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1.  Low-density-lipoprotein cholesterol concentrations and risk of incident diabetes: epidemiological and genetic insights from the Framingham Heart Study 
Diabetologia  2015;58(12):2774-2780.
Aims/hypothesis
Statins and niacin (nicotinic acid) reduce circulating LDL-cholesterol (LDLC) levels by different mechanisms. Yet, both increase the risk of diabetes mellitus. Our objective was to relate blood LDL-C concentrations and a genetic risk score (GRS) for LDLC to the risk of incident diabetes in individuals not treated with lipid-modifying therapy.
Methods
We evaluated participants of the Framingham Heart Study who attended any of Offspring cohort examination cycles 3–8 and Third Generation cohort examination cycle 1 (N =14,120 person-observations, 6,011 unique individuals; mean age 50 ± 11 years, 56% women), who were not treated with lipid-modifying or antihypertensive medications and who were free from cardiovascular disease at baseline. Incident diabetes was assessed at the next examination.
Results
The GRS was significantly associated with LDL-C concentrations (sex- and age-adjusted estimated influence 0.24, p < 0.0001). On follow-up (mean 4.5 ± 1.5 years), 312 individuals (2.2%) developed new-onset diabetes. In multivariable models, a higher LDL-C concentration was associated with lower risk of diabetes (OR per SD increment 0.81, 95% CI 0.70, 0.93, p = 0.004). The GRS was associated with incident diabetes in similar direction and of comparable magnitude (OR per SD increment 0.85, 95% CI 0.76, 0.96, p = 0.009).
Conclusions/interpretation
Among individuals not treated with lipid-modifying therapy low LDL-C concentrations were associated with increased diabetes risk. These observations may contribute to our understanding of why lipid-lowering treatment may cause diabetes in some individuals. Additional studies are warranted to elucidate the molecular mechanisms underlying our observations.
doi:10.1007/s00125-015-3762-x
PMCID: PMC4631796  PMID: 26409460
Low-density lipoprotein concentrations; Diabetes risk; Mendelian randomisation; Untreated individuals
2.  Cohort Profile: The Framingham Heart Study (FHS): overview of milestones in cardiovascular epidemiology 
The Framingham Heart Study (FHS) has conducted seminal research defining cardiovascular disease (CVD) risk factors and fundamentally shaping public health guidelines for CVD prevention over the past five decades. The success of the Original Cohort, initiated in 1948, paved the way for further epidemiological research in preventive cardiology. Due to the keen observations suggesting the role of shared familial factors in the development of CVD, in 1971 the FHS began enroling the second generation cohort, comprising the children of the Original Cohort and the spouses of the children. In 2002, the third generation cohort, comprising the grandchildren of the Original Cohort, was initiated to additionally explore genetic contributions to CVD in greater depth. Additionally, because of the predominance of White individuals of European descent in the three generations of FHS participants noted above, the Heart Study enrolled the OMNI1 and OMNI2 cohorts in 1994 and 2003, respectively, aimed to reflect the current greater racial and ethnic diversity of the town of Framingham. All FHS cohorts have been examined approximately every 2–4 years since the initiation of the study. At these periodic Heart Study examinations, we obtain a medical history and perform a cardiovascular-focused physical examination, 12-lead electrocardiography, blood and urine samples testing and other cardiovascular imaging studies reflecting subclinical disease burden.
The FHS has continually evolved along the cutting edge of cardiovascular science and epidemiological research since its inception. Participant studies now additionally include study of cardiovascular imaging, serum and urine biomarkers, genetics/genomics, proteomics, metabolomics and social networks. Numerous ancillary studies have been established, expanding the phenotypes to encompass multiple organ systems including the lungs, brain, bone and fat depots, among others. Whereas the FHS was originally conceived and designed to study the epidemiology of cardiovascular disease, it has evolved over the years with staggering expanded breadth and depth that have far greater implications in the study of the epidemiology of a wide spectrum of human diseases. The FHS welcomes research collaborations using existing or new collection of data. Detailed information regarding the procedures for research application submission and review are available at [http://www.framinghamheartstudy.org/researchers/index.php].
doi:10.1093/ije/dyv337
PMCID: PMC5156338  PMID: 26705418
3.  Development and Validation of Risk Prediction Models for Cardiovascular Events in Black Adults 
JAMA cardiology  2016;1(1):15-25.
IMPORTANCE
Cardiovascular risk assessment is a fundamental component of prevention of cardiovascular disease (CVD). However, commonly used prediction models have been formulated in primarily or exclusively white populations. Whether risk assessment in black adults is dissimilar to that in white adults is uncertain.
OBJECTIVES
To develop and validate risk prediction models for CVD incidence in black adults, incorporating standard risk factors, biomarkers, and subclinical disease.
DESIGN, SETTING, AND PARTICIPANTS
The Jackson Heart Study (JHS), a longitudinal community-based study of 5301 black adults in Jackson, Mississippi. Inclusive study dates were the date of a participant’s first visit (September 2000 to March 2004) to December 31, 2011. The median (75th percentile) follow-up was 9.1 (9.7) years. The dates of the analysis were August 2013 to May 2015. Measurements included standard risk factors, including age, sex, body mass index, systolic and diastolic blood pressure, ratio of fasting total cholesterol to high-density lipoprotein cholesterol, estimated glomerular filtration rate, antihypertensive therapy, diabetes mellitus, and smoking; blood biomarkers; and subclinical disease measures, including ankle-brachial index, carotid intimal-medial thickness, and echocardiographic left ventricular hypertrophy and systolic dysfunction.
