
Abstract Background Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) are associated with adverse cardiometabolic risk profiles. Objectives This study explored the degree to which ...changes in abdominal fat quantity and quality are associated with changes in cardiovascular disease (CVD) risk factors. Methods Study participants (n = 1,106; 44.1% women; mean baseline age 45.1 years) were drawn from the Framingham Heart Study Third Generation cohort who participated in the computed tomography (CT) substudy Exams 1 and 2. Participants were followed for 6.1 years on average. Abdominal adipose tissue volume in cm3 and attenuation in Hounsfield units (HU) were determined by CT-acquired abdominal scans. Results The mean fat volume change was an increase of 602 cm3 for SAT and an increase of 703 cm3 for VAT; the mean fat attenuation change was a decrease of 5.5 HU for SAT and an increase of 0.07 HU for VAT. An increase in fat volume and decrease in fat attenuation were associated with adverse changes in CVD risk factors. An additional 500 cm3 increase in fat volume was associated with incident hypertension (odds ratio OR: 1.21 for SAT; OR: 1.30 for VAT), hypertriglyceridemia (OR: 1.15 for SAT; OR: 1.56 for VAT), and metabolic syndrome (OR: 1.43 for SAT; OR: 1.82 for VAT; all p < 0.05). Similar trends were observed for each additional 5 HU decrease in abdominal adipose tissue attenuation. Most associations remained significant even after further accounting for body mass index change, waist circumference change, or respective abdominal adipose tissue volumes. Conclusions Increasing accumulation of fat quantity and decreasing fat attenuation are associated with worsening of CVD risk factors beyond the associations with generalized adiposity, central adiposity, or respective adipose tissue volumes.
Emerging technologies allow the high-throughput profiling of metabolic status from a blood specimen (metabolomics). We investigated whether metabolite profiles could predict the development of ...diabetes. Among 2,422 normoglycemic individuals followed for 12 years, 201 developed diabetes. Amino acids, amines and other polar metabolites were profiled in baseline specimens by liquid chromatography-tandem mass spectrometry (LC-MS). Cases and controls were matched for age, body mass index and fasting glucose. Five branched-chain and aromatic amino acids had highly significant associations with future diabetes: isoleucine, leucine, valine, tyrosine and phenylalanine. A combination of three amino acids predicted future diabetes (with a more than fivefold higher risk for individuals in top quartile). The results were replicated in an independent, prospective cohort. These findings underscore the potential key role of amino acid metabolism early in the pathogenesis of diabetes and suggest that amino acid profiles could aid in diabetes risk assessment.
Objective: Obesity is a major driver of cardiometabolic risk. Abdominal visceral adipose tissue (VAT) and sc adipose tissue (SAT) may confer differential metabolic risk profiles. We investigated the ...relations of VAT and SAT with cardiometabolic risk factors in the Jackson Heart Study cohort.
Methods: Participants from the Jackson Heart Study (n = 2477; 64% women; mean age, 58 yr) underwent multidetector computed tomography, and the volumetric amounts of VAT and SAT were assessed between 2007 and 2009. Cardiometabolic risk factors were examined by sex in relation to VAT and SAT.
Results: Men had a higher mean volume of VAT (873 vs. 793 cm3) and a lower mean volume of SAT (1730 vs. 2659 cm3) than women (P = 0.0001). Per 1-sd increment in either VAT or SAT, we observed elevated levels of fasting plasma glucose and triglyceride, lower levels of high-density lipoprotein-cholesterol, and increased odds ratios for hypertension, diabetes, and metabolic syndrome. The effect size of VAT in women was larger than that of SAT fasting plasma glucose, 5.51 ± 1.0 vs. 3.36 ± 0.9; triglyceride, 0.17 ± 0.01 vs. 0.05 ± 0.01; high-density lipoprotein-cholesterol, −5.36 ± 0.4 vs. −2.85 ± 0.4; and odds ratio for hypertension, 1.62 (1.4–1.9) vs. 1.40 (1.2–1.6); diabetes, 1.82 (1.6–2.1) vs. 1.58 (1.4–1.8); and metabolic syndrome, 3.34 (2.8–4.0) vs. 2.06 (1.8–2.4), respectively; P < 0.0001 for difference between VAT and SAT. Similar patterns were also observed in men. Furthermore, VAT remained associated with most risk factors even after accounting for body mass index (P ranging from 0.006–0.0001). The relationship of VAT to most risk factors was significantly different between women and men.
Conclusions: Abdominal VAT and SAT are both associated with adverse cardiometabolic risk factors, but VAT remains more strongly associated with these risk factors. The results from this study suggest that relations with cardiometabolic risk factors are consistent with a pathogenic role of abdominal adiposity in participants of African ancestry.
Both visceral and subcutaneous adipose tissues are associated with adverse cardiometabolic risk factors, but visceral adipose tissue remains more strongly associated with these risk factors.
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