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1.  A Genome-Wide Association Study of the Human Metabolome in a Community-Based Cohort 
Cell metabolism  2013;18(1):130-143.
SUMMARY
Because metabolites are hypothesized to play key roles as markers and effectors of cardio-metabolic diseases, recent studies have sought to annotate the genetic determinants of circulating metabolite levels. We report a genome-wide association study (GWAS) of 217 plasma metabolites, including >100 not measured in prior GWAS, in 2,076 participants of the Framingham Heart Study. For the majority of analytes, we find that estimated heritability explains >20% of inter-individual variation, and that variation attributable to heritable factors is greater than that attributable to clinical factors. Further, we identify 31 genetic loci associated with plasma metabolites, including 23 that have not previously been reported. Importantly, we include GWAS results for all surveyed metabolites, and demonstrate how this information highlights a role for AGXT2 in cholesterol ester and triacylglycerol metabolism. Thus, our study outlines the relative contributions of inherited and clinical factors on the plasma metabolome and provides a resource for metabolism research.
doi:10.1016/j.cmet.2013.06.013
PMCID: PMC3973158  PMID: 23823483
2.  Relations of Long-Term and Contemporary Lipid Levels and Lipid Genetic Risk Scores with Coronary Artery Calcium in the Framingham Heart Study 
Objectives
This study evaluated the association of timing of lipid levels and lipid genetic risk score (GRS) with subclinical atherosclerosis.
Background
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).
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jacc.2012.09.007
PMCID: PMC3702262  PMID: 23141485
Lipids; Genetic risk score; Coronary artery calcium
3.  Atherosclerotic Biomarkers and Aortic Atherosclerosis by Cardiovascular Magnetic Resonance Imaging in the Framingham Heart Study 
Background
The relations between subclinical atherosclerosis and inflammatory biomarkers have generated intense interest but their significance remains unclear. We sought to determine the association between a panel of biomarkers and subclinical aortic atherosclerosis in a community‐based cohort.
Methods and Results
We evaluated 1547 participants of the Framingham Heart Study Offspring cohort who attended the 7th examination cycle and underwent both cardiovascular magnetic resonance imaging (CMR) and assays for 10 biomarkers associated with atherosclerosis: high‐sensitivity C‐reactive protein, fibrinogen, intercellular adhesion molecule‐1, interleukin‐6, interleukin‐18, lipoprotein‐associated phospholipase‐A2 activity and mass, monocyte chemoattractant protein‐1, P‐selectin, and tumor necrosis factor receptor‐2. In logistic regression analysis, we found no significant association between the biomarker panel and the presence of aortic plaque (global P=0.53). Using Tobit regression with aortic plaque as a continuous variable, we noted a modest association between biomarker panel and aortic plaque volume in age‐ and sex‐adjusted analyses (P=0.003). However, this association was attenuated after further adjustment for clinical covariates (P=0.09).
Conclusions
In our community‐based cohort, we found no significant association between our multibiomarker panel and aortic plaque. Our results underscore the strengths and limitations of the use of biomarkers for the identification of subclinical atherosclerosis and the importance of traditional risk factors.
doi:10.1161/JAHA.113.000307
PMCID: PMC3886740  PMID: 24242683
aorta; atherosclerosis; biomarkers; cardiovascular magnetic resonance imaging
5.  Development and Application of a Longitudinal ECG Repository: the Framingham Heart Study 
Journal of electrocardiology  2012;45(6):673-676.
The electrocardiogram (ECG) has wide-spread use in clinical care and research. Despite its extensive use and study, important gaps remain in examining prospective, repeated longitudinal ECG measures and their association with cardiovascular outcomes. The Framingham Heart Study (FHS) is a community-based study designed to examine risk factors and outcomes associated with cardiovascular disease. Here we describe a novel effort in the FHS to develop a unique resource: serial ECGs conducted on three generations of study participants spanning multiple decades (1986 to the present). We describe the FHS and the role the ECG has had in conducting cardiovascular epidemiology in the FHS. We then describe potential applications for a longitudinal ECG repository. We expect the Framingham ECG repository to enhance cardiovascular research and epidemiologic study. Such a resource will complement the FHS’ phenotypic and genotypic characterization, facilitating novel investigations of cardiovascular epidemiology.
doi:10.1016/j.jelectrocard.2012.06.016
PMCID: PMC3483375  PMID: 22832152
electrocardiography; epidemiology; repository; Framingham
6.  Left Ventricular Trabeculae and Papillary Muscles: Correlation With Clinical and Cardiac Characteristics and Impact on Cardiovascular Magnetic Resonance Measures of Left Ventricular Anatomy and Function 
JACC. Cardiovascular imaging  2012;5(11):1115-1123.
