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1.  Intramuscular Fat and Associations with Metabolic Risk Factors in the Framingham Heart Study 
Intramuscular fat accumulates between muscle fibers or within muscle cells. We investigated the association of intramuscular fat with other ectopic fat deposits and metabolic risk factors.
Approach and Results
Participants (n = 2945; 50.2% women; mean age 50.8 years) from the Framingham Heart Study underwent multidetector computed tomography scanning of the abdomen. Regions of interest were placed on the left and right paraspinous muscle and the muscle attenuation (MA) in Hounsfield units were averaged. We examined the association between MA and metabolic risk factors in multivariable models and additionally adjusted for BMI and visceral fat (VAT) in separate models. MA was associated with dysglycemia, dyslipidemia, and hypertension in both sexes. In women, per standard deviation decrease in MA, there was a 1.34 (95% CI 1.10–1.64) increase in the odds of diabetes, a 1.40 (95% CI 1.22 – 1.61) increase in the odds of high triglycerides, and a 1.29 (95% CI 1.12 – 1.48) increase in the odds of hypertension. However, none of these associations persisted after adjustment for BMI or VAT. In men, we observed similar patterns for most risk factors. The exception was metabolic syndrome, which retained association in women even after adjustment for BMI and VAT, and low HDL and high triglycerides in men, whose associations also persisted after adjustment for BMI and VAT.
MA was associated with metabolic risk factors, but most of these associations were lost after adjustment for BMI or VAT. However, a unique association remained for metabolic syndrome in women and lipids in men.
PMCID: PMC3696991  PMID: 23349188
Metabolism; obesity; intramuscular fat; epidemiology
2.  Biomarkers Of Cardiovascular Stress And Incident Chronic Kidney Disease 
Clinical chemistry  2013;59(11):1613-1620.
Growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and high-sensitivity troponin I (hsTnI) are emerging predictors of adverse clinical outcomes. We sought to examine whether circulating concentrations are related to the development of kidney disease in the community.
Plasma GDF-15, sST2, and hsTnI concentrations were measured in 2,614 Framingham Offspring cohort participants (mean age 57 years, 54% women) at the sixth examination cycle (1995–1998). Associations of biomarkers with incident chronic kidney disease (CKD, eGFR<60 ml/min/1.73m2, n=276), microalbuminuria (urinary albumin to creatinine ratio ≥ 25 mg/g in women and 17 mg/g in men, n=191), and rapid decline in renal function (decline in eGFR ≥ 3 ml/min/1.73m2 per year, n=237), were evaluated using multivariable logistic regression; P<0.006 was considered statistically significant in primary analyses.
Participants were followed over a mean of 9.5 years. Higher plasma GDF-15 was associated with incident CKD (multivariable-adjusted OR 1.9 per 1-unit increase in log-GDF-15, 95% CI 1.6–2.3, P<0.0001) and rapid decline in renal function (OR 1.6, 95% CI 1.3–1.8, P<0.0001). GDF-15, sST2, and hsTnI had suggestive associations with incident microalbuminuria but did not meet the pre-specified P-value threshold after multivariable adjustment. Adding plasma GDF-15 to clinical covariates improved risk prediction of incident CKD: the c-statistic increased from 0.826 to 0.845 (P=0.0007), and categorical net reclassification was 6.3% (95% CI 2.7–9.9%).
Higher circulating GDF-15 is associated with incident renal outcomes, and improves risk prediction of incident CKD. These findings may provide insights into mechanisms of renal injury.
PMCID: PMC3972213  PMID: 23873716
Kidney; Risk Factors; Epidemiology
3.  Importance of different types of prior knowledge in selecting genome-wide findings for follow-up 
Genetic epidemiology  2013;37(2):10.1002/gepi.21705.
Biological plausibility and other prior information could help select genome-wide association (GWA) findings for further follow-up, but there is no consensus on which types of knowledge should be considered or how to weight them. We used experts’ opinions and empirical evidence to estimate the relative importance of 15 types of information at the single nucleotide polymorphism (SNP) and gene levels. Opinions were elicited from ten experts using a two-round Delphi survey. Empirical evidence was obtained by comparing the frequency of each type of characteristic in SNPs established as being associated with seven disease traits through GWA meta-analysis and independent replication, with the corresponding frequency in a randomly selected set of SNPs. SNP and gene characteristics were retrieved using a specially developed bioinformatics tool. Both the expert and the empirical evidence rated previous association in a meta-analysis or more than one study as conferring the highest relative probability of true association, while previous association in a single study ranked much lower. High relative probabilities were also observed for location in a functional protein domain, while location in a region evolutionarily conserved in vertebrates was ranked high by the data but not by the experts. Our empirical evidence did not support the importance attributed by the experts to whether the gene encodes a protein in a pathway or shows interactions relevant to the trait. Our findings provide insight into the selection and weighting of different types of knowledge in SNP or gene prioritization, and point to areas requiring further research.
PMCID: PMC3725558  PMID: 23307621
Gene prioritization; Genome-wide association studies; Bioinformatics databases
4.  SNP prioritization using a Bayesian probability of association 
Genetic epidemiology  2012;37(2):10.1002/gepi.21704.
