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1.  Dissecting the Roles of microRNAs in Coronary Heart Disease via Integrative Genomics Analyses 
The roles of microRNAs (miRNAs) in coronary heart disease (CHD) have not been well characterized. This study sought to systematically characterize the complex genomic architecture of CHD by integrating whole blood miRNA and mRNA expression with genetic variation in 186 CHD cases and 186 controls.
Approach and Results
At FDR<0.2, 15 miRNAs were differentially expressed between CHD cases and controls. To explore regulatory mechanisms, we integrated miRNA and mRNA expression with genotype data genome-wide to investigate miRNA and mRNA associations and relations of genetic variation to miRNAs. We identified a large number of correlated miRNA-mRNA pairs and genetic loci that appear to regulate miRNA levels. Subsequently, we explored the relations of these complex molecular associations to CHD status. We identified a large difference in miRNA-mRNA associations between CHD cases and controls, as demonstrated by a significantly higher proportion of inversely correlated miRNA-mRNA pairs in cases vs. controls (80% vs. 30%; p<1e-16), suggesting a genome-wide shift in the regulatory structure of the transcriptome in CHD. The differentially co-expressed miRNA-mRNA pairs showed enrichment for CHD risk genetic variants affecting both miRNA and mRNA expression levels, implicating a putatively causal role in CHD. Furthermore, three miRNAs (miR-1275, miR-365a-3p, and miR-150-5p) were associated with an mRNA co-expression module that was causally linked to CHD and reflected dysregulation of B-cell centered immune function.
Our results provide novel evidence that miRNAs are important regulators of biological processes involved in CHD via genetic control and via their tight co-expression with mRNAs.
PMCID: PMC4376567  PMID: 25657313
microRNA expression; coronary heart disease; systems biology; genetics
2.  Genome-Wide Association Study for Endothelial Growth Factors 
Endothelial growth factors including angiopoietin-2 (Ang-2), its soluble receptor Tie-2 (sTie-2) and hepatocyte growth factor (HGF) play important roles in angiogenesis, vascular remodeling, local tumor growth and metastatic potential of various cancers. Circulating levels of these biomarkers have a heritable component (between 13% and 56%), but the underlying genetic variation influencing these biomarker levels is largely unknown.
Methods and Results
We performed a genome-wide association study for circulating Ang-2, sTie-2, and HGF in 3571 Framingham Heart Study (FHS) participants and assessed replication of the top hits for Ang-2 and sTie-2 in 3184 participants of the Study of Health in Pomerania (SHIP). In multivariable-adjusted models, sTie-2 and HGF concentrations were associated with single nucleotide polymorphisms (SNPs) in the genes encoding the respective biomarkers (top p=2.40×10−65 [rs2273720] and 3.64×10−19 [rs5745687], respectively). Likewise, rs2442517 in the MCPH1 gene (in which the Ang-2 gene is embedded) was associated with Ang-2 levels (p=5.05×10−8 in FHS and 8.39×10−5 in SHIP). Furthermore, SNPs in the AB0 gene were associated with sTie-2 (top SNP rs8176693 with p=1.84×10−33 in FHS; p=2.53×10−30 in SHIP) and Ang-2 (rs8176746 with p=2.07×10−8 in FHS; p=0.001 in SHIP) levels on a genome-wide significant level. The top genetic loci explained between 1.7% (Ang-2) and 11.2% (sTie-2) of the inter-individual variation in biomarker levels.
Genetic variation contributes to the inter-individual variation in growth factor levels and explains a modest proportion of circulating HGF, Ang-2, and Tie-2. This may potentially contribute to the familial susceptibility to cancer, a premise that warrants further studies.
PMCID: PMC4406801  PMID: 25552591
Genome Wide Association Study; genetics; endothelial growth factors; HGF; Ang-2; Tie-2
3.  Metabolomic Profiles of Body Mass Index in the Framingham Heart Study Reveal Distinct Cardiometabolic Phenotypes 
PLoS ONE  2016;11(2):e0148361.
Although obesity and cardiometabolic traits commonly overlap, underlying pathways remain incompletely defined. The association of metabolite profiles across multiple cardiometabolic traits may lend insights into the interaction of obesity and metabolic health. We sought to investigate metabolic signatures of obesity and related cardiometabolic traits in the community using broad-based metabolomic profiling.
Methods and Results
We evaluated the association of 217 assayed metabolites and cross-sectional as well as longitudinal changes in cardiometabolic traits among 2,383 Framingham Offspring cohort participants. Body mass index (BMI) was associated with 69 of 217 metabolites (P<0.00023 for all), including aromatic (tyrosine, phenylalanine) and branched chain amino acids (valine, isoleucine, leucine). Additional metabolic pathways associated with BMI included the citric acid cycle (isocitrate, alpha-ketoglutarate, aconitate), the tryptophan pathway (kynurenine, kynurenic acid), and the urea cycle. There was considerable overlap in metabolite profiles between BMI, abdominal adiposity, insulin resistance [IR] and dyslipidemia, modest overlap of metabolite profiles between BMI and hyperglycemia, and little overlap with fasting glucose or elevated blood pressure. Metabolite profiles were associated with longitudinal changes in fasting glucose, but the involved metabolites (ornithine, 5-HIAA, aminoadipic acid, isoleucine, cotinine) were distinct from those associated with baseline glucose or other traits. Obesity status appeared to “modify” the association of 9 metabolites with IR. For example, bile acid metabolites were strongly associated with IR among obese but not lean individuals, whereas isoleucine had a stronger association with IR in lean individuals.
In this large-scale metabolite profiling study, body mass index was associated with a broad range of metabolic alterations. Metabolite profiling highlighted considerable overlap with abdominal adiposity, insulin resistance, and dyslipidemia, but not with fasting glucose or blood pressure traits.
PMCID: PMC4749349  PMID: 26863521
4.  Revisiting heritability accounting for shared environmental effects and maternal inheritance 
Human genetics  2014;134(2):169-179.