Objective
We sought to assess the relationship of left ventricular (LV) trabeculae and papillary muscles (TPM) with clinical characteristics in a community-based, free living adult cohort and to determine the effect of TPM on quantitative measures of LV volume, mass and ejection fraction (EF).
Background
Hypertrabeculation has been associated with adverse cardiovascular events, but the distribution and clinical correlates of the volume and mass of the TPM in a normal left ventricle have not been well characterized.
Methods
Short-axis cine cardiovascular magnetic resonance (CMR) images, obtained using a steady-state free precession sequence, from 1494 members of the Framingham Offspring cohort were analyzed using software that automatically segments TPM. Absolute TPM volume, TPM as a fraction of end-diastolic volume (TPM/EDV), and TPM mass as a fraction of LV mass (TPMm/LVM) were determined on all Offspring and in a referent group of Offspring free of clinical cardiovascular disease and hypertension.
Results
In the referent group (aged 61±9 years, with 262 men and 423 women) TPM was 23±3 % of LV EDV in both sexes (p=0.9). TPM/EDV decreased with age (p<0.02) but was not associated with body mass index (BMI). TPMm/LVM was inversely correlated with age (p<0.0001), BMI (p<0.018) and systolic blood pressure (p<0.0001). Among all 1494 participants (699 men) LV volumes decreased 23%, LV mass increased 28% and EF increased by 7.5 EF units (p<0.0001) when TPM were considered myocardial mass rather than part of the LV blood pool.
Conclusions
Global CMR LV parameters are significantly affected by whether TPM are considered as part of the LV blood pool or as part of LV mass. Our cross-sectional data from a healthy referent group of adults free of clinical cardiovascular disease demonstrate that TPM/EDV decreases with increasing age in both sexes, but is not related to hypertension or obesity.
doi:10.1016/j.jcmg.2012.05.015
PMCID: PMC3502069  PMID: 23153911
magnetic resonance imaging; population study; trabeculae; papillary muscle; left ventricular ejection fraction
7.  QT interval and long-term mortality risk in the Framingham Heart Study 
Background
The association between QT interval and mortality has been demonstrated in large, prospective population-based studies, but the strength of the association varies considerably based on the method of heart rate correction. We examined the QT-mortality relationship in the Framingham Heart Study (FHS).
Methods
Participants in the first (original cohort, n = 2,365) and second generation (offspring cohort, n = 4,530) cohorts were included in this study with a mean follow up of 27.5 years. QT interval measurements were obtained manually using a highly reproducible digital caliper technique.
Results
Using Cox proportional hazards regression adjusting for age and sex, a 20 msec increase in QTC (using Bazett’s correction; QT/RR1/2 interval) was associated with a modest increase in risk of all-cause mortality (HR 1.14, 95% CI 1.10–1.18, p<0.0001), coronary heart disease (CHD) mortality (HR 1.15, 95% CI 1.05–1.26, p = 0.003), and sudden cardiac death (SCD, HR 1.19, 95% CI 1.03–1.37, p = 0.02). However, adjustment for heart rate using RR interval in linear regression attenuated this association. The association of QT interval with all-cause mortality persisted after adjustment for cardiovascular risk factors, but associations with CHD mortality and SCD were no longer significant.