MAIN OUTCOMES AND MEASURES
Incident CVD event was defined as the first occurrence of myocardial infarction, coronary heart disease death, congestive heart failure, stroke, incident angina, or intermittent claudication. Model performance was compared with the American College of Cardiology/American Heart Association (ACC/AHA) CVD risk algorithm and the Framingham Risk Score (FHS) refitted to the JHS data and evaluated in the Atherosclerosis Risk in Communities (ARIC) and Multi-Ethnic Study of Atherosclerosis cohorts.
RESULTS
The study cohort comprised 3689 participants with mean (SD) age at baseline was 53 (11) years, and 64.8% (n = 2390) were female. Over a median of 9.1 years, 270 participants (166 women) experienced a first CVD event. A simple combination of standard CVD risk factors, B-type natriuretic peptide, and ankle-brachial index (model 6) yielded modest improvement over a model without B-type natriuretic peptide and ankle-brachial index (C statistic, 0.79; 95% CI, 0.75–0.83 [relative integrated discrimination improvement, 0.22; 95% CI, 0.15–0.30]). However, the reclassification improvement was not substantially different between model 6 and the ACC/AHA CVD Pooled Cohort risk equations or between model 6 and the FHS. The models discriminated reasonably well in the ARIC and Multi-Ethnic Study of Atherosclerosis data (C statistic range, 0.70–0.77).
CONCLUSIONS AND RELEVANCE
Our findings using the JHS data in the present study are valuable because they confirm that current FHS and ACC/AHA risk algorithms work well in black individuals and are not easily improved on. A unique risk calculator for black adults may not be necessary.
doi:10.1001/jamacardio.2015.0300
PMCID: PMC5115626  PMID: 27437649
4.  Lipophilic Statins and Aldosterone Secretion: A Bridge Too Far? 
Circulation  2015;132(19):1783-1785.
doi:10.1161/CIRCULATIONAHA.115.019130
PMCID: PMC4974093  PMID: 26432672
Editorial; statin; aldosterone; mineralocorticoids
6.  Genome-wide Association and Functional Studies Identify a Role for IGFBP3 in Hip Osteoarthritis 
Annals of the rheumatic diseases  2014;74(10):1861-1867.
Objectives
To identify genetic associations with hip osteoarthritis (HOA), we performed a meta-analysis of genome-wide association studies (GWAS) of HOA.
Methods
The GWAS meta-analysis included approximately 2.5 million imputed HapMap single nucleotide polymorphisms (SNPs). HOA cases and controls defined radiographically and by total hip replacement were selected from the Osteoporotic Fractures in Men (MrOS) Study and the Study of Osteoporotic Fractures (SOF) (654 cases and 4697 controls, combined). Replication of genome-wide significant SNP associations (P-value ≤ 5x10−8) was examined in five studies (3243 cases and 6891 controls, combined). Functional studies were performed using in vitro models of chondrogenesis and osteogenesis.
Results
The A allele of rs788748, located 65 kb upstream of the IGFBP3 gene, was associated with lower HOA odds at the genome-wide significance level in the discovery stage (OR = 0.71, P-value = 2x10−8). The association replicated in five studies (OR = 0.92, P-value = 0.020), but the joint analysis of discovery and replication results was not genome-wide significant (P-value = 1x10−6). In separate study populations, the rs788748 A allele was also associated with lower circulating IGFBP3 protein levels (P-value = 4x10−13), suggesting that this SNP or a variant in linkage disequilibrium (LD) could be an IGFBP3 regulatory variant. Results from functional studies were consistent with association results. Chondrocyte hypertrophy, a deleterious event in OA pathogenesis, was largely prevented upon IGFBP3 knockdown in chondrocytes. Furthermore, IGFBP3 overexpression induced cartilage catabolism and osteogenic differentiation.
Conclusions
Results from GWAS and functional studies provided suggestive links between IGFBP3 and HOA.
doi:10.1136/annrheumdis-2013-205020
PMCID: PMC4449305  PMID: 24928840
Osteoarthritis of hip; genome-wide association study; functional study; chondrogenesis; IGFBP3
7.  Serum leptin levels and the risk of stroke: The Framingham Study 
Background and Purpose
Leptin is a major adipokine that regulates weight balance and energy homeostasis. There is inconsistent evidence linking circulating leptin levels to risk of stroke. We tested the hypothesis that leptin levels are associated with risk of incident stroke in an elderly community-based sample.
Methods
Serum leptin levels were assayed in 757 stroke-free individuals (mean age 79 years, 62% women) from the Framingham Original cohort at the 22nd examination cycle (1990–1994). Incidence of all-stroke and ischemic stroke were prospectively ascertained.
Results
During a mean follow-up of 10 years, 119 individuals developed stroke (99 ischemic stroke). In multivariable Cox regression models, log-leptin levels were not associated with incidence of all-stroke or ischemic stroke (hazard ratios[HR] per standard deviation(SD) increment in log-leptin 0.9 [0.73–1.09] and 0.89 [0.72–1.11], respectively). The results were suggestive for potential effect modification by waist-hip ratio(WHR) for the association between leptin and stroke (P=0.03). Adjusting for age, sex and established stroke risk factors, analysis stratified by WHR quartiles revealed a lower incidence of first-ever all-stroke and ischemic stroke associated with higher leptin levels among only subjects in the top WHR quartile (HR, 0.64 [0.43, 0.95] versus 0.98 [0.77, 1.25], for incident all-stroke and 0.61 [0.39, 0.95] versus 0.96 [0.74, 1.26] for ischemic stroke).