Heritability measures the proportion of phenotypic variation attributable to genetic factors. In addition to a shared nuclear genetic component, a number of additional variance components, such as spousal correlation, sibship, household and maternal effects, may have strong contributions to inter-individual phenotype variation. In humans, the confounding effects of these components on heritability have not been studied thoroughly. We sought to obtain unbiased heritability estimates for complex traits in the presence of multiple variance components and also to estimate the contributions of these variance components to complex traits. We compared regression and variance component methods to estimate heritability in simulations when additional variance components existed. We then revisited heritability for several traits in Framingham Heart Study (FHS) participants. Using simulations, we found that failure to account for or misclassification of necessary variance components yielded biased heritability estimates. The direction and magnitude of the bias varied depending on a variance structure and an estimation method. Using the best fitted models to account for necessary variance components, we found that heritability estimates for most FHS traits were overestimated, ranging from 4 to 47 %, when we compared models that considered necessary variance components to models that only considered familial relationships. Spousal correlation explained 14–36 % of phenotypic variation in several anthropometric and lifestyle traits. Maternal and sibling effects also contributed to phenotypic variation, ranging from 3 to 5 % and 4 to 7 %, respectively, in several anthropometric and metabolic traits. Our findings may explain, in part, the missing heritability for some traits.
PMCID: PMC4303043  PMID: 25381465
5.  Components of Hemodynamic Load and Cardiovascular Events: The Framingham Heart Study 
Circulation  2014;131(4):354-361.
Elevated blood pressure is the leading modifiable risk factor for cardiovascular disease (CVD) and premature death. The blood pressure waveform consists of discrete hemodynamic components, derived from measured central pressure and flow, which may contribute separately to risk for an adverse outcome. However, pressure-flow measures have not been studied in a large, community-based sample.
Methods and Results
We used proportional hazards models to examine association of incident CVD with forward pressure wave amplitude, mean arterial pressure, and global reflection coefficient derived from wave separation analysis and echocardiography in 2492 participants (mean age 66 ± 9 years, 56% women) in the Framingham Heart Study. During follow up (0.04 – 6.8 years), 149 participants (6%) had a CVD event. In multivariable models adjusting for age, sex, antihypertensive therapy, body mass index, heart rate, total and high density lipoprotein cholesterol concentrations, smoking, and presence of diabetes, forward pressure wave amplitude (HR=1.40; 95% CI: 1.16, 1.67; P=0.0003) was associated with incident CVD whereas mean arterial pressure (HR=1.10; 95% CI: 0.94, 1.29; P=0.25) and global wave reflection (HR=0.93; 95% CI: 0.78, 1.12; P=0.58) were not. After adding systolic blood pressure and carotid-femoral pulse wave velocity to the model, forward pressure wave amplitude persisted as a correlate of events (HR=1.33; 95% CI, 1.05, 1.68; P=0.02).
Higher forward pressure wave amplitude (a measure of proximal aortic geometry and stiffness) was whereas mean arterial pressure and relative wave reflection (correlates of resistance vessel structure and function) were not associated with increased risk for incident CVD.
PMCID: PMC4308473  PMID: 25416177
hemodynamic load; pulsatile hemodynamics; forward pressure wave amplitude; cardiovascular disease
6.  Familial Clustering of Mitral Valve Prolapse in the Community 
Circulation  2014;131(3):263-268.
Knowledge of mitral valve prolapse (MVP) inheritance is based on pedigree observation and M-mode echocardiography. The extent of familial clustering of MVP among unselected individuals in the community based on current, more specific echocardiographic criteria is unknown. In addition, the importance of non-diagnostic MVP morphologies (NDM; first described in large pedigrees) has not been investigated in the general population. We hypothesized that parental MVP and NDM increase the risk of offspring MVP.
Methods and Results
Study participants were 3679 Generation 3 individuals with available parental data in the Offspring or the New Offspring Spouse cohorts. MVP and NDM were distinguished by leaflet displacement > 2 mm versus ≤ 2 mm beyond the mitral annulus, respectively. We compared MVP prevalence in Generation 3 participants with at least one parent with MVP (n=186) with that in individuals without parental MVP (n=3493). Among 3679 participants (53% women; mean age 40±9 years), 49 (1%) had MVP. Parental MVP was associated with a higher prevalence of MVP in Generation 3 participants (10/186 [5.4%]) compared to no parental MVP (39/3493 [1.1%] - adjusted odds ratio [OR], 4.51, 95% confidence interval [CI], 2.13–9.54; p<0.0001). When parental NDM was examined alone, prevalence of Generation 3 MVP remained higher (12/484 [2.5%]) compared to those without parental MVP or NDM (27/3009 [0.9%] - adjusted OR 2.52, 95% CI, 1.25–5.10; p=0.01).
Parental MVP and NDM are associated with increased prevalence of offspring MVP, highlighting the genetic substrate of MVP and the potential clinical significance of NDM in the community.
PMCID: PMC4301989  PMID: 25361552
mitral valve prolapse; echocardiography; epidemiology; genetics
7.  Meta-analysis of genome-wide association studies identifies two loci associated with circulating osteoprotegerin levels 
Human Molecular Genetics  2014;23(24):6684-6693.
Osteoprotegerin (OPG) is involved in bone homeostasis and tumor cell survival. Circulating OPG levels are also important biomarkers of various clinical traits, such as cancers and atherosclerosis. OPG levels were measured in serum or in plasma. In a meta-analysis of genome-wide association studies in up to 10 336 individuals from European and Asian origin, we discovered that variants >100 kb upstream of the TNFRSF11B gene encoding OPG and another new locus on chromosome 17q11.2 were significantly associated with OPG variation. We also identified a suggestive locus on chromosome 14q21.2 associated with the trait. Moreover, we estimated that over half of the heritability of OPG levels could be explained by all variants examined in our study. Our findings provide further insight into the genetic regulation of circulating OPG levels.