Conclusion
In FHS, there is evidence of a graded relation between QTC and all-cause mortality, CHD death, and SCD; however, this association is attenuated by adjustment for RR interval. These data confirm that using Bazett’s heart rate correction, QTC, overestimates the association with mortality. An association with all-cause mortality persists despite a more complete adjustment for heart rate and known cardiovascular risk factors.
doi:10.1111/j.1542-474X.2012.00535.x
PMCID: PMC3481183  PMID: 23094880
Heart rate; Mortality; QT interval; Sudden cardiac death
8.  Novel measurements of periaortic adipose tissue in comparison to anthropometric measures of obesity, and abdominal adipose tissue 
Background
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1038/ijo.2008.267
PMCID: PMC3779879  PMID: 19139753
Adipose Tissue; Intra-Abdominal Fat; Tomography; Spiral Computed; Framingham Heart Study; Metabolic Risk Factors
9.  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.
doi:10.1172/JCI64801
PMCID: PMC3784523  PMID: 24091325
10.  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.
doi:10.1016/j.amjcard.2012.05.020
PMCID: PMC3432173  PMID: 22727181
atherosclerosis; aorta; calcification; computed tomography; epidemiology
11.  Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling  
The Journal of Clinical Investigation  2013;123(10):4208-4218.
The suppression of tumorigenicity 2/IL-33 (ST2/IL-33) pathway has been implicated in several immune and inflammatory diseases. ST2 is produced as 2 isoforms. The membrane-bound isoform (ST2L) induces an immune response when bound to its ligand, IL-33. The other isoform is a soluble protein (sST2) that is thought to be a decoy receptor for IL-33 signaling. Elevated sST2 levels in serum are associated with an increased risk for cardiovascular disease. We investigated the determinants of sST2 plasma concentrations in 2,991 Framingham Offspring Cohort participants. While clinical and environmental factors explained some variation in sST2 levels, much of the variation in sST2 production was driven by genetic factors. In a genome-wide association study (GWAS), multiple SNPs within IL1RL1 (the gene encoding ST2) demonstrated associations with sST2 concentrations. Five missense variants of IL1RL1 correlated with higher sST2 levels in the GWAS and mapped to the intracellular domain of ST2, which is absent in sST2. In a cell culture model, IL1RL1 missense variants increased sST2 expression by inducing IL-33 expression and enhancing IL-33 responsiveness (via ST2L). Our data suggest that genetic variation in IL1RL1 can result in increased levels of sST2 and alter immune and inflammatory signaling through the ST2/IL-33 pathway.
doi:10.1172/JCI67119
PMCID: PMC3784527  PMID: 23999434
12.  Fasting Glucose, Obesity, and Coronary Artery Calcification in Community-Based People Without Diabetes 
Diabetes Care  2012;35(9):1944-1950.
OBJECTIVE
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.
RESEARCH DESIGN AND METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.2337/dc11-1950
PMCID: PMC3425010  PMID: 22773705
13.  Usefulness of the Left Ventricular Myocardial Contraction Fraction in Healthy Men and Women to Predict Cardiovascular Morbidity and Mortality 
The American journal of cardiology  2012;109(10):1454-1458.
We sought to determine whether depressed myocardial contraction fraction (MCF, the ratio of left ventricular (LV) stroke volume to myocardial volume) predicts cardiovascular disease (CVD) events in initially healthy adults. A subset (N=318, 60±9 yrs, 158 men) of the Framingham Heart Study Offspring cohort free of clinical CVD underwent volumetric cardiovascular magnetic resonance (CMR) imaging in 1998–1999. LV ejection fraction (EF), mass and MCF were determined. “Hard” CVD events comprised cardiovascular death, myocardial infarction, stroke or new heart failure. A Cox proportional hazards model adjusting for Framingham Coronary Risk Score (FCRS) was used to estimate hazard ratios for incident hard CVD events for sex-specific quartiles of MCF, LV mass and LVEF. The lowest quartile of LV mass and highest quartiles of MCF and EF served as referent. Kaplan-Meier survival plots and the log rank test were used to compare event-free survival. MCF was greater in women (0.58±0.13) than men (0.52±0.11), p<0.01. Nearly all (99%) participants had EF ≥ 0.55. Over up to 9-year (median 5.2) follow-up, 31 participants (10%) experienced an incident hard CVD event. Lowest-quartile MCF was 7 times more likely to develop hard CVD (hazard ratio 7.11, p=0.010) compared to the lowest quartile, and the elevated hazards persisted even after adjustment for LV mass (hazard ratio=6.09, p=0.020). The highest-quartile LV mass/height2.7 had nearly five-fold risk (hazard ratio 4.68, p=0.016). Event-free survival was shorter in lowest-quartile MCF, p = 0.0006, but not in lowest-quartile LVEF. Conclusion: In a cohort of adults initially without clinical CVD, lowest-quartile MCF conferred an increased hazard for hard CVD events after adjustment for traditional CVD risk factors and LV mass.
doi:10.1016/j.amjcard.2012.01.357
PMCID: PMC3742100  PMID: 22381161
magnetic resonance imaging; myocardial contraction fraction; risk factors; left ventricular function
15.  Relations of Exercise Blood Pressure Response to Cardiovascular Risk Factors and Vascular Function in the Framingham Heart Study 
Circulation  2012;125(23):2836-2843.