Conclusions
Leptin levels were not directly related to risk of incident stroke overall but there was an inverse association with stroke in the top WHR quartile. Further investigations are required to confirm these findings and explore possible mechanisms for the observed association.
doi:10.1161/STROKEAHA.115.009463
PMCID: PMC4589501  PMID: 26337973
Leptin; Adipokines; Risk; Stroke; Obesity
8.  Genomewide meta‐analysis identifies loci associated with IGF‐I and IGFBP‐3 levels with impact on age‐related traits 
Teumer, Alexander | Qi, Qibin | Nethander, Maria | Aschard, Hugues | Bandinelli, Stefania | Beekman, Marian | Berndt, Sonja I. | Bidlingmaier, Martin | Broer, Linda | Cappola, Anne | Ceda, Gian Paolo | Chanock, Stephen | Chen, Ming‐Huei | Chen, Tai C. | Chen, Yii‐Der Ida | Chung, Jonathan | Del Greco Miglianico, Fabiola | Eriksson, Joel | Ferrucci, Luigi | Friedrich, Nele | Gnewuch, Carsten | Goodarzi, Mark O. | Grarup, Niels | Guo, Tingwei | Hammer, Elke | Hayes, Richard B. | Hicks, Andrew A. | Hofman, Albert | Houwing‐Duistermaat, Jeanine J. | Hu, Frank | Hunter, David J. | Husemoen, Lise L. | Isaacs, Aaron | Jacobs, Kevin B. | Janssen, Joop A. M. J. L. | Jansson, John‐Olov | Jehmlich, Nico | Johnson, Simon | Juul, Anders | Karlsson, Magnus | Kilpelainen, Tuomas O. | Kovacs, Peter | Kraft, Peter | Li, Chao | Linneberg, Allan | Liu, Yongmei | Loos, Ruth J. F. | Lorentzon, Mattias | Lu, Yingchang | Maggio, Marcello | Magi, Reedik | Meigs, James | Mellström, Dan | Nauck, Matthias | Newman, Anne B. | Pollak, Michael N. | Pramstaller, Peter P. | Prokopenko, Inga | Psaty, Bruce M. | Reincke, Martin | Rimm, Eric B. | Rotter, Jerome I. | Saint Pierre, Aude | Schurmann, Claudia | Seshadri, Sudha | Sjögren, Klara | Slagboom, P. Eline | Strickler, Howard D. | Stumvoll, Michael | Suh, Yousin | Sun, Qi | Zhang, Cuilin | Svensson, Johan | Tanaka, Toshiko | Tare, Archana | Tönjes, Anke | Uh, Hae‐Won | van Duijn, Cornelia M. | van Heemst, Diana | Vandenput, Liesbeth | Vasan, Ramachandran S. | Völker, Uwe | Willems, Sara M. | Ohlsson, Claes | Wallaschofski, Henri | Kaplan, Robert C.
Aging Cell  2016;15(5):811-824.
Summary
The growth hormone/insulin‐like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF‐related proteins including IGF‐I and IGF‐binding protein‐3 (IGFBP‐3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF‐I and IGFBP‐3 concentrations (IGF1, IGFBP3,GCKR,TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype–phenotype associations between men and women, were found only for associations of IGFBP‐3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF‐I and IGFBP‐3 concentrations. The IGF‐I‐decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity‐associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF‐I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF‐I‐ and IGFBP‐3‐associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF‐I and IGFBP‐3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity‐associated loci.
doi:10.1111/acel.12490
PMCID: PMC5013013  PMID: 27329260
aging; genomewide association study; growth hormone axis; IGF‐I; IGFBP‐3; longevity
9.  A Global View of the Relationships between the Main Behavioural and Clinical Cardiovascular Risk Factors in the GAZEL Prospective Cohort 
PLoS ONE  2016;11(9):e0162386.
Although it has been recognized for a long time that the predisposition to cardiovascular diseases (CVD) is determined by many risk factors and despite the common use of algorithms incorporating several of these factors to predict the overall risk, there has yet been no global description of the complex way in which CVD risk factors interact with each other. This is the aim of the present study which investigated all existing relationships between the main CVD risk factors in a well-characterized occupational cohort. Prospective associations between 12 behavioural and clinical risk factors (gender, age, parental history of CVD, non-moderate alcohol consumption, smoking, physical inactivity, obesity, hypertension, dyslipidemia, diabetes, sleep disorder, depression) were systematically tested using Cox regression in 10,736 middle-aged individuals free of CVD at baseline and followed over 20 years. In addition to independently predicting CVD risk (HRs from 1.18 to 1.97 in multivariable models), these factors form a vast network of associations where each factor predicts, and/or is predicted by, several other factors (n = 47 with p<0.05, n = 37 with p<0.01, n = 28 with p<0.001, n = 22 with p<0.0001). Both the number of factors associated with a given factor (1 to 9) and the strength of the associations (HRs from 1.10 to 6.12 in multivariable models) are very variable, suggesting that all the factors do not have the same influence within this network. These results show that there is a remarkably extensive network of relationships between the main CVD risk factors which may have not been sufficiently taken into account, notably in preventive strategies aiming to lower CVD risk.
doi:10.1371/journal.pone.0162386
PMCID: PMC5012694  PMID: 27598908
10.  Preventing Heart Failure: The Role of Physical Activity 
Current opinion in cardiology  2015;30(5):543-550.
Purpose of review
Heart failure prevention is an important public health goal. Increased physical activity and exercise may help to prevent heart failure, as they are associated with reduced heart failure incidence and potentially act through a variety of mechanisms to slow disease progression.