PMCID: PMC4240210  PMID: 25080503
8.  Association of circulating endothelial microparticles with cardiometabolic risk factors in the Framingham Heart Study 
European Heart Journal  2014;35(42):2972-2979.
To examine the relation of endothelial microparticles (EMPs) with cardiometabolic risk in the community.
Circulating EMPs are small membrane vesicles released after endothelial cell injury. Endothelial microparticles are reportedly increased among individuals with a high burden of cardiovascular risk factors. However, prior investigations have been limited to small, highly selected samples.
We studied 844 individuals without a history of cardiovascular disease in the Framingham Offspring cohort (mean age 66 ± 9 years, 57% women). We used standardized flow cytometry methods to identify and quantify circulating CD144+ and CD31+/CD41− EMPs. We then used multivariable regression analyses to investigate the relations of EMP phenotypes with cardiovascular and metabolic risk factors.
In multivariable analyses, the following cardiovascular risk factors were associated with one or more of the circulating EMP populations: hypertension (P = 0.025 for CD144+,), elevated triglycerides (P = 0.002 for CD144+, P < 0.0001 for CD31+/CD41−), and metabolic syndrome (P < 0.0001 for CD144+,). Overall, each tertile increase in the Framingham risk score corresponded to a 9% increase in log-CD31+/CD41− EMPs (P = 0.022). Furthermore, the presence of hypertriglyceridaemic waist status was associated with 38% higher levels of CD144+ EMPs (P < 0.0001) and 46% higher levels of CD31+/CD41− EMPs (P < 0.0001).
In a large community-based sample, circulating EMP levels were associated with the presence of cardiometabolic risk factors, particularly dyslipidaemia. These data underscore the potential influence of high-risk metabolic profiles on endothelial integrity.
PMCID: PMC4223610  PMID: 24742886
Microparticles; Cardiovascular risk factors; Endothelium
9.  Distinct Metabolomic Signatures Are Associated with Longevity in Humans 
Nature communications  2015;6:6791.
Alterations in metabolism influence lifespan in experimental models, but data in humans are lacking. Here we use liquid chromatography/mass spectrometry to quantify 217 plasma metabolites and examine their relation to longevity in a large cohort of men and women. In 647 individuals followed for up to 20 years, higher concentrations of the citric acid cycle intermediate, isocitrate, and the bile acid, taurocholate, are associated with lower odds of longevity, defined as attaining 80 years of age. In a larger cohort of 2,327 individuals with metabolite data available, higher concentrations of isocitrate but not taurocholate are also associated with worse cardiovascular health at baseline, as well as risk of future cardiovascular disease and death. None of the metabolites identified are associated with cancer risk. Our findings suggest that some, but not all, metabolic pathways to human longevity are dependent on modifying risk for the two most common causes of death.
PMCID: PMC4396657  PMID: 25864806
10.  B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies 
Europace  2014;16(10):1426-1433.
B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information.
Methods and results
We ascertained AF incidence in 18 556 Whites and African Americans from the Atherosclerosis Risk in Communities Study (ARIC, n=10 675), Cardiovascular Health Study (CHS, n = 5043), and Framingham Heart Study (FHS, n = 2838), followed for 5 years (prediction horizon). We added BNP (ARIC/CHS: N-terminal pro-B-type natriuretic peptide; FHS: BNP), CRP, or both to a previously reported AF risk score, and assessed model calibration and predictive ability [C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI)]. We replicated models in two independent European cohorts: Age, Gene/Environment Susceptibility Reykjavik Study (AGES), n = 4467; Rotterdam Study (RS), n = 3203. B-type natriuretic peptide and CRP were significantly associated with AF incidence (n = 1186): hazard ratio per 1-SD ln-transformed biomarker 1.66 [95% confidence interval (CI), 1.56–1.76], P < 0.0001 and 1.18 (95% CI, 1.11–1.25), P < 0.0001, respectively. Model calibration was sufficient (BNP, χ2 = 17.0; CRP, χ2 = 10.5; BNP and CRP, χ2 = 13.1). B-type natriuretic peptide improved the C-statistic from 0.765 to 0.790, yielded an IDI of 0.027 (95% CI, 0.022–0.032), a relative IDI of 41.5%, and a continuous NRI of 0.389 (95% CI, 0.322–0.455). The predictive ability of CRP was limited (C-statistic increment 0.003). B-type natriuretic peptide consistently improved prediction in AGES and RS.
B-type natriuretic peptide, not CRP, substantially improved AF risk prediction beyond clinical factors in an independently replicated, heterogeneous population. B-type natriuretic peptide may serve as a benchmark to evaluate novel putative AF risk biomarkers.
PMCID: PMC4197895  PMID: 25037055
Atrial fibrillation; Risk prediction; Epidemiology; Biomarker; B-type natriuretic peptide; C-reactive protein
11.  Genome-wide Identification of microRNA Expression Quantitative Trait Loci 
Nature communications  2015;6:6601.
Identification of microRNA expression quantitative trait loci (miR-eQTL) can yield insights into regulatory mechanisms of microRNA transcription, and can help elucidate the role of microRNA as mediators of complex traits. Here we present a miR-eQTL mapping study of whole blood from 5239 individuals, and identify 5269 cis-miR-eQTLs for 76 mature microRNAs. Forty-nine percent of cis-miR-eQTLs are located 300–500kb upstream of their associated intergenic microRNAs, suggesting that distal regulatory elements may affect the interindividual variability in microRNA expression levels. We find that cis-miR-eQTLs are highly enriched for cis-mRNA-eQTLs and regulatory SNPs. Among 243 cis-miR-eQTLs that were reported to be associated with complex traits in prior genome-wide association studies, many cis-miR-eQTLs miRNAs display differential expression in relation to the corresponding trait (e.g., rs7115089, miR-125b-5p, and HDL cholesterol). Our study provides a roadmap for understanding the genetic basis of miRNA expression, and sheds light on miRNA involvement in a variety of complex traits.