Background
Exercise blood pressure (BP) is an important marker of left ventricular hypertrophy, incident hypertension and future cardiovascular events. Although impaired vascular function is hypothesized to influence the BP response during exercise, limited data exist on the association of vascular function with exercise BP in the community.
Methods and Results
Framingham Offspring cohort participants (n=2115, 53% women, mean age 59 years) underwent a submaximal exercise test (first 2 stages of the Bruce protocol), applanation tonometry and brachial artery flow-mediated dilation (FMD) testing. We related exercise systolic and diastolic BP at second stage of the Bruce protocol to standard cardiovascular risk factors and to vascular function measures. In multivariable linear regression models, exercise systolic BP was positively related to age, standing BP, standing heart rate, smoking, body mass index, and the total cholesterol-to-high-density cholesterol (HDL) ratio (p≤0.01 for all). Similar associations were observed for exercise diastolic BP. Carotid-femoral pulse wave velocity (p=0.02), central pulse pressure (p<0.0001), mean arterial pressure (p=0.04) and baseline brachial flow (p=0.002) were positively associated with exercise systolic BP, whereas FMD was negatively associated (P<0.001). For exercise diastolic BP, forward pressure wave amplitude was negatively related (p<0.0001) whereas mean arterial pressure was positively related (p<0.0001).
Conclusions
Increased arterial stiffness and impaired endothelial function are significant correlates of a higher exercise systolic BP response. Our findings suggest that impaired vascular function may contribute to exaggerated BP responses during daily living, resulting in repetitive increments in load on the heart and vessels and increased cardiovascular disease risk.
doi:10.1161/CIRCULATIONAHA.111.063933
PMCID: PMC3636551  PMID: 22572915
blood pressure; endothelial function; exercise; vascular function; vascular stiffness
16.  Population Health, Outcomes Research and Prevention Policy: Example of the American Heart Association 2020 Goals 
doi:10.1161/CIRCOUTCOMES.111.964734
PMCID: PMC3676931  PMID: 22253367
Prevention; Healthcare delivery; Outcomes
17.  Accurate Computer-Aided Quantification of Left Ventricular Parameters: Experience in 1555 CMR Studies from the Framingham Heart Study 
Magnetic Resonance in Medicine  2011;67(5):1478-1486.
Quantitative analysis of short-axis functional cardiac magnetic resonance (CMR) images can be performed using automatic contour detection methods. The resulting myocardial contours must be reviewed and possibly corrected, which can be time-consuming, particularly when performed across all cardiac phases. We quantified the impact of manual contour corrections on both analysis time and quantitative measurements obtained from left ventricular (LV) short-axis cine images acquired from 1555 participants of the Framingham Heart Study Offspring cohort using computer aided contour detection methods. The total analysis time for a single case was 7.6±1.7 minutes for an average of 221±36 myocardial contours per participant. This included 4.8±1.6 minutes for manual contour correction of 2% of all automatically-detected endocardial contours and 8% of all automatically-detected epicardial contours. However, the impact of these corrections on global LV parameters was limited, introducing differences of 0.4±4.1ml for end-diastolic volume, −0.3±2.9ml for end-systolic volume, 0.7±3.1 ml for stroke volume and 0.3±1.8% for ejection fraction. We conclude that LV functional parameters can be obtained under 5 minutes from short-axis functional CMR images using automatic contour detection methods. Manual correction more than doubles analysis time, with minimal impact on LV volumes and ejection fraction.
doi:10.1002/mrm.23127
PMCID: PMC3267005  PMID: 22021128
18.  An Increased Burden of Common and Rare Lipid-Associated Risk Alleles Contributes to the Phenotypic Spectrum of Hypertriglyceridemia 
Objective
Earlier studies have suggested that a common genetic architecture underlies the clinically heterogeneous polygenic Fredrickson hyperlipoproteinemia (HLP) phenotypes defined by hypertriglyceridemia (HTG). Here, we comprehensively analyzed 504 HLP-HTG patients and 1213 normotriglyceridemic controls and confirmed that a spectrum of common and rare lipid-associated variants underlies this heterogeneity.