Recent findings
Increased physical activity, higher cardiorespiratory fitness, and lower sedentary time are associated with reduced heart failure incidence. These associations are consistent for occurrence of both heart failure with preserved versus reduced ejection fraction, the common subphenotypes of the condition. Physiologic cardiac and vascular remodeling occur across the normal range of physical activity in the community, and regular exercise (4–5 sessions per week) is necessary to mitigate age-associated reductions in ventricular compliance and cardiac mass.
Summary
Greater physical activity, lesser sedentary time and improved cardiorespiratory fitness are associated with reductions in heart failure risk. Various mechanisms may explain these findings including: reducing the prevalence of standard and novel cardiovascular risk factors, inhibiting pathologic cardiovascular remodeling, promoting physiologic remodeling, and improving cardiac, neurohormonal, skeletal muscle, pulmonary, renal, and vascular performance. Future research is needed to elucidate the optimal timing, duration, and modality of physical activity and exercise training necessary to prevent the development of heart failure.
doi:10.1097/HCO.0000000000000206
PMCID: PMC4615715  PMID: 26154074
heart failure; physical activity; exercise; remodeling; prevention
11.  Associations of Circulating GDF-15 and ST2 concentrations with Subclinical Vascular Brain Injury and Incident Stroke 
Background and Purpose
Growth differentiation factor-15 (GDF-15) and soluble (s)ST2 are markers of cardiac and vascular stress. We investigated the associations between circulating concentrations of these biomarkers and incident stroke and subclinical vascular brain injury in a sample from the Framingham Offspring cohort.
Methods
We followed 3374 stroke- and dementia-free individuals (mean age 59.0±9.7 years, 53% women) attending the Framingham Offspring 6th examination cycle 11.8±3.0 years for incident stroke. A subsample of 2463 individuals underwent brain magnetic resonance imaging and neuropsychological testing approximately 4.0±1.7 years after the 6th examination.
Results
After adjustment for traditional cardiovascular risk factors, B-type natriuretic peptide, high-sensitivity C-reactive protein, and urine albumin levels, higher stress biomarker levels were associated cross-sectionally with lower brain volumes (βs for intracranial volume comparing 4rth [Q4] vs. 1st biomarker [Q1] quartiles −0.71% for GDF-15, p=0.002, and 0.47% for sST2, p=0.02) and worse performance on the visual reproduction test (βs for Q4 vs. Q1=−0.62 for GDF-15, p=0.009, and −0.40 for sST2, p=0.04). Higher GDF-15 concentrations were also associated with greater log-transformed white-matter hyperintensity volumes (β for Q4 vs. Q1=0.19, p=0.01). Prospectively, a total of 203 (6%) individuals developed incident stroke/transient ischemic attack (TIA) during follow-up. After multivariable adjustment, sST2 remained significantly associated with stroke/TIA, hazard ratio for Q4 vs. Q1 of 1.76, 95% confidence interval 1.06–2.92, p=0.03.
Conclusions
Circulating GDF-15 and sST2 are associated with subclinical brain injury and cognitive impairment. Higher sST2 concentrations are also associated with incident stroke, suggesting potential links between cardiac stress biomarkers and brain injury.
doi:10.1161/STROKEAHA.115.009026
PMCID: PMC4550531  PMID: 26219649
12.  Alcohol Consumption, Left Atrial Diameter, and Atrial Fibrillation 
Background
Alcohol consumption has been associated with atrial fibrillation (AF) in several epidemiologic studies, but the underlying mechanisms remain unknown. We sought to test the hypothesis that an atrial myopathy, manifested by echocardiographic left atrial enlargement, explains the association between chronic alcohol use and AF.
Methods and Results
We evaluated the relationship between cumulative alcohol consumption and risk of incident AF in 5220 Offspring and Original Framingham Heart Study participants (mean age 56.3 years, 54% women) with echocardiographic left atrial size measurements. The incidence of AF was 8.4 per 1000 person‐years, with 1088 incident AF cases occurring over a median 6.0 years (25th–75th percentiles 4.0–8.7 years) of follow‐up. After multivariable adjustment for potential confounders, every additional 10 g of alcohol per day (just under 1 drink per day) was associated with a 0.16 mm (95% CI, 0.10–0.21 mm) larger left atrial dimension. Also in multivariable adjusted analysis, every 10 g per day of alcohol consumed was associated with a 5% higher risk of developing new‐onset AF (hazard ratio, 1.05; 95% CI, 1.01–1.09). An estimated 24% (95% CI, 8–75) of the association between alcohol and AF risk was explained by left atrial enlargement.
Conclusions
Our study of a large, community‐based sample identified alcohol consumption as a predictor of left atrial enlargement and subsequent incident AF. Left atrial enlargement may be an intermediate phenotype along the causal pathway linking long‐term alcohol consumption to AF.
doi:10.1161/JAHA.116.004060
PMCID: PMC5079048  PMID: 27628571
alcohol; atrial fibrillation; echocardiography; epidemiology; left atrium; Atrial Fibrillation; Epidemiology; Remodeling
13.  Genetic variants primarily associated with type 2 diabetes are related to coronary artery disease risk 
Atherosclerosis  2015;241(2):419-426.
Background
The mechanisms underlying the association between diabetes and coronary artery disease (CAD) risk are unclear. We aimed to assess this association by studying genetic variants that have been shown to associate with type 2 diabetes (T2DM). If the association between diabetes and CAD is causal, we expected to observe an association of these variants with CAD as well.