PMCID: PMC4369777  PMID: 25791433
12.  Stromal Cell-Derived Factor 1 (SDF-1) as a Biomarker of Heart Failure and Mortality Risk 
CXCL12 encodes stromal cell-derived factor 1 alpha (SDF-1), which binds to the receptor encoded by CXCR4. Variation at the CXCL12 locus is associated with coronary artery disease (CAD) and endothelial progenitor cell (EPC) numbers, while variation at the CXCR4 locus is associated with leukocyte telomere length (LTL), which has been shown to be associated with CAD. We therefore examined the relations of plasma SDF-1 levels to cardiovascular disease (CVD)-related outcomes, risk factors, LTL, and EPCs.
Approach and Results
SDF-1 was measured in 3359 Framingham Heart Study participants. We used Cox regression to examine relations of SDF-1 to new-onset CVD, myocardial infarction (MI), heart failure (HF), and all-cause mortality; we used linear regression to evaluate associations of SDF-1 with risk factors, LTL, and CD34+ cell phenotypes. In multivariable models, higher SDF-1 levels were associated with older age, lower levels of HDL cholesterol, and cigarette smoking. Higher SDF-1 levels were associated with lower CD34+ cell frequency (p=0.02), but not with LTL. During follow-up (median 9.3 years), there were 263 new-onset CVD events, 160 MIs, 200 HF events, and 385 deaths. After adjusting for clinical risk factors, SDF-1 levels were associated with HF (p=0.04) and all-cause mortality (p=0.003), but not with CVD (p=0.39) or MI (p=0.10). The association of SDF-1 levels with MI was attenuated after adjustment for HDL cholesterol.
After adjusting for traditional CVD risk factors, SDF-1 is associated with HF and all-cause mortality risk. Further studies are needed to determine whether measurement of SDF-1 levels has clinical utility.
PMCID: PMC4142677  PMID: 25060794
Cardiovascular disease; epidemiology; myocardial infarction; heart failure; mortality; stromal cell-derived factor 1; progenitor cells
13.  The Natural History of Left Ventricular Geometry in the Community: Clinical Correlates and Prognostic Significance of Change in LV Geometric Pattern 
JACC. Cardiovascular imaging  2014;7(9):870-878.
We evaluated pattern and clinical correlates of change in left ventricular (LV) geometry over a 4-year period in the community; we also assessed whether the pattern of change in LV geometry over 4 years predicts incident cardiovascular disease (CVD), including myocardial infarction, heart failure and cardiovascular death during an additional subsequent follow-up period.
It is unclear how LV geometric patterns change over time and whether changes in LV geometry have prognostic significance.
We evaluated 4492 observations (2604 unique Framingham Study participants attending consecutive examinations) to categorize LV geometry at baseline and after 4 years. Four groups were defined based on the sex-specific distributions of LV mass (LVM) and relative wall thickness (RWT) (normal: LVM and RWT<80th percentile; concentric remodeling: LVM< but RWT≥80th percentile; eccentric hypertrophy: LVM≥ but RWT<80th percentile; and concentric hypertrophy: LVM and RWT≥80th percentile).
At baseline, 2874/4492 observations (64%) had normal LVM and RWT. Individuals with normal geometry or concentric remodeling progressed infrequently (4–8%) to eccentric or concentric hypertrophy. Change from eccentric to concentric hypertrophy was uncommon (8%). Among participants with concentric hypertrophy, 19% developed eccentric hypertrophy within the 4-years period. Among individuals with abnormal LV geometry at baseline, a significant proportion (29–53%) reverted to normal geometry within 4-years. Higher blood pressure, greater body mass index (BMI), advancing age and male sex were key correlates of developing an abnormal geometry. Development of an abnormal LV geometric pattern over 4 years was associated with increased CVD risk (140 events) during a subsequent median follow-up of 12.0 years (adjusted-hazards ratio, 1.59; 95%CI, 1.04–2.43).
Our longitudinal observations in the community suggest that dynamic changes in LV geometric pattern over time are common. Higher blood pressure and greater BMI are modifiable factors associated with the development of abnormal LV geometry, and such progression portends an adverse prognosis.
PMCID: PMC4163746  PMID: 25129518
LV geometry; change over time; remodeling; echocardiography; cardiovascular disease; heart failure; epidemiology
14.  Forward and backward wave morphology and central pressure augmentation in men and women in the Framingham Heart Study 
Hypertension  2014;64(2):259-265.
Central pressure augmentation is associated with greater backward wave amplitude and shorter transit time and is higher in women for reasons only partially elucidated. Augmentation also is affected by left ventricular function and shapes of the forward and backward waves. The goal of this study was to examine the relative contributions of forward and backward wave morphology to central pressure augmentation in men and women. From noninvasive measurements of central pressure and flow in 7437 participants (4036 women) from 19 to 90 years of age (mean age 51 years), we calculated several variables: augmentation index, backward wave arrival time, reflection factor, forward wave amplitude, forward wave peak width and slope of the backward wave upstroke. Linear regression models for augmentation index, adjusted for height and heart rate, demonstrated non-linear relations with age (age: βx00302; =4.6±0.1%, P<0.001; age2: βx00302;=−4.2±0.1%, P<0.001) and higher augmentation in women (βx00302; =4.5±0.4%, P<0.001, model R2=0.35). Addition of reflection factor and backward wave arrival time improved model fit (R2=0.62) and reduced the age coefficients: age (βx00302; =2.3±0.1%, P<0.001) and age2 (βx00302; =−2.2±0.1%, P<0.001). Addition of width of forward wave peak, slope of backward wave upstroke and forward wave amplitude further improved model fit (R2=0.75) and attenuated the sex coefficient (βx00302;=1.9±0.2%, P<0.001). Thus, shape and amplitude of the forward wave may be important correlates of augmentation index, and part of the sex-difference in augmentation index may be explained by forward and backward wave morphology.