Methods and Results
First, we demonstrated that genetic determinants of plasma lipids and lipoproteins, including common variants associated with plasma triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) from the Global Lipids Genetics Consortium were associated with multiple HLP-HTG phenotypes. Second, we demonstrated that weighted risk scores composed of common TG-associated variants were distinctly increased across all HLP-HTG phenotypes compared with controls; weighted HDL-C and LDL-C risk scores were also increased, although to a less pronounced degree with some HLP-HTG phenotypes. Interestingly, decomposition of HDL-C and LDL-C risk scores revealed that pleiotropic variants (those jointly associated with TG) accounted for the greatest difference in HDL-C and LDL-C risk scores. The APOE E2/E2 genotype was significantly overrepresented in HLP type 3 versus other phenotypes. Finally, rare variants in 4 genes accumulated equally across HLP-HTG phenotypes.
Conclusion
HTG susceptibility and phenotypic heterogeneity are both influenced by accumulation of common and rare TG-associated variants.
doi:10.1161/ATVBAHA.111.226365
PMCID: PMC3562702  PMID: 21597005
lipoproteins; genetic risk scores; genetic variation; hypertriglyceridemia; pleiotropy
22.  Reference Values for Normal Pulmonary Artery Dimensions by Noncontrast Cardiac Computed Tomography: The Framingham Heart Study 
Background
Main pulmonary artery diameter (mPA) and ratio of mPA to ascending aorta diameter (ratio PA) derived from chest CT are commonly reported in clinical practice. We determined the age and sex-specific distribution and normal reference values for mPA and ratio PA by CT in an asymptomatic community-based population.
Methods and Results
In 3171 men and women (mean age 51 ± 10 years, 51% men) from the Framingham Heart Study, a non-contrast ECG gated eight-slice cardiac multi-detector CT was performed. We measured the mPA and transverse axial diameter of the ascending aorta at the level of the bifurcation of the right pulmonary artery and calculated the ratio PA. We defined the healthy referent cohort (n=706) as those without obesity, hypertension, current and past smokers, chronic obstructive pulmonary disease, history of pulmonary embolism, diabetics, cardiovascular disease, and heart valvular surgery. The mean mPA diameter in the overall cohort was 25.1 ± 2.8mm and mean ratio PA was 0.77 ± 0.09. The sex-specific 90th percentile cutoff value for mPA diameter was 28.9 mm in men and 26.9 mm in women and was associated with increase risk for self-reported dyspnea (adjusted odds ratio 1.31, p=0.02). The 90th percentile cutoff value for ratio PA of the healthy referent group was 0.91, similar between gender, but decreased with increasing age (range 0.82 to 0.94), though not associated with dyspnea.
Conclusions
For simplicity, we established 29 mm in men and 27 mm in women as sex-specific normative reference values for mPA and 0.9 for ratio PA.
doi:10.1161/CIRCIMAGING.111.968610
PMCID: PMC3275437  PMID: 22178898
pulmonary artery; Framingham Heart Study; computed tomography
23.  Genome-wide Association Study for Coronary Artery Calcification with Follow-up in Myocardial Infarction 
Circulation  2011;124(25):2855-2864.
Background
Coronary artery calcification (CAC) detected by computed tomography is a non-invasive measure of coronary atherosclerosis, that underlies most cases of myocardial infarction (MI). We aimed to identify common genetic variants associated with CAC and further investigate their associations with MI.