Methods and Results
We studied all genetic variants currently known to be associated with T2DM at a genome-wide significant level (p<5*10−8) in CARDIoGRAM, a genome-wide data-set of CAD including 22,233 CAD cases and 64,762 controls. Out of the 44 published T2DM SNPs 10 were significantly associated with CAD in CARDIoGRAM (OR>1, p<0.05), more than expected by chance (p=5.0*10−5). Considering all 44 SNPs, the average CAD risk observed per individual T2DM risk allele was 1.0076 (95% confidence interval (CI), 0.9973–1.0180). Such average risk increase was significantly lower than the increase expected based on i) the published effects of the SNPs on T2DM risk and ii) the effect of T2DM on CAD risk as observed in the Framingham Heart Study, which suggested a risk of 1.067 per allele (p=7.2*10−10 vs. the observed effect). Studying two risk scores based on risk alleles of the diabetes SNPs, one score using individual level data in 9856 subjects, and the second score on average effects of reported beta-coefficients from the entire CARDIoGRAM data-set, we again observed a significant - yet smaller than expected - association with CAD.
Conclusions
Our data indicate that an association between type 2 diabetes related SNPs and CAD exists. However, the effects on CAD risk appear to be by far lower than what would be expected based on the effects of risk alleles on T2DM and the effect of T2DM on CAD in the epidemiological setting.
doi:10.1016/j.atherosclerosis.2015.05.033
PMCID: PMC4536952  PMID: 26074316
genome-wide association; cardiovascular disease; coronary artery disease; SNP; type-2 diabetes
14.  An exome array study of the plasma metabolome 
Nature Communications  2016;7:12360.
The study of rare variants may enhance our understanding of the genetic determinants of the metabolome. Here, we analyze the association between 217 plasma metabolites and exome variants on the Illumina HumanExome Beadchip in 2,076 participants in the Framingham Heart Study, with replication in 1,528 participants of the Atherosclerosis Risk in Communities Study. We identify an association between GMPS and xanthosine using single variant analysis and associations between HAL and histidine, PAH and phenylalanine, and UPB1 and ureidopropionate using gene-based tests (P<5 × 10−8 in meta-analysis), highlighting novel coding variants that may underlie inborn errors of metabolism. Further, we show how an examination of variants across the spectrum of allele frequency highlights independent association signals at select loci and generates a more integrated view of metabolite heritability. These studies build on prior metabolomics genome wide association studies to provide a more complete picture of the genetic architecture of the plasma metabolome.
Several GWAS have identified many common variants associated with blood metabolites. Here, the authors use an exome array to identify low frequency, potentially functional variants that impact human metabolism.
doi:10.1038/ncomms12360
PMCID: PMC4962516  PMID: 27453504
15.  Fifty-Year Trends in Atrial Fibrillation Prevalence, Incidence, Risk Factors, and Mortality in the Community 
Lancet (London, England)  2015;386(9989):154-162.
Summary
Background
Comprehensive long-term data on atrial fibrillation trends in men and women are scant.
Methods
We investigated trends in atrial fibrillation incidence, prevalence, and risk factors, and in stroke and mortality following its onset in Framingham Heart Study participants (n=9511) from 1958 to 2007. To accommodate sex differences in atrial fibrillation risk factors and disease manifestations, sex-stratified analyses were performed.
Findings
During 50 years of observation (202,417 person-years), there were 1,544 new-onset atrial fibrillation cases (46.8% women). We observed about a fourfold increase in the age-adjusted prevalence and more than a tripling in age-adjusted incidence of atrial fibrillation (prevalence 20.4 versus 96.2 per 1000 person-years in men; 13.7 versus 49.4 in women; incidence rates in first versus last decade 3.7 versus 13.4 per 1000 person-years in men; 2.5 versus 8.6 in women, ptrend<0.0001).
For atrial fibrillation diagnosed by ECG during routine Framingham examinations, age-adjusted prevalence increased (12.6versus 25.7 per 1000 person-years in men; 8.1 versus 11.8 in women, ptrend<0.0001). The age-adjusted incidence increased, but did not achieve statistical significance. Although the prevalence of most risk factors changed over time, their associated hazards for atrial fibrillation changed little. Multivariable-adjusted proportional hazards models revealed a 73.5% decline in stroke and a 25.4% decline in mortality following atrial fibrillation onset (ptrend=0.0001, ptrend=0.003, respectively).
Interpretation
Our data suggest that observed trends of increased incidence of atrial fibrillation in the community were partially due to enhanced surveillance. Stroke occurrence and mortality following atrial fibrillation onset declined over the decades, and prevalence increased approximately fourfold. The hazards for atrial fibrillation risk factors remained fairly constant. Our data indicate a need for measures to enhance early detection of atrial fibrillation through increased awareness coupled with targeted screening programs, and risk factor-specific prevention.
doi:10.1016/S0140-6736(14)61774-8
PMCID: PMC4553037  PMID: 25960110
atrial fibrillation; secular trends; mortality
16.  Filtration Markers as Predictors of ESRD and Mortality in Southwestern American Indians With Type 2 Diabetes 
Background
A growing number of serum filtration markers are associated with mortality and end-stage renal disease (ESRD) in adults. Whether β-trace protein (BTP) and β2-microglobulin (B2M) are associated with these outcomes in adults with type 2 diabetes is not known.
Study Design
Longitudinal cohort study.
Setting & Participants
250 Pima Indians with type 2 diabetes (69% women; mean age, 42 years; mean diabetes duration, 11 years).
Predictors
Serum BTP, B2M, and glomerular filtration rate measured by iothalamate clearance (mGFR) or estimated using creatinine (eGFRcr) or cystatin C (eGFRcys).