PMCID: PMC4184952  PMID: 24866142
augmentation index; wave reflection; pulse pressure; aortic stiffness; left ventricular contraction
15.  Pleiotropic genes for metabolic syndrome and inflammation 
Molecular genetics and metabolism  2014;112(4):317-338.
Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up in meta-analyses, out of 130,305 possible combinations between metabolic traits and inflammatory markers studied. (c) We performed correlated meta-analyses for 8 metabolic traits and 6 inflammatory markers by using existing GWAS published genetic summary results, with about 2.5 million SNPs from twelve predominantly largest GWAS consortia. These analyses yielded 130 unique SNPs/genes with pleiotropic associations (a SNP/gene associating at least one metabolic trait and one inflammatory marker). Of them twenty-five variants (seven loci newly reported) are proposed as MetS candidates. They map to genes MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Based on large data evidence, we conclude that inflammation is a feature of MetS and several gene variants show pleiotropic genetic associations across phenotypes and might explain a part of MetS correlated genetic architecture. These findings warrant further functional investigation.
PMCID: PMC4122618  PMID: 24981077
16.  Galectin 3 and incident atrial fibrillation in the community 
American heart journal  2014;167(5):729-734.e1.
Galectin 3 (Gal-3) is a potential mediator of cardiac fibrosis, and Gal-3 concentrations predict incident heart failure. The same mechanisms that lead to cardiac fibrosis in heart failure may influence development of atrial fibrosis and atrial fibrillation (AF). We examined the association of Gal-3 and incident AF in the community.
Plasma Gal-3 concentrations were measured in 3,306 participants of the Framingham Offspring cohort who attended the sixth examination cycle (1995–1998, mean age 58 years, 54% women). Cox proportional hazards regression models were used to assess the association of baseline Gal-3 concentrations and incident AF.
Over a median follow-up period of 10 years, 250 participants developed incident AF. Crude incidence rates of AF by increasing sex-specific Gal-3 quartiles were 3.7%, 5.9%, 9.1%, and 11.5% (log-rank test P < .0001). In age- and sex-adjusted analyses, each 1-SD increase in loge-Gal-3 was associated with a 19% increased hazard of incident AF (hazard ratio 1.19, 95% CI 1.05–1.36, P = .009). This association was not significant after adjustment for traditional clinical AF risk factors (hazard ratio 1.12, 95% CI 0.98–1.28, P = .10).
Higher circulating Gal-3 concentrations were associated with increased risk of developing AF over the subsequent 10 years in age- and sex-adjusted analyses but not after accounting for other traditional clinical AF risk factors. Our results do not support a role for Gal-3 in AF risk prediction. Further studies are needed to evaluate whether Gal-3 plays a role in the development of AF substrate similar to HF.
PMCID: PMC4007212  PMID: 24766984
17.  Relations between circulating microRNAs and atrial fibrillation: data from the Framingham Offspring Study 
MicroRNA (miRNA) expression in atrial tissue has been implicated in pathologic susceptibility to atrial fibrillation (AF). Nevertheless, data are limited on how circulating levels relate to AF.
To test the hypothesis that circulating miRNAs would be associated with AF.
Among 2445 Framingham Heart Study Offspring participants, we measured the expression of 385 circulating whole blood miRNAs by high-throughput quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). We related miRNA levels with prevalent and new-onset AF.
The mean age in the cohort was 66.3 ± 8.9 years and 56% were women; 153 participants had clinically apparent AF at baseline and 107 developed AF during a median of 5.4 years of follow-up. miRNA-328 (miR-328) expression was lower among participants with prevalent AF [8.76 cycle threshold (Ct)] compared to individuals with no AF (7.75 Ct, p <0.001). The association between miR-328 and prevalent AF persisted after adjustment for age, sex, and technical covariates (OR=1.21, P = 1.8 × 10−4) but was attenuated in analyses adjusting for clinical AF risk factors (OR=1.14, P = 0.017). In contrast to the associations between miR-328 and prevalent AF, none of the circulating miRNAs were associated with incident AF.
Circulating levels of miR-328, a miRNA known to promote atrial electrical remodeling by reducing L-type Ca2+ channel density, were associated with prevalent AF. Adjustment for risk factors that promote atrial remodeling, including hypertension, attenuated the association between miR-328 and AF, potentially implicating miR-328 as a potential mediator of atrial remodeling and AF vulnerability.
PMCID: PMC4219255  PMID: 24444445
atrial fibrillation; epidemiology, circulation; microRNA; risk factors
18.  Implications of the US Cholesterol Guidelines on Eligibility for Statin Therapy in the Community: Comparison of Observed and Predicted Risks in the Framingham Heart Study Offspring Cohort 
Concerns have been raised that the 2013 atherosclerotic cardiovascular disease (ASCVD) risk estimator overpredicts risk in contemporary cohorts. Whether suboptimal calibration will lead to overtreatment with statins is unknown. We investigated the numbers of people eligible for statin treatment in the Framingham Heart Study Offspring Cohort, based on the 2013 cholesterol guidelines, and estimated the proportion that may be overtreated as a result of potential miscalibration of the ASCVD estimator.
Methods and Results
During a median follow‐up of 10 years, we observed 285 ASCVD events (8.4%; comprising ischemic stroke, myocardial infarction, and coronary artery disease death) among 3396 men and 112 events (2.9%) among 3838 women. Hosmer–Lemeshow chi‐square statistics were 16.3 in men (340 predicted versus 285 observed events) and 29.1 in women (166 predicted versus 112 observed events). Overprediction predominantly occurred among women in the highest risk decile and among men in the ≥7th risk deciles, for which observed ASCVD event rates were ≥7.5%. In total, 2615 participants (36%; 867 women) were eligible for statins based on the new guidelines. Of these, 171 women (20%) and 154 men (9%) were reclassified downward (as not eligible for statin therapy) using a recalibrated ASCVD estimator. In the latter group, 18 women (10.5%; 95% CI 5.9% to 15.2%) and 11 men (7.1%; 95% CI 3.0% to 11.3%) experienced ASCVD.