Prioritization is the process whereby a set of possible candidate genes or SNPs is ranked so that the most promising can be taken forward into further studies. In a genome-wide association study, prioritization is usually based on the p-values alone, but researchers sometimes take account of external annotation information about the SNPs such as whether the SNP lies close to a good candidate gene. Using external information in this way is inherently subjective and is often not formalized, making the analysis difficult to reproduce. Building on previous work that has identified fourteen important types of external information, we present an approximate Bayesian analysis that produces an estimate of the probability of association. The calculation combines four sources of information: the genome-wide data, SNP information derived from bioinformatics databases, empirical SNP weights, and the researchers’ subjective prior opinions. The calculation is fast enough that it can be applied to millions of SNPS and although it does rely on subjective judgments, those judgments are made explicit so that the final SNP selection can be reproduced. We show that the resulting probability of association is intuitively more appealing than the p-value because it is easier to interpret and it makes allowance for the power of the study. We illustrate the use of the probability of association for SNP prioritization by applying it to a meta-analysis of kidney function genome-wide association studies and demonstrate that SNP selection performs better using the probability of association compared with p-values alone.
PMCID: PMC3725584  PMID: 23280596
replication; prior knowledge; genome-wide studies
5.  Low Ankle Brachial Index and the Development of Rapid Estimated GFR Decline and CKD 
Low ankle brachial index (ABI) is associated with increases in serum creatinine. Whether low ABI is associated with the development of rapid estimated glomerular filtration rate (eGFR) decline, stage 3 chronic kidney disease (CKD), or microalbuminuria is uncertain.
Study Design
Prospective cohort study.
Setting & Participants
Framingham Offspring cohort participants who attended the sixth (1995-98) and eighth (2005-08) exams.
ABI, categorized as normal (>1.1 to <1.4), low-normal (>0.9 to 1.1), and low (≤0.9).
Rapid eGFR decline (eGFR decline ≥3mL/min/1.73m2 per year), incident stage 3 CKD (eGFR<60mL/min/1.73m2), incident microalbuminuria.
GFR was estimated using the serum creatinine-based CKD-EPI (CKD Epidemiology Collaboration) equation. Urinary albumin-creatinine ratio (UACR) was determined based on spot urine samples.
Over 9.5 years, 9.0% (232 of 2592) experienced rapid eGFR decline and 11.1% (270 of 2426) developed stage 3 CKD. Compared to a normal ABI, low ABI was associated with a 5.73-fold increased odds of rapid eGFR decline (95% CI, 2.77-11.85; p<0.001) after age, sex, and baseline eGFR adjustment; this persisted after multivariable adjustment for standard CKD risk factors (OR, 3.60; 95% CI, 1.65-7.87; p=0.001). After adjustment for age, sex, and baseline eGFR, low ABI was associated with a 2.51-fold increased odds of stage 3 CKD (OR, 2.51; 95% CI, 1.16-5.44; p=0.02), although this was attenuated after multivariable adjustment (OR, 1.68; 95% CI, 0.75-3.76; p=0.2). Among 1902 free of baseline microalbuminuria, low ABI was associated with an increased odds of microalbuminuria after adjustment for age, sex, and baseline UACR (OR, 2.81; 95% CI, 1.07-7.37; p=0.04), with attenuation upon further adjustment (OR, 1.88; p=0.1).
Limited number of events with a low ABI. Outcomes based on single serum creatinine and UACR measurements at each exam.
Low ABI is associated with an increased risk of rapid eGFR decline, suggesting that systemic atherosclerosis predicts decline in kidney function.
PMCID: PMC3517695  PMID: 22901770
6.  Depressive symptoms are associated with visceral adiposity in a community-based sample of middle-aged women and men 
Obesity (Silver Spring, Md.)  2013;21(8):1713-1719.
To examine the relation between measures of adiposity and depressive symptoms in a large well characterized community-based sample, we examined the relations of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) to depressive symptoms in 1581 women (mean age 52.2 years) and 1718 men (mean age 49.8 years) in the Framingham Heart Study. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression (CES-D) scale. Regression models were created to examine the association between each fat depot (exposure) and depressive symptoms (outcome). Sex specific models were adjusted for age, body mass index, smoking, alcohol consumption, diabetes, hypertension, total and HDL cholesterol, lipid lowering treatment, CVD, menopause, C-reactive protein, and physical activity. Mean CES-D scores were 6.8 and 5.6 in women and men. High levels of depressive symptoms were present in 22.5% of women and 12.3% of men. In women, one standard deviation increase in VAT was associated with a 1.3 point higher CES-D score after adjusting for age and BMI (p<0.01) and remained significant in the fully adjusted model (p=0.03). The odds ratio of depressive symptoms per 1 standard deviation increase in VAT in women was 1.33 (p=0.015); results were attenuated in fully adjusted models (OR 1.29, p=0.055). In men, the association between VAT and CES-D score and depressive symptoms was not significant. SAT was not associated with CES-D score or depressive symptoms. This study supports an association between VAT and depressive symptoms in women. Further work is needed to uncover the complex biologic mechanisms mediating the association.
PMCID: PMC3748158  PMID: 23666906
7.  Relation of Circulating Liver Transaminase Concentrations to Risk of New-onset Atrial Fibrillation 
The American journal of cardiology  2012;111(2):219-224.