Outcomes & Measurements
Incident ESRD and all-cause mortality through December 2013. HRs were reported per interquartile range decrease of the inverse of BTP and B2M (1/BTP and 1/B2M) using Cox regression. Improvement in risk prediction with the addition of BTP or B2M to established markers (eGFRcys with mGFR or eGFRcr) was evaluated using C-statistics, continuous net reclassification improvement (NRI), and relative integrated discrimination improvement (rIDI).
Results
During median follow-up of 14 years, 69 participants developed ESRD and 95 died. Both novel markers were associated with ESRD in multivariable models. BTP remained statistically significant after further adjustment for mGFR (1/BTP, 1.53 [95% CI, 1.01-2.30]; 1/B2M, 1.54 [95% CI, 0.98-2.42]). B2M was associated with mortality in multivariable models and after further adjustment for mGFR (HR, 2.12; 95% CI, 1.38-3.26). The addition of B2M to established markers increased the C statistic for mortality but only weakly when assessed by either continuous NRI or rIDI; none were improved for ESRD by the addition of these markers.
Limitations
Small sample size, single measures of markers.
Conclusions
In Pima Indians with type 2 diabetes, BTP, and to a lesser extent B2M, was associated with ESRD. B2M was associated with mortality after adjustment for traditional risk factors and established filtration markers. Further studies are warranted to confirm whether inclusion of B2M in a multi-marker approach leads to improved risk prediction for mortality in this population..
doi:10.1053/j.ajkd.2015.01.013
PMCID: PMC4485524  PMID: 25773485
Beta-trace protein (BTP); beta-2 microglobulin (B2M); end-stage renal disease (ESRD); type 2 diabetes mellitus; diabetic kidney failure; mortality; filtration markers; glomerular filtration rate (GFR); kidney function; Pima Indians; CKD Biomarkers Consortium
17.  Plasma Fibroblast Growth Factor 23: Clinical Correlates and Association With Cardiovascular Disease and Mortality in the Framingham Heart Study 
Background
Fibroblast growth factor 23 (FGF23) is emerging as a novel biomarker of bone metabolism, chronic kidney disease, and cardiovascular disease (CVD). However, its clinical correlates and potential predictive role in a community‐based setting are incompletely understood.
Methods and Results
We evaluated participants of the Framingham Heart Study (seventh examination cycle of the Offspring cohort plus second examination cycle of the multiethnic Omni cohort) to identify clinical correlates of plasma FGF23 (N=3236) and examine its cross‐sectional association with vascular function (N=2209), and longitudinal association with 10‐year incidence of CVD (N=2823), and all‐cause mortality (N=3223).
Circulating FGF23 concentrations were positively related to African‐American and Asian ethnicity, waist circumference, current smoking, serum glucose, history of CVD, and antihypertensive medication use; and negatively related to male sex, hormone replacement therapy, and estimated glomerular filtration rate. Multivariable‐adjusted cross‐sectional analyses showed no consistent association of FGF23 with vascular function measures. During a median follow‐up time of 10.8 years, 347 incident CVD events and 412 deaths occurred. Multivariable‐adjusted Cox regression models revealed a positive association of FGF23 with all‐cause mortality (hazard ratio [HR] per SD increase, 1.31; 95% CI, 1.20–1.42), but not with incident CVD (HR per SD increase, 1.05; 95% CI, 0.94–1.17).
Conclusions
In our large, community‐based sample, FGF23 was associated with mortality risk, but not with vascular function or incident CVD.
doi:10.1161/JAHA.116.003486
PMCID: PMC5015386  PMID: 27385427
cardiovascular disease risk factors; epidemiology; metabolism; mineral; Epidemiology; Risk Factors
18.  Association of Serum Vitamin D with the Risk of Incident Dementia and Subclinical Indices of Brain Aging: The Framingham Heart Study 
Background
Identifying nutrition- and lifestyle-based risk factors for cognitive impairment and dementia may aid future primary prevention efforts.
Objective
We aimed to examine the association of serum vitamin D levels with incident all-cause dementia, clinically characterized Alzheimer’s disease (AD), MRI markers of brain aging, and neuropsychological function.
Methods
Framingham Heart Study participants had baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations measured between 1986 and 2001. Vitamin D status was considered both as a continuous variable and dichotomized as deficient (<10 ng/mL), or at the cohort-specific 20th and 80th percentiles. Vitamin D was related to the 9-year risk of incident dementia (n= 1663), multiple neuropsychological tests (n= 1291) and MRI markers of brain volume, white matter hyperintensities and silent cerebral infarcts (n = 1139).
Results
In adjusted models, participants with vitamin D deficiency (n = 104, 8% of the cognitive sample) displayed poorer performance on Trail Making B-A (β = −0.03 to −0.05 ±0.02) and the Hooper Visual Organization Test (β = −0.09 to −0.12 ±0.05), indicating poorer executive function, processing speed, and visuo-perceptual skills. These associations remained when vitamin D was examined as a continuous variable or dichotomized at the cohort specific 20th percentile. Vitamin D deficiency was also associated with lower hippocampal volumes (β = −0.01 ±0.01) but not total brain volume, white matter hyperintensities, or silent brain infarcts. No association was found between vitamin D deficiency and incident all-cause dementia or clinically characterized AD.