The risk estimator overpredicted ASCVD risk but did so mainly among high‐risk participants who would be considered eligible for statin use anyway. Our findings may mitigate concerns regarding the potential impact of miscalibration of the ASCVD estimator in contemporary cohorts.
PMCID: PMC4579932  PMID: 25888372
primary prevention; risk prediction; statin
19.  Biomarkers of Cardiovascular Stress and Subclinical Atherosclerosis in the Community 
Clinical chemistry  2014;60(11):1402-1408.
Biomarkers of cardiovascular stress have been associated with incident cardiovascular outcomes. Their relations with measures of subclinical atherosclerosis, as assessed by carotid intima-media thickness, have not been well described.
Plasma growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and high-sensitivity troponin I (hsTnI) were measured in 3111 Framingham Offspring participants who also underwent carotid ultrasonography during the sixth examination (1995 – 1998, mean age 58 years, 54% women). Carotid measurements included maximal internal carotid artery (ICA) intima-media thickness (IMT), plaque presence (defined as ICA IMT > 1.5 mm), and mean common carotid artery IMT. Multivariable regressions for carotid measurements versus biomarkers were carried out using linear and logistic models; P < 0.0056 was deemed statistically significant.
Maximal ICA IMT was significantly associated with plasma GDF-15 (β-estimate 0.04 per 1 unit increase in log-GDF-15 SE 0.01, P < 0.0001). Similarly, the odds of having carotid plaque increased 33% (OR 1.33 per 1-unit increase in log-GDF-15, 95% CI 1.20-1.48, P < 0.0001). In contrast, there was no significant association of maximal ICA IMT or plaque presence with sST2 or hsTnI, and none of the three biomarkers was significantly associated with mean CCA IMT. GDF-15 was a stronger predictor of maximal ICA thickness and plaque presence compared with BNP and CRP when these conventional biomarkers were tested together.
Higher GDF-15 concentrations are associated with subclinical atherosclerosis, including maximal ICA IMT and carotid plaque presence. Future studies investigating the role of GDF-15 for screening and management of patients with subclinical atherosclerosis are warranted.
PMCID: PMC4376479  PMID: 25237063
carotid intima-media thickness; atherosclerosis; biomarkers
20.  Physical Activity Measured by Accelerometry and its Associations With Cardiac Structure and Vascular Function in Young and Middle‐Aged Adults 
Physical activity is associated with several health benefits, including lower cardiovascular disease risk. The independent influence of physical activity on cardiac and vascular function in the community, however, has been sparsely investigated.
Measures and Results
We related objective measures of moderate‐ to vigorous‐intensity physical activity (MVPA, assessed by accelerometry) to cardiac and vascular indices in 2376 participants of the Framingham Heart Study third generation cohort (54% women, mean age 47 years). Using multivariable regression models, we related MVPA to the following echocardiographic and vascular measures: left ventricular mass, left atrial and aortic root sizes, carotid–femoral pulse wave velocity, augmentation index, and forward pressure wave. Men and women engaged in MVPA 29.9±21.4 and 25.5±19.4 min/day, respectively. Higher values of MVPA (per 10‐minute increment) were associated with lower carotid–femoral pulse wave velocity (estimate −0.53 ms/m; P=0.006) and lower forward pressure wave (estimate −0.23 mm Hg; P=0.03) but were not associated with augmentation index (estimate 0.13%; P=0.25). MVPA was associated positively with loge left ventricular mass (estimate 0.006 loge [g/m2]; P=0.0003), left ventricular wall thickness (estimate 0.07 mm; P=0.0001), and left atrial dimension (estimate 0.10 mm; P=0.01). MVPA also tended to be positively associated with aortic root dimension (estimate 0.05 mm; P=0.052). Associations of MVPA with cardiovascular measures were similar, in general, for bouts lasting <10 versus ≥10 minutes.
In our community‐based sample, greater physical activity was associated with lower vascular stiffness but with higher echocardiographic left ventricular mass and left atrial size. These findings suggest complex relations of usual levels of physical activity and cardiovascular remodeling.
PMCID: PMC4392434  PMID: 25792127
echocardiography; epidemiology; physical activity; vascular measures
21.  Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization 