Heart failure, a strong risk factor for atrial fibrillation (AF), often is accompanied by elevated liver transaminases. We hypothesized that elevated transaminases are associated with the risk of incident AF in the community. We studied 3,744 participants (mean age 65 ± 10 years, 56.8% women) of the Framingham Heart Study Original and Offspring cohorts, free of clinical heart failure. We examined Cox proportional hazards models adjusted for standard AF risk factors (age, sex, body mass index, systolic blood pressure, electrocardiographic PR interval, anti-hypertensive treatment, smoking, diabetes, valvular heart disease, alcohol consumption) to investigate associations between baseline serum transaminase levels [alanine transaminase (ALT), aspartate transaminase (AST)] and incidence of AF in up to 10 years (29,099 person years) follow-up. During follow-up, 383 individuals developed AF. Both transaminases were significantly associated with greater risk of incident AF (hazard ratio expressed per standard deviation of natural logarithmically transformed biomarker: ALT hazard ratio 1.19, 95% confidence interval 1.07 to1.32, p = 0.002; AST hazard ratio 1.12, 95% confidence interval 1.01 to1.24, p = 0.03). The associations between transaminases and AF remained consistent after exclusion of participants with moderate-to-severe alcohol consumption. However, when added to known risk factors for AF, ALT and AST only subtly improved the prediction of AF. In conclusion, elevated transaminase concentrations are associated with increased AF incidence. The mechanisms by which higher mean transaminase concentrations are associated with incident AF remain to be determined.
PMCID: PMC3538882  PMID: 23127690
atrial fibrillation; biomarker; risk factors; liver function tests
9.  Aminotransferase Levels are Associated with Cardiometabolic Risk above and beyond Visceral Fat and Insulin Resistance: The Framingham Heart Study 
We sought to characterize associations between aminotransferase levels and cardiometabolic risk after accounting for visceral adipose tissue (VAT) and insulin resistance.
Methods and Results
Participants (n=2621) from the Framingham Heart Study (mean age 51, 49.8% women) were included. Sex-specific linear and logistic regressions were used to evaluate associations between aminotransferase levels and cardiometabolic risk factors. In multivariable models, increased ALT levels were associated with elevated blood pressure, fasting plasma glucose, and triglycerides and lower HDL levels (all p ≤ 0.007). Further, each 1 standard deviation (SD) increase in ALT corresponded to an increased odds of hypertension, diabetes, the metabolic syndrome, impaired fasting glucose, and insulin resistance estimated by HOMA-IR (OR 1.29–1.85, all p ≤ 0.002). Associations with ALT persisted after additional adjustment for VAT, insulin resistance, and BMI with the exception of HDL cholesterol in both sexes and blood pressure in women. Results were materially unchanged when moderate drinkers were excluded, when the sample was restricted to those with ALT<40 U/L, and when the sample was restricted to those without diabetes. Similar trends were observed for AST levels, but associations were more modest.
Aminotransferase levels are correlated with multiple cardiometabolic risk factors above and beyond VAT and insulin resistance.
PMCID: PMC3593729  PMID: 23162012
liver function tests; obesity; visceral fat; insulin resistance; cardiometabolic risk factors
10.  Yogurt consumption is associated with better diet quality and metabolic profile in American men and women 
The evidence-based Dietary Guidelines for Americans recommends increasing the intake of fat-free or low-fat milk and milk products. However, yogurt, a nutrient-dense milk product, has been understudied. This cross-sectional study examined whether yogurt consumption was associated with better diet quality and metabolic profile among adults (n = 6526) participating in the Framingham Heart Study Offspring (1998-2001) and Third Generation (2002-2005) cohorts. A validated food frequency questionnaire was used to assess dietary intake, and the Dietary Guidelines Adherence Index (DGAI) was used to measure overall diet quality. Standardized clinical examinations and laboratory tests were conducted. Generalized estimating equations examined the associations of yogurt consumption with diet quality and levels of metabolic factors. Approximately 64% of women (vs 41% of men) were yogurt consumers (ie, consumed >0 servings/week). Yogurt consumers had a higher DGAI score (ie, better diet quality) than nonconsumers. Adjusted for demographic and lifestyle factors and DGAI, yogurt consumers, compared with nonconsumers, had higher potassium intakes (difference, 0.12 g/d) and were 47%, 55%, 48%, 38%, and 34% less likely to have inadequate intakes (based on Dietary Reference Intake) of vitamins B2 and B12, calcium, magnesium, and zinc, respectively (all P ≤ .001). In addition, yogurt consumption was associated with lower levels of circulating triglycerides, glucose, and lower systolic blood pressure and insulin resistance (all P < .05). Yogurt is a good source of several micronutrients and may help to improve diet quality and maintain metabolic well-being as part of a healthy, energy-balanced dietary pattern.
PMCID: PMC3606818  PMID: 23351406
Yogurt; Milk; Diet; Nutrition status; Metabolic profile; Human
11.  Thoracic Periaortic and Visceral Adipose Tissue and Their Cross-sectional Associations with Measures of Vascular Function 
Obesity (Silver Spring, Md.)  2013;21(7):1496-1503.
Perivascular fat may have a local adverse effect on the vasculature. We evaluated whether thoracic periaortic adipose tissue (TAT), a type of perivascular fat, and visceral adipose tissue (VAT) are associated with vascular function.