Methods and Results
Computed tomography was used to assess quantity of CAC. A meta-analysis of genome-wide association studies for CAC was carried out in 9,961 men and women from five independent community-based cohorts, with replication in three additional independent cohorts (n=6,032). We examined the top single nucleotide polymorphisms (SNPs) associated with CAC quantity for association with MI in multiple large genome-wide association studies of MI. Genome-wide significant associations with CAC for SNPs on chromosome 9p21 near CDKN2A and CDKN2B (top SNP: rs1333049, P=7.58×10−19) and 6p24 (top SNP: rs9349379, within the PHACTR1 gene, P=2.65×10−11) replicated for CAC and for MI. Additionally, there is evidence for concordance of SNP associations with both CAC and with MI at a number of other loci, including 3q22 (MRAS gene), 13q34 (COL4A1/COL4A2 genes), and 1p13 (SORT1 gene).
Conclusions
SNPs in the 9p21 and PHACTR1 gene loci were strongly associated with CAC and MI, and there are suggestive associations with both CAC and MI of SNPs in additional loci. Multiple genetic loci are associated with development of both underlying coronary atherosclerosis and clinical events.
doi:10.1161/CIRCULATIONAHA.110.974899
PMCID: PMC3397173  PMID: 22144573
cardiac computed tomography; coronary artery calcification; coronary atherosclerosis; genome-wide association studies; myocardial infarction
24.  Post-Genomic Update on a Classical Candidate Gene for Coronary Artery Disease: ESR1 
Background
After age, gender is the most important risk factor for coronary artery disease (CAD). The mechanism through which women are protected from CAD is still largely unknown, but the observed gender difference suggests the involvement of the reproductive steroid hormone signaling system. Genetic association studies of the gene encoding Estrogen Receptor alpha (ESR1) have shown conflicting results, although only a limited range of variation in the gene has been investigated.
Methods and Results
We exploited information made available by advanced new methods and resources in complex disease genetics to revisit the question of ESR1's role in risk of CAD. We performed a meta-analysis of 14 genome-wide association studies (CARDIoGRAM discovery analysis, N~87,000) to search for population-wide and gender-specific associations between CAD risk and common genetic variants throughout the coding, non-coding and flanking regions of ESR1. In additional samples from the MIGen (N~6,000), WTCCC (N~7,400) and Framingham (N~3,700) studies, we extended this search to a larger number of common and uncommon variants by imputation into a panel of haplotypes constructed using data from the 1000 Genomes project. Despite the widespread expression of ER alpha in vascular tissues, we find no evidence for involvement of common or low-frequency genetic variation throughout the ESR1 gene in modifying risk of CAD, either in the general population or as a function of gender.
Conclusions
We suggest that future research on the genetic basis of gender-related differences in CAD risk should initially prioritize other genes in the reproductive steroid hormone biosynthesis system.
doi:10.1161/CIRCGENETICS.111.960583
PMCID: PMC3260440  PMID: 21984528
coronary artery disease; estrogen receptor alpha; menopause; polymorphism, single nucleotide; genetic association studies; meta-analysis
25.  Periaortic Adipose Tissue and Aortic Dimensions in the Framingham Heart Study 
Background
Periaortic fat, because of its contiguity with the aorta, may promote vascular remodeling and aortic dilatation. However, the relations between perioartic fat depots and aortic dimensions have not been previously described.
Methods and Results
A total of 3001 individuals (mean age 50±10 years, 49% women) from the Framingham Offspring and Third Generation cohorts underwent computed tomography for quantification of periaortic fat and aortic dimensions. We estimated the association between quantitative periaortic and visceral adipose tissue volumes (per standard deviation [SD] increment of volume) with aortic dimensions in both the thorax and abdomen. Thoracic periaortic fat was associated with higher thoracic aortic dimensions (β coefficient per SD of fat volume 0.67 mm, 95% confidence interval 0.58 to 0.76 mm; P<0.001). The association persisted after adjustment for age, sex, and cardiovascular risk factors including body mass index and visceral adipose tissue volume. Results for the association of periaortic fat and abdominal aortic dimensions were similar. Further adjustment for adipokines (resistin and adiponectin) had no significant impact on these associations.
Conclusions
Periaortic fat volume was associated with aortic dimensions in both the thorax and abdomen, supporting the notion that local fat depots may contribute to aortic remodeling. Further work to understand the mechanisms underlying this association is warranted.
doi:10.1161/JAHA.112.000885
PMCID: PMC3540669  PMID: 23316310
adipose tissue; aneurysm; aorta; peripheral vascular disease

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