Arking, Dan E. | Pulit, Sara L. | Crotti, Lia | van der Harst, Pim | Munroe, Patricia B. | Koopmann, Tamara T. | Sotoodehnia, Nona | Rossin, Elizabeth J. | Morley, Michael | Wang, Xinchen | Johnson, Andrew D. | Lundby, Alicia | Gudbjartsson, Daníel F. | Noseworthy, Peter A. | Eijgelsheim, Mark | Bradford, Yuki | Tarasov, Kirill V. | Dörr, Marcus | Müller-Nurasyid, Martina | Lahtinen, Annukka M. | Nolte, Ilja M. | Smith, Albert Vernon | Bis, Joshua C. | Isaacs, Aaron | Newhouse, Stephen J. | Evans, Daniel S. | Post, Wendy S. | Waggott, Daryl | Lyytikäinen, Leo-Pekka | Hicks, Andrew A. | Eisele, Lewin | Ellinghaus, David | Hayward, Caroline | Navarro, Pau | Ulivi, Sheila | Tanaka, Toshiko | Tester, David J. | Chatel, Stéphanie | Gustafsson, Stefan | Kumari, Meena | Morris, Richard W. | Naluai, Åsa T. | Padmanabhan, Sandosh | Kluttig, Alexander | Strohmer, Bernhard | Panayiotou, Andrie G. | Torres, Maria | Knoflach, Michael | Hubacek, Jaroslav A. | Slowikowski, Kamil | Raychaudhuri, Soumya | Kumar, Runjun D. | Harris, Tamara B. | Launer, Lenore J. | Shuldiner, Alan R. | Alonso, Alvaro | Bader, Joel S. | Ehret, Georg | Huang, Hailiang | Kao, W.H. Linda | Strait, James B. | Macfarlane, Peter W. | Brown, Morris | Caulfield, Mark J. | Samani, Nilesh J. | Kronenberg, Florian | Willeit, Johann | Smith, J. Gustav | Greiser, Karin H. | zu Schwabedissen, Henriette Meyer | Werdan, Karl | Carella, Massimo | Zelante, Leopoldo | Heckbert, Susan R. | Psaty, Bruce M. | Rotter, Jerome I. | Kolcic, Ivana | Polašek, Ozren | Wright, Alan F. | Griffin, Maura | Daly, Mark J. | Arnar, David O. | Hólm, Hilma | Thorsteinsdottir, Unnur | Denny, Joshua C. | Roden, Dan M. | Zuvich, Rebecca L. | Emilsson, Valur | Plump, Andrew S. | Larson, Martin G. | O'Donnell, Christopher J. | Yin, Xiaoyan | Bobbo, Marco | D'Adamo, Adamo P. | Iorio, Annamaria | Sinagra, Gianfranco | Carracedo, Angel | Cummings, Steven R. | Nalls, Michael A. | Jula, Antti | Kontula, Kimmo K. | Marjamaa, Annukka | Oikarinen, Lasse | Perola, Markus | Porthan, Kimmo | Erbel, Raimund | Hoffmann, Per | Jöckel, Karl-Heinz | Kälsch, Hagen | Nöthen, Markus M. | consortium, HRGEN | den Hoed, Marcel | Loos, Ruth J.F. | Thelle, Dag S. | Gieger, Christian | Meitinger, Thomas | Perz, Siegfried | Peters, Annette | Prucha, Hanna | Sinner, Moritz F. | Waldenberger, Melanie | de Boer, Rudolf A. | Franke, Lude | van der Vleuten, Pieter A. | Beckmann, Britt Maria | Martens, Eimo | Bardai, Abdennasser | Hofman, Nynke | Wilde, Arthur A.M. | Behr, Elijah R. | Dalageorgou, Chrysoula | Giudicessi, John R. | Medeiros-Domingo, Argelia | Barc, Julien | Kyndt, Florence | Probst, Vincent | Ghidoni, Alice | Insolia, Roberto | Hamilton, Robert M. | Scherer, Stephen W. | Brandimarto, Jeffrey | Margulies, Kenneth | Moravec, Christine E. | Fabiola Del, Greco M. | Fuchsberger, Christian | O'Connell, Jeffrey R. | Lee, Wai K. | Watt, Graham C.M. | Campbell, Harry | Wild, Sarah H. | El Mokhtari, Nour E. | Frey, Norbert | Asselbergs, Folkert W. | Leach, Irene Mateo | Navis, Gerjan | van den Berg, Maarten P. | van Veldhuisen, Dirk J. | Kellis, Manolis | Krijthe, Bouwe P. | Franco, Oscar H. | Hofman, Albert | Kors, Jan A. | Uitterlinden, André G. | Witteman, Jacqueline C.M. | Kedenko, Lyudmyla | Lamina, Claudia | Oostra, Ben A. | Abecasis, Gonçalo R. | Lakatta, Edward G. | Mulas, Antonella | Orrú, Marco | Schlessinger, David | Uda, Manuela | Markus, Marcello R.P. | Völker, Uwe | Snieder, Harold | Spector, Timothy D. | Ärnlöv, Johan | Lind, Lars | Sundström, Johan | Syvänen, Ann-Christine | Kivimaki, Mika | Kähönen, Mika | Mononen, Nina | Raitakari, Olli T. | Viikari, Jorma S. | Adamkova, Vera | Kiechl, Stefan | Brion, Maria | Nicolaides, Andrew N. | Paulweber, Bernhard | Haerting, Johannes | Dominiczak, Anna F. | Nyberg, Fredrik | Whincup, Peter H. | Hingorani, Aroon | Schott, Jean-Jacques | Bezzina, Connie R. | Ingelsson, Erik | Ferrucci, Luigi | Gasparini, Paolo | Wilson, James F. | Rudan, Igor | Franke, Andre | Mühleisen, Thomas W. | Pramstaller, Peter P. | Lehtimäki, Terho J. | Paterson, Andrew D. | Parsa, Afshin | Liu, Yongmei | van Duijn, Cornelia | Siscovick, David S. | Gudnason, Vilmundur | Jamshidi, Yalda | Salomaa, Veikko | Felix, Stephan B. | Sanna, Serena | Ritchie, Marylyn D. | Stricker, Bruno H. | Stefansson, Kari | Boyer, Laurie A. | Cappola, Thomas P. | Olsen, Jesper V. | Lage, Kasper | Schwartz, Peter J. | Kääb, Stefan | Chakravarti, Aravinda | Ackerman, Michael J. | Pfeufer, Arne | de Bakker, Paul I.W. | Newton-Cheh, Christopher
Nature genetics  2014;46(8):826-836.
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD.
PMCID: PMC4124521  PMID: 24952745
genome-wide association study; QT interval; Long QT Syndrome; sudden cardiac death; myocardial repolarization; arrhythmias
22.  Relationship Among Circulating Inflammatory Proteins, Platelet Gene Expression, and Cardiovascular Risk 
Cardiovascular disease is a complex disorder influenced by interactions of genetic variants with environmental factors. However, there is no information from large community-based studies examining the relationship of circulating cell–specific RNA to inflammatory proteins. In light of the associations among inflammatory biomarkers, obesity, platelet function, and cardiovascular disease, we sought to examine the relationships of C-reactive protein (CRP) and interleukin-6 (IL-6) to the expression of key inflammatory transcripts in platelets.