Design and Methods
TAT and VAT were quantified in Framingham Heart Study participants using multidetector computed tomography; vascular function was assessed using brachial artery vasodilator function, peripheral arterial tone and arterial tonometry (n= 2735, 48% women, mean age 50 years, mean BMI 27.7 kg/m2). Using multiple linear regression, we examined relations between TAT, VAT, and vascular measures while adjusting for cardiovascular risk factors.
Mean TAT and VAT volumes were 13.2 and 1763 cm3. TAT and VAT were associated with multiple vascular function measures after multivariable adjustment. After BMI adjustment, TAT and VAT remained negatively associated with peripheral arterial tone and inverse carotid femoral pulse wave velocity (p<0.02); TAT was negatively associated with hyperemic mean flow velocity (p=0.03). Associations of TAT with vascular function were attenuated after VAT adjustment (all p>0.06).
Thoracic periaortic and visceral fat are associated with microvascular function and large artery stiffness after BMI adjustment. These findings support the growing recognition of associations between ectopic fat and vascular function.
PMCID: PMC3742564  PMID: 23754461
obesity; vascular function; arterial stiffness; perivascular adipose tissue; visceral adipose tissue
12.  Relations of Long-Term and Contemporary Lipid Levels and Lipid Genetic Risk Scores with Coronary Artery Calcium in the Framingham Heart Study 
This study evaluated the association of timing of lipid levels and lipid genetic risk score (GRS) with subclinical atherosclerosis.
Atherosclerosis is a slowly progressive disorder influenced by suboptimal lipid levels. Long-term versus contemporary lipid levels may more strongly impact the development of coronary artery calcium (CAC).
Framingham Heart Study (FHS) Offspring Cohort participants (n=1156, 44%M, 63±9 years) underwent serial fasting lipids [low-density lipoprotein (LDL-C), high-density lipoprotein, and triglycerides], Exam 1 (1971–1975) – Exam 7 (1998–2001). FHS Third Generation Cohort participants (n=1954, 55%M, 45±6 years) had fasting lipid profiles assessed, 2002–2005. Computed tomography (2002–2005) measured CAC. Lipid GRSs were computed from significantly associated single nucleotide polymorphisms. The association between early, long-term average, and contemporary lipids, and lipid GRS, with elevated CAC was assessed using logistic regression.
In FHS Offspring, Exam 1 and long-term average versus Exam 7 lipid measurements, including untreated lipid levels, were strongly associated with elevated CAC. In the FHS Third Generation, contemporary lipids were associated with CAC. The LDL-C GRS was associated with CAC (age/sex-adjusted OR 1.14, 95%CI 1.00–1.29, p=0.04). However, addition of the GRS to the lipid models did not result in a significant increase in the OR or C-statistic for any lipid measure.
Early and long-term average lipid levels, as compared with contemporary measures, are more strongly associated with elevated CAC. Lipid GRS was associated with lipid levels but did not predict elevated CAC. Adult early and long-term average lipid levels provide important information when assessing subclinical atherosclerosis and cardiovascular risk.
PMCID: PMC3702262  PMID: 23141485
Lipids; Genetic risk score; Coronary artery calcium
13.  Dietary Patterns, Abdominal Visceral Adipose Tissue and Cardiometabolic Risk Factors in African Americans: the Jackson Heart Study 
Obesity (Silver Spring, Md.)  2013;21(3):10.1002/oby.20265.
Dietary behavior is an important lifestyle factor to impact an individual’s risk of developing cardiovascular disease (CVD). However, the influence of specific dietary factors on CVD risk for African Americans remains unclear. We conducted a cross-sectional study of 1775 participants from Jackson Heart Study (JHS) Exam 2 (between 2006 and 2009) who were free of hypertension, diabetes and CVD at the baseline (between 2001 and 2004). Dietary intakes were documented using a validated food-frequency questionnaire (FFQ) and dietary patterns were generated by factor analysis. Three major dietary patterns were identified: a “southern”, a “fast food” and a “prudent” pattern. After adjustment for age, sex, smoking and alcohol status, education level and physical activity, high “southern” pattern score was associated with an increased odds ratio (OR) for high abdominal visceral adipose tissue (VAT) (OR:1.80, 95%CI:1.1–3.0, p=0.02), hypertension (OR:1.42, 95%CI:1.1–1.9, p=0.02), diabetes (OR:2.03, 95%CI:1.1–3.9, p=0.03) and metabolic syndrome (OR:2.16, 95%CI:1.3–3.6, p=0.004). Similar associations were also observed in the “fast food” pattern (p ranges 0.03–0.0001). The “prudent” pattern was significantly associated, in a protective direction, with hypertension (OR 0.69, 95%CI 0.5–0.9, p=0.02). In conclusion, dietary patterns, especially the “southern” pattern, identified from a regional specific FFQ in this Deep South African Americans, are correlated with abdominal VAT and cardiometabolic risk factors.
PMCID: PMC3478414  PMID: 23592674
Jackson Heart Study; dietary patterns; cardiometabolic risk factors
15.  Association of smoking cessation and weight change with cardiovascular disease among people with and without diabetes 
Smoking cessation reduces the risks of cardiovascular disease (CVD), but weight gain that follows quitting smoking may weaken the CVD benefit of quitting.