Conclusions
In this large community-based sample, low 25(OH)D concentrations were associated with smaller hippocampal volume and poorer neuropsychological function.
doi:10.3233/JAD-150991
PMCID: PMC4911705  PMID: 26890771
Alzheimer’s disease; brain; dementia; diet; lifestyle; magnetic resonance imaging; neuropsychology; nutritional status; risk factors; vitamin D
19.  Endothelial function, arterial stiffness, and adherence to the 2010 Dietary Guidelines for Americans: a cross-sectional analysis 
The British journal of nutrition  2015;113(11):1773-1781.
Endothelial dysfunction and arterial stiffness are early predictors of cardiovascular disease. Intervention studies suggest that diet is related to vascular health, but most prior studies tested individual foods or nutrients and relied on small samples of younger adults. The purpose of this study was to examine relations between adherence to the 2010 Dietary Guidelines for Americans and vascular health in a large, cross-sectional analysis. In 5887 adults in the Framingham Heart Study Offspring and Third Generation cohorts, diet quality was quantified with the 2010 Dietary Guidelines for Americans Index (DGAI-2010). Endothelial function was assessed via brachial artery ultrasound and arterial stiffness via arterial tonometry. In age-, sex-, and cohort-adjusted analyses, higher DGAI-2010 score (greater adherence) was modestly associated with lower resting flow velocity, hyperemic response, mean arterial pressure, carotid-femoral pulse wave velocity, and augmentation index, but not associated with resting arterial diameter or flow-mediated dilation. In multivariable models adjusting for cardiovascular risk factors, only the association of higher DGAI-2010 with lower baseline flow and augmentation index persisted (β=−0.002, P=0.003 and β=−0.05 ± 0.02, P<0.001, respectively). Age-stratified multivariate-adjusted analyses suggested that the relation of higher DGAI-2010 scores with lower mean arterial pressure, pulse wave velocity, and augmentation index was more pronounced among adults younger than 50 years. Better adherence to the 2010 Dietary Guidelines for Americans, particularly in younger adults, is associated with lower peripheral blood flow velocity and arterial wave reflection but not flow-mediated dilation. Our results suggest a link between adherence to the Dietary Guidelines and favorable vascular health.
doi:10.1017/S0007114515000859
PMCID: PMC4466070  PMID: 25885520
endothelial function; arterial stiffness; Dietary Guidelines for Americans; Framingham Heart Study
20.  Red Blood Cell Fatty Acids and Biomarkers of Inflammation: A Cross-sectional Study in a Community-based Cohort 
Atherosclerosis  2015;240(2):431-436.
Introduction
Inflammation and inflammatory biomarkers have emerged as integral components and predictors of incident cardiovascular (CV) disease. Omega-3 fatty acids, particularly eicosapentaenoic and docosahexaenoic acids (EPA and DHA) have anti-inflammatory properties, and have been variably associated with lower blood pressure, favorable blood lipid changes, and reduced CV events.
Methods and Results
We examined the cross-sectional association of red blood cell (RBC) fatty acids, representative of body membrane fatty acid composition, with 10 biomarkers active in multiple inflammatory pathways in 2724 participants (mean age 66±9 years, 54% women, 8% minorities) from the Framingham Offspring and minority Omni Cohorts. . After multivariable adjustment, the RBC EPA and DHA content was inversely correlated (all P≤0.001) with 8 markers of inflammation, receptors, or pathways: urinary isoprostanes (r=−0.16); and soluble interleukin-6 (r=−0.10); C-reactive protein (r=−0.08); tumor necrosis factor receptor 2 (r=−0.08); intercellular adhesion molecule-1 (r=−0.08); P-selectin (r=−0.06); lipoprotein-associated phospholipase-A2 mass (r=−0.11) and activity (r=−0.08). The correlations for monocyte chemoattractant protein-1 was −0.05, P=0.006 and osteoprotegerin (r= −0.06, P=0.002) were only nominally significant.
Conclusion
In our large community-based study, we observed modest inverse associations between several types of inflammatory biomarkers with RBC omega-3 fatty acid levels. Our findings are consistent with the hypothesis that omega-3 fatty acids have anti-inflammatory properties.
doi:10.1016/j.atherosclerosis.2015.03.043
PMCID: PMC4511480  PMID: 25897795
omega-3 fatty acids; biomarkers; inflammation; cross-sectional study
21.  Submaximal Exercise Systolic Blood Pressure and Heart Rate at 20 Years of Follow‐up: Correlates in the Framingham Heart Study 
Background
Beyond their resting values, exercise responses in blood pressure (BP) and heart rate (HR) may add prognostic information for cardiovascular disease (CVD). In cross‐sectional studies, exercise BP and HR responses correlate with CVD risk factors; however, it is unclear which factors influence longitudinal changes in exercise responses over time, which is important for our understanding of the development of CVD.
Methods and Results
We assessed BP and HR responses to low‐level exercise tests (6‐minute Bruce protocol) in 1231 Framingham Offspring participants (55% women) who underwent a routine treadmill test in 1979–1983 (baseline; mean age 39±8 years) that was repeated in 1998–2001 (follow‐up; mean age 58±8 years). Adjusting for baseline exercise responses, we related the follow‐up exercise responses to baseline CVD risk factors and to their changes between examinations. Compared with men, women had greater rise in exercise systolic (S)BP and HR at 20‐year follow‐up (both P<0.005). Baseline blood lipid levels, resting SBP and HR, and smoking status were associated with greater exercise SBP at follow‐up (all P<0.05). Weight gain across examinations was associated with higher exercise SBP and HR at follow‐up (both P<0.0001). Smoking cessation was associated with a 53% reduced risk of attaining the highest quartile of exercise SBP (≥180 mm Hg) at follow‐up (P<0.05).