Approach and Results
We quantified circulating levels of CRP and IL-6 in 1625 participants of the Framingham Heart Study (FHS) Offspring cohort examination 8 (mean age, 66.6±6.6 years; 46% men). We measured the expression of 15 relevant genes by high-throughput quantitative reverse transcriptase polymerase chain reaction from platelet-derived RNA and used multivariable regression to relate serum concentrations of CRP and IL-6 with gene expression. Levels of CRP and IL-6 were associated with 10 of the 15 platelet-derived inflammatory transcripts, ALOX5, CRP, IFIT1, IL6, PTGER2, S100A9, SELENBP1, TLR2, TLR4, and TNFRSF1B (P<0.001). Associations between platelet mRNA expression with CRP and IL-6 persisted after multivariable adjustment for potentially confounding factors. Six genes positively associated with CRP or IL-6 in the FHS sample were also upregulated in megakaryocytes in response to CRP or IL-6 exposure.
Our data highlight the strong connection between the circulating inflammatory biomarkers CRP and IL-6 and platelet gene expression, adjusting for cardiovascular disease risk factors. Our results also suggest that body weight may directly influence these associations.
PMCID: PMC4289138  PMID: 23968978
cardiovascular disease; inflammation; mRNA platelets
23.  Early Expression of Mitral Valve Prolapse in the Framingham Offspring: Phenotypic Spectrum 
Mitral valve prolapse (MVP) is a common disorder associated with mitral regurgitation (MR), endocarditis, heart failure and sudden death. In the familial context, prior studies have described non-diagnostic mitral valve morphologies (‘prodromal forms’ and ‘minimal superior displacement’ [MSD]) that may represent early expression of MVP in those genetically predisposed. Our objective was to explore the spectrum of MVP abnormalities in the community and compare their clinical and echocardiographic features.
Phenotypic heterogeneity of MVP was assessed by measuring annular diameter (D), leaflet displacement (Dis), thickness (T), anterior/posterior leaflet projections (A, P) onto the annulus, coaptation height (C or P/D), and MR jet height (JH) in a sample of 296 individuals of the Framingham Offspring Study who were identified as having MVP (n=77) or its prodromal form (N=11) or MSD (N=57), with 151 controls with no feature of MVP or its non-diagnostic forms.
The prodromal form did not meet diagnostic criteria but resembled fully diagnostic MVP with regards to D, T and JH (all p > 0.05); they were similar to individuals with posterior MVP with regard to leaflet asymmetry and coaptation height (p = 0.91). Compared to MSDs and controls, prodromals had greater C, T, D and JH (all p < 0.05). MSDs shared the posterior leaflet asymmetry with classic MVP, but their coaptation point was more posterior (C = 31% versus 42%, p<0.0001).
Non-diagnostic morphologies of MVP are observed in the community and share the common feature of posterior leaflet asymmetry with fully affected individuals. Prodromal morphology and MSD may represent early expressions of MVP and additional studies are warranted to elucidate the natural history of these phenotypes.
PMCID: PMC4239996  PMID: 24206636
mitral valve prolapse; echocardiography
24.  Relation between soluble ST2, GDF-15 and hsTnI and Incident Atrial Fibrillation 
American heart journal  2013;167(1):10.1016/j.ahj.2013.10.003.
We investigated whether circulating concentrations of soluble ST2, growth differentiation factor-15 (GDF-15), and high-sensitivity troponin I (hsTnI) are associated with incident atrial fibrillation (AF), and whether these biomarkers, improve current risk prediction models including AF risk factors, B-type natriuretic peptide (BNP) and C-reactive protein (CRP).
We studied the relation between soluble ST2, GDF-15, and hsTnI and development of AF in Framingham Heart Study participants without prevalent AF. We used Cox proportional hazard regression analysis to examine the relation of incident AF during a 10-year follow-up period with each biomarker. We adjusted for standard AF clinical risk factors, BNP, and CRP.
The mean age of the 3,217 participants was 59±10 years and 54% were women. During 10 years of follow-up, 242 participants developed AF. In age- and sex-adjusted models, GDF-15 and hsTnI were associated with risk of incident AF; however, after including the AF risk factors and BNP and CRP, only hsTnI was significantly associated with AF (hazard ratio per 1 standard deviation of loge hsTnI, 1.12; 95%CI, 1.00-1.26; P=0.045). The C-statistic of the base model including AF risk factors, BNP and CRP was 0.803 (95% CI 0.777–0.830), and did not improve by adding individual or all 3 biomarkers. None of the discrimination and reclassification statistics was significant compared to the base model.
In a community-based cohort, circulating hsTnI concentrations were associated with incident AF. None of the novel biomarkers evaluated improved AF risk discrimination or reclassification beyond standard clinical AF risk factors and biomarkers.
PMCID: PMC3884900  PMID: 24332149
atrial fibrillation; biomarker; risk factor
25.  Reproducibility of Speckle-Tracking Based Strain Measures of Left Ventricular Function in a Community-Based Study 
The reproducibility of echocardiographic measurements of myocardial strain, performed in a community-based setting, has not been reported previously.
We examined the reproducibility of left ventricular (LV) strain measurements in two samples of 20 participants each from the Offspring cohort of the Framingham Heart Study (mean age 63±9 years, 59% women). Two-dimensional speckle tracking-based measurements of global peak LV strain in systole were performed in the apical 4-chamber, apical 2-chamber, and mid-ventricular parasternal short-axis views.
Inter-observer intra-class correlation coefficients (ICC) were ≥0.84 for all global strain measurements, with average coefficients of variation (CV) of ≤4% for global longitudinal and circumferential strain, and <8% for global transverse and radial strain. For LV strain measurements performed in each of the 3 views, intra-observer ICCs were ≥0.91 among time points spanning a total 8-month period. The average CVs were <6% for global longitudinal and circumferential strain, and <9% for global transverse and radial strain. Inter- and intra-observer reproducibility findings were similar in analyses adjusting for frame rate.
We observed excellent reproducibility of global longitudinal and circumferential strain measurements and very good reproducibility of global transverse and radial strain measurements. Taken together, our findings demonstrate the reproducibility of performing echocardiographic strain measurements in a large, epidemiologic community-based setting.
PMCID: PMC3812381  PMID: 23953701

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