To test the hypothesis that weight gain following smoking cessation does not attenuate the benefits of smoking cessation among people with and without diabetes.
Design, Setting, and Participants
Prospective community-based cohort study using data from the Framingham Offspring Study collected from 1984 to 2011. At each 4-year exam, self-reported smoking status was assessed and categorized as smoker, recent quitter (≤ 4 years), long-term quitter (> 4 years), and non-smoker. Pooled Cox proportional hazards models were used to estimate the association between quitting smoking and 6-year CVD events and to test whether 4-year change in weight following smoking cessation modified the association between smoking cessation and CVD events.
Main outcome measure
Incidence over 6 years of total CVD events, comprising coronary heart disease, cerebrovascular events, peripheral artery disease, and congestive heart failure.
After a mean follow-up of 25 years (SD, 9.6), 631 CVD events occurred among 3251 participants. Median 4-year weight gain was greater for recent quitters without diabetes (2.7 kg, Interquartile range [IQR] −0.5-6.4) and with diabetes (3.6 kg, IQR −1.4-8.2) than for long term quitters (0.9 kg, IQR −1.4-3.2 and 0.0 kg, IQR −3.2-3.2, respectively, p<0.001). Among people without diabetes, age and sex-adjusted incidence rate of CVD was 5.9/ 100 person-exams (95% confidence interval [CI] 4.9-7.1) in smokers, 3.2/ 100 person-exams (95% CI 2.1-4.5) in recent quitters, 3.1 /100 person-exams (95% CI 2.6-3.7) in long-term quitters, and 2.4 /100 person-exams (95% CI 2.0-3.0) in non-smokers. After adjustment for CVD risk factors, compared with smokers, recent quitters had a hazard ratio (HR) for CVD of 0.47 (95% CI, 0.23-0.94) and long-term quitters had an HR of 0.46 (95% CI, 0.34-0.63); these associations had only a minimal change after further adjustment for weight change. Among people with diabetes, there were similar point estimates that did not reach statistical significance.
Conclusions and Relevance
In this community based cohort, smoking cessation was associated with a lower risk of CVD events among participants without diabetes, and weight gain that occurred following smoking cessation did not modify this association. This supports a net cardiovascular benefit of smoking cessation despite subsequent weight gain.
PMCID: PMC3791107  PMID: 23483176
16.  Fine-scale spatiotemporal influences of salmon on growth and nitrogen signatures of Sitka spruce tree rings 
BMC Ecology  2013;13:38.
The marine-terrestrial transfer of salmon (Oncorhynchus spp.) provides a substantial pulse of nutrients to receiving ecosystems along the Pacific coast of North America and has been shown to enhance productivity and isotopic signatures of conifers and other riparian vegetation. An explicitly spatial, within-watershed investigation of the influence of salmon on conifers has never been previously investigated. In a small salmon-bearing watershed in Haida Gwaii, Canada, the transfer and distributional pattern of salmon carcasses into the riparian zone by black bears provided a spatial basis for investigating the influence of salmon on Sitka spruce tree ring growth and nitrogen isotopic signatures (δ15N) across a gradient of salmon carcass densities in relation to salmon escapement.
Annual growth was found to be highest in the high salmon carcass zone and δ15N signatures closely tracked the known distribution of salmon carcasses at distances into the forest and upstream. Tree diameter demonstrated a positive relationship with δ15N signatures for trees with and without salmon carcass influence. Using an information theoretics approach with general linear mixed models (GLMMs), we show that salmon abundance, mean annual temperature and the interaction terms salmon abundance*temperature and salmon abundance*distance into the forest best predict tree growth. In addition, spatial variables (distance into forest and upstream) and their interaction are the strongest predictors of δ15N signatures. However patterns observed in individual trees, particularly those at increased distance into the forest, suggest positive relationships with historical salmon abundance.
Using a replicated spatial sampling design across a sharp gradient in salmon nutrient loading, our study provides clear evidence that the temporal pattern in an allochthonous nutrient source and an interaction with temperature and spatial location influences conifer growth. Although salmon abundance has been previously linked to annual conifer growth and δ15N levels, our approach demonstrates the need to incorporate additional predictors including tree size and opens up the prospect of their dual use as historical proxies for salmon abundance.
PMCID: PMC3850941  PMID: 24093666
Spatial subsidy; Salmon; Nitrogen; Sitka spruce; Conifer; Riparian; Stable isotope
17.  Fatty Liver, Abdominal Adipose Tissue and Atherosclerotic Calcification in African Americans: the Jackson Heart Study 
Atherosclerosis  2012;224(2):521-525.
Both fatty liver and abdominal visceral fat (VAT) are associated with cardiometabolic risk factors. Whether fatty liver and VAT are jointly associated with coronary artery (CAC) or abdominal aortic (AAC) calcification is not clear.
Jackson Heart Study (JHS) participants (n=2884, mean age 60 years, 65% women) underwent non-contrast CT Exam for assessment of fatty liver, VAT, and CAC and AAC. Fatty liver was measured by liver attenuation (LA; low LA=high fatty liver). The Agatston score was used to quantify the amount of calcified artery plaque and the presence of calcified artery plaque was defined as Agatston score>0. Cross-sectional associations of LA and VAT with CAC and AAC were examined in logistic regression models.
LA (per 1-standard deviation [SD] decrement) was associated inversely with CAC in age-sex-adjusted (OR 0.84, 95%CI 0.7–0.9, p=0.0001) and multivariable adjusted models (OR 0.89, 95%CI 0.8–0.9, p=0.01). The association persisted for LA with CAC when additionally adjusted for body mass index (BMI) (OR 0.89, 95%CI 0.8–0.9, p=0.03) or VAT (OR 0.90, 95%CI 0.8–0.9, p=0.04). Abdominal VAT (per 1-SD increment) was positively associated with CAC in age-sex-adjusted models (OR 1.27, 95%CI 1.2–1.4, p=0.0001), but the association was diminished with multivariable adjustment (OR 1.10, 95%CI 0.9–1.2, p=0.09) and with additional adjustment for LA (p = 0.24) or BMI (p = 0.33). For AAC, the associations with LA and VAT were only present in age-sex-adjusted models. Finally, we did not observe interactions between LA and VAT for CAC (p=0.18) or AAC (p=0.24).
Fatty liver is associated with coronary atherosclerotic calcification independent of abdominal VAT or BMI in African Americans. Further investigations to uncover the clinical implications of fatty liver on coronary atherosclerosis in obesity are warranted.
PMCID: PMC3459068  PMID: 22902209
18.  Novel measurements of periaortic adipose tissue in comparison to anthropometric measures of obesity, and abdominal adipose tissue 
Perivascular adipose tissue may be associated with the amount of local atherosclerosis. We developed a novel and reproducible method to standardize volumetric quantification of periaortic adipose tissue by computed tomography (CT) and determined the association with anthropometric measures of obesity, and abdominal adipose tissue.
Measurements of adipose tissue were performed in a random subset of participants from the Framingham Heart Study (n=100) who underwent multidetector CT of the thorax (ECG triggering, 2.5 mm slice thickness) and the abdomen (helical CT acquisition, 2.5 mm slice thickness). Abdominal periaortic adipose tissue (AAT) was defined by a 5 mm cylindrical region of interest around the aortic wall; thoracic periaortic adipose tissue (TAT) was defined by anatomic landmarks. TAT and AAT were defined as any voxel between −195 HU to −45HU and volumes were measured using dedicated semiautomatic software. Measurement reproducibility and association with anthropometric measures of obesity, and abdominal adipose tissue were determined.
The intra- and inter-observer reproducibility for both AAT and TAT was excellent (ICC: 0.97, 0.97; 0.99, and 0.98, respectively). Similarly, the relative intra-and inter-observer difference was small for both AAT (−1.85±1.28% and 7.85±6.08%; respectively) and TAT (3.56±0.83% and −4.56±0.85%, respectively). Both AAT and TAT were highly correlated with visceral abdominal fat (r=0.65 and 0.77, p<0.0001 for both) and moderately correlated with subcutaneous abdominal fat (r=0.39 and 0.42, p<0.0001 and p=0.009), waist circumference (r=0.49 and 0.57, p<0.0001 for both), and body mass index (r=0.47 and 0.58, p<0.0001 for both).
Standardized semiautomatic CT-based volumetric quantification of periaortic adipose tissue is feasible and highly reproducible. Further investigation is warranted regarding associations of periaortic adipose tissue with other body fat deposits, cardiovascular risk factors, and clinical outcomes.
PMCID: PMC3779879  PMID: 19139753
Adipose Tissue; Intra-Abdominal Fat; Tomography; Spiral Computed; Framingham Heart Study; Metabolic Risk Factors
19.  2-Aminoadipic acid is a biomarker for diabetes risk 
The Journal of Clinical Investigation  2013;123(10):4309-4317.
Improvements in metabolite-profiling techniques are providing increased breadth of coverage of the human metabolome and may highlight biomarkers and pathways in common diseases such as diabetes. Using a metabolomics platform that analyzes intermediary organic acids, purines, pyrimidines, and other compounds, we performed a nested case-control study of 188 individuals who developed diabetes and 188 propensity-matched controls from 2,422 normoglycemic participants followed for 12 years in the Framingham Heart Study. The metabolite 2-aminoadipic acid (2-AAA) was most strongly associated with the risk of developing diabetes. Individuals with 2-AAA concentrations in the top quartile had greater than a 4-fold risk of developing diabetes. Levels of 2-AAA were not well correlated with other metabolite biomarkers of diabetes, such as branched chain amino acids and aromatic amino acids, suggesting they report on a distinct pathophysiological pathway. In experimental studies, administration of 2-AAA lowered fasting plasma glucose levels in mice fed both standard chow and high-fat diets. Further, 2-AAA treatment enhanced insulin secretion from a pancreatic β cell line as well as murine and human islets. These data highlight a metabolite not previously associated with diabetes risk that is increased up to 12 years before the onset of overt disease. Our findings suggest that 2-AAA is a marker of diabetes risk and a potential modulator of glucose homeostasis in humans.
PMCID: PMC3784523  PMID: 24091325
20.  Prevalence and Distribution of Abdominal Aortic Calcium by Sex and Age-Group in a Community-based Cohort (From The Framingham Heart Study) 
The American journal of cardiology  2012;110(6):891-896.
Abdominal aortic calcium (AAC) is associated with incident cardiovascular disease but the age and sex-related distribution of AAC in a community-dwelling population free of standard cardiovascular disease risk factors has not been described. A total of 3285 participants (aged 50.2±9.9 years) in the Framingham Heart Study Offspring and Third Generation cohorts underwent abdominal multidetector computed tomography (MDCT) scanning during 1998-2005. The presence and amount of AAC was quantified (Agatston score) by an experienced reader using standardized criteria. A healthy referent subsample (N=1656, 803 men) free of hypertension, hyperlipidemia, diabetes, obesity and smoking was identified, and participants were stratified by sex and age group (<45, 45-54, 55-64, 65-74, ≥75 years). The prevalence and burden of AAC increased monotonically and supralinearly with age in both sexes but was greater in men than women in each age group. Below age 45 <16% of referent-subsample participants had any quantifiable AAC, while above age 65 nearly 90% of referent participants had >0 AAC. Across the entire study sample, AAC prevalence and burden similarly increased with greater age. Defining the 90th percentile of referent group AAC as “high,” the prevalence of high AAC was 19% for each sex in the overall study sample. AAC also increased across categories of 10-year coronary heart disease risk, as calculated using the Framingham Risk Score, in the entire study sample. We found AAC to be widely prevalent, with the burden of AAC associated with 10-year coronary risk, in a white, free-living adult cohort.
PMCID: PMC3432173  PMID: 22727181
atherosclerosis; aorta; calcification; computed tomography; epidemiology
21.  Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis 
Lancet  2012;380(9854):1662-1673.
Chronic kidney disease is characterised by low estimated glomerular filtration rate (eGFR) and high albuminuria, and is associated with adverse outcomes. Whether these risks are modified by diabetes is unknown.
We did a meta-analysis of studies selected according to Chronic Kidney Disease Prognosis Consortium criteria. Data transfer and analyses were done between March, 2011, and June, 2012. We used Cox proportional hazards models to estimate the hazard ratios (HR) of mortality and end-stage renal disease (ESRD) associated with eGFR and albuminuria in individuals with and without diabetes.
We analysed data for 1 024 977 participants (128 505 with diabetes) from 30 general population and high-risk cardiovascular cohorts and 13 chronic kidney disease cohorts. In the combined general population and high-risk cohorts with data for all-cause mortality, 75 306 deaths occurred during a mean follow-up of 8·5 years (SD 5·0). In the 23 studies with data for cardiovascular mortality, 21 237 deaths occurred from cardiovascular disease during a mean follow-up of 9·2 years (SD 4·9). In the general and high-risk cohorts, mortality risks were 1·2–1·9 times higher for participants with diabetes than for those without diabetes across the ranges of eGFR and albumin-to-creatinine ratio (ACR). With fixed eGFR and ACR reference points in the diabetes and no diabetes groups, HR of mortality outcomes according to lower eGFR and higher ACR were much the same in participants with and without diabetes (eg, for all-cause mortality at eGFR 45 mL/min per 1·73 m2 [νs 95 mL/min per 1·73 m2], HR 1·35; 95% CI 1·18–1·55; νs 1·33; 1·19–1·48 and at ACR 30 mg/g [νs 5 mg/g], 1·50; 1·35–1·65 νs 1·52; 1·38–1·67). The overall interactions were not significant. We identified much the same findings for ESRD in the chronic kidney disease cohorts.
Despite higher risks for mortality and ESRD in diabetes, the relative risks of these outcomes by eGFR and ACR are much the same irrespective of the presence or absence of diabetes, emphasising the importance of kidney disease as a predictor of clinical outcomes.
PMCID: PMC3771350  PMID: 23013602
22.  Fasting Glucose, Obesity, and Coronary Artery Calcification in Community-Based People Without Diabetes 
Diabetes Care  2012;35(9):1944-1950.
Our objective was to assess whether impaired fasting glucose (IFG) and obesity are independently related to coronary artery calcification (CAC) in a community-based population.
We assessed CAC using multidetector computed tomography in 3,054 Framingham Heart Study participants (mean [SD] age was 50 [10] years, 49% were women, 29% had IFG, and 25% were obese) free from known vascular disease or diabetes. We tested the hypothesis that IFG (5.6–6.9 mmol/L) and obesity (BMI ≥30 kg/m2) were independently associated with high CAC (>90th percentile for age and sex) after adjusting for hypertension, lipids, smoking, and medication.
High CAC was significantly related to IFG in an age- and sex-adjusted model (odds ratio 1.4 [95% CI 1.1–1.7], P = 0.002; referent: normal fasting glucose) and after further adjustment for obesity (1.3 [1.0–1.6], P = 0.045). However, IFG was not associated with high CAC in multivariable-adjusted models before (1.2 [0.9–1.4], P = 0.20) or after adjustment for obesity. Obesity was associated with high CAC in age- and sex-adjusted models (1.6 [1.3–2.0], P < 0.001) and in multivariable models that included IFG (1.4 [1.1–1.7], P = 0.005). Multivariable-adjusted spline regression models suggested nonlinear relationships linking high CAC with BMI (J-shaped), waist circumference (J-shaped), and fasting glucose.
In this community-based cohort, CAC was associated with obesity, but not IFG, after adjusting for important confounders. With the increasing worldwide prevalence of obesity and nondiabetic hyperglycemia, these data underscore the importance of obesity in the pathogenesis of CAC.
PMCID: PMC3425010  PMID: 22773705
23.  Functional validation of GWAS gene candidates for abnormal liver function during zebrafish liver development 
Disease Models & Mechanisms  2013;6(5):1271-1278.
Genome-wide association studies (GWAS) have revealed numerous associations between many phenotypes and gene candidates. Frequently, however, further elucidation of gene function has not been achieved. A recent GWAS identified 69 candidate genes associated with elevated liver enzyme concentrations, which are clinical markers of liver disease. To investigate the role of these genes in liver homeostasis, we narrowed down this list to 12 genes based on zebrafish orthology, zebrafish liver expression and disease correlation. To assess the function of gene candidates during liver development, we assayed hepatic progenitors at 48 hours post fertilization (hpf) and hepatocytes at 72 hpf using in situ hybridization following morpholino knockdown in zebrafish embryos. Knockdown of three genes (pnpla3, pklr and mapk10) decreased expression of hepatic progenitor cells, whereas knockdown of eight genes (pnpla3, cpn1, trib1, fads2, slc2a2, pklr, mapk10 and samm50) decreased cell-specific hepatocyte expression. We then induced liver injury in zebrafish embryos using acetaminophen exposure and observed changes in liver toxicity incidence in morphants. Prioritization of GWAS candidates and morpholino knockdown expedites the study of newly identified genes impacting liver development and represents a feasible method for initial assessment of candidate genes to instruct further mechanistic analyses. Our analysis can be extended to GWAS for additional disease-associated phenotypes.
PMCID: PMC3759346  PMID: 23813869
24.  Association of pericardial fat and coronary high-risk lesions as determined by cardiac CT 
Atherosclerosis  2012;222(1):129-134.
Pericardial adipose tissue (PAT) is a pathogenic fat depot associated with coronary atherosclerosis and cardiovascular events. We hypothesized that higher PAT is associated with coronary high-risk lesions as determined by cardiac CT.
We included 358 patients (38% female; median age 51 years) who were admitted to the ED with acute chest pain and underwent 64-slice CT angiography. The cardiac CT data sets were assessed for presence and morphology of CAD and PAT. Coronary high-risk lesions were defined as >50% luminal narrowing and at least two of the following characteristics: positive remodeling, low-density plaque, and spotty calcification. PAT was defined as any pixel with CT attenuation of −190 to −30 HU within the pericardial sac.
Based on cardiac CT, 50% of the patients (n = 180) had no CAD, 46% (n = 165) had CAD without high-risk lesions, and 13 patients had CAD with high-risk lesions. The median PAT in patients with high-risk lesions was significantly higher compared to patients without high-risk lesions and without any CAD (151.9 [109.0–179.4] cm3 vs. 110.0 [81.5–137.4] cm3, vs. 74.8 [58.2–111.7] cm3, respectively p = 0.04 and p < 0.0001). These differences remained significant after adjusting for traditional risk factors including BMI (all p < 0.05). The area under the ROC curve for the identification of high-risk lesions was 0.756 in a logistic regression model with PAT as a continuous predictor.
PAT volume is nearly twice as high in patients with high-risk coronary lesions as compared to those without CAD. PAT volume is significantly associated with high risk coronary lesion morphology independent of clinical characteristics and general obesity.
PMCID: PMC3738181  PMID: 22417843
Coronary artery disease; Cardiac CT angiography; Pericardial fat; Adipose tissue; Vulnerable plaque; High-risk lesions
25.  Relationships of BMI to Cardiovascular Risk Factors Differ by Ethnicity* 
Obesity (Silver Spring, Md.)  2009;18(8):1638-1645.
The burden of cardiovascular risk associated with obesity disproportionately affects African Americans and little is known about ethnic/racial differences in the relationship of obesity to cardiometabolic risk. This report assesses whether obesity is similarly associated with cardiometabolic risk factors in African Americans and whites of European ancestry. Cross-sectional observational data from the Jackson Heart Study (JHS) and the Framingham Heart Study (FHS) were compared. This analysis uses participants aged 35–74 years with BMI >18.5 kg/m2, and free of prevalent cardiovascular disease (CVD), from the initial JHS clinical examination (2000–2004) and the FHS Offspring (1998–2001) and Third Generation (2002–2005) cohorts. Participants were evaluated for the presence of lipid abnormalities, hypertension, and diabetes. Overall, 4,030 JHS (mean age 54 years, 64% women) and 5,245 FHS (mean age 51 years, 54% women) participants were available for analysis. The prevalence of all risk factors except high triglycerides and low high-density lipoprotein (HDL) was substantially higher in JHS (all P < 0.001) and BMI was associated with increasing prevalence of most CVD risk factors within each race. For diabetes mellitus, hypertension, and low HDL, steeper relationships to BMI were observed in FHS than in JHS (P values <0.001–0.016). There were larger proportional increases in risk factor prevalence with increasing BMI in whites than in African Americans. The higher prevalence rates of cardiometabolic risk factors at nearly all levels of BMI in African Americans, however, suggest that additional factors contribute to the burden of CVD risk in African Americans.
PMCID: PMC3716014  PMID: 19927137

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