Conclusion
An adverse CVD risk factor profile in young adults and its worsening over time were associated with higher SBP and HR responses to low‐level exercise in midlife. Maintaining or adopting a healthy risk factor profile may favorably impact the exercise responses over time.
doi:10.1161/JAHA.115.002821
PMCID: PMC4937245  PMID: 27233297
aging; blood pressure; epidemiology; exercise; heart rate; risk factors; Aging; Epidemiology; Exercise; Risk Factors; Blood Pressure
22.  Relations Between Subclinical Disease Markers and Type 2 Diabetes, Metabolic Syndrome, and Incident Cardiovascular Disease: The Jackson Heart Study 
Diabetes Care  2015;38(6):1082-1088.
OBJECTIVE
The presence of subclinical disease measures has been directly associated with the development of cardiovascular disease (CVD) in whites. African Americans (AAs) in the U.S. are at higher risk of CVD compared with non-Hispanic whites; however, data on the prevalence of subclinical disease measures in AAs and their association to CVD remain unclear and may explain the higher CVD risk in this group.
RESEARCH DESIGN AND METHODS
We evaluated 4,416 participants attending the first examination of the Jackson Heart Study (mean age 54 years; 64% women) with available subclinical disease measures.
RESULTS
There were 1,155 participants (26%) with subclinical disease, defined as the presence of one or more of the following: peripheral arterial disease, left ventricular hypertrophy, microalbuminuria, high coronary artery calcium (CAC) score, and low left ventricular ejection fraction. In cross-sectional analyses using multivariable-adjusted logistic regression, participants with metabolic syndrome (MetS) or diabetes (DM) had higher odds of subclinical disease compared with those without MetS and DM (odds ratios 1.55 [95% CI 1.30–1.85] and 2.86 [95% CI 2.32–3.53], respectively). Furthermore, the presence of a high CAC score and left ventricular hypertrophy were directly associated with the incidence of CVD (265 events) in multivariable-adjusted Cox proportional hazards regression models (P < 0.05). In prospective analyses, having MetS or DM significantly increased the hazard of incident CVD, independent of the presence of subclinical disease (P < 0.001).
CONCLUSIONS
In our community-based sample of AAs, we observed a moderately high prevalence of subclinical disease, which in turn translated into a greater risk of CVD, especially in people with MetS and DM.
doi:10.2337/dc14-2460
PMCID: PMC4439537  PMID: 25765357
23.  Hepatic Steatosis is Associated with Lower Levels of Physical Activity Measured via Accelerometry 
Obesity (Silver Spring, Md.)  2015;23(6):1259-1266.
Objective
Prior studies on the association of physical activity (PA) and non-alcoholic fatty liver disease are limited by reliance on subjective measures of PA. We examined the association between objectively measured PA and hepatic steatosis defined by computed tomography (CT).
Methods
We conducted a cross-sectional study of 1060 Framingham Heart Study participants who participated in the Multi-Detector CT 2 substudy and who underwent assessment of PA via accelerometry. Hepatic steatosis was estimated by liver attenuation, as measured by CT. We explored the relationship between liver attenuation and PA using multivariable regression models.
Results
In multivariable-adjusted models, we observed an inverse association between PA and liver attenuation. Each 30 min/day increase in moderate-to-vigorous PA (MVPA) was associated with a reduced odds of hepatic steatosis (OR=0.62, p<0.001). This association was attenuated and no longer statistically significant after adjustment for BMI (OR=0.77, p=0.05) or VAT (OR=0.83, p=0.18). Participants who met the national PA recommendations of engaging in ≥150 minutes/week of MVPA, had the lowest odds of hepatic steatosis, even after adjusting for BMI (OR=0.63, p=0.007) or VAT (OR=0.67, p=0.03).
Conclusions
There is an inverse association between PA and hepatic steatosis. Participants who met the national PA guidelines had the lowest prevalence of hepatic steatosis.
doi:10.1002/oby.21058
PMCID: PMC4446168  PMID: 25959049
24.  Long-Term Outcomes of Secondary Atrial Fibrillation in the Community: The Framingham Heart Study 
Circulation  2015;131(19):1648-1655.
Background
Guidelines have proposed that atrial fibrillation (AF) can occur as an isolated event, particularly when precipitated by a secondary, or reversible, condition. However, knowledge of long-term AF outcomes after diagnosis during a secondary precipitant is limited.
Methods and Results
In 1409 Framingham Heart Study participants with new-onset AF, we examined associations between first-detected AF episodes occurring with and without a secondary precipitant, and both long-term AF recurrence and morbidity. We selected secondary precipitants based on guidelines (surgery, infection, acute myocardial infarction, thyrotoxicosis, acute alcohol consumption, acute pericardial disease, pulmonary embolism, or other acute pulmonary disease). Among 439 (31%) people with AF diagnosed during a secondary precipitant, cardiothoracic surgery (n=131, 30%), infection (n=102, 23%), non-cardiothoracic surgery (n=87, 20%), and acute myocardial infarction (n=78, 18%) were most common. AF recurred in 544 of 846 eligible individuals without permanent AF (5-, 10-, and 15-year recurrences of 42%, 56% and 62% with versus 59%, 69% and 71% without secondary precipitants; multivariable-adjusted hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.54–0.78). Stroke risk (n=209/1262 at risk, HR 1.13, 95%CI 0.82–1.57) and mortality (n=1098/1409 at risk, HR 1.00, 95%CI 0.87–1.15) were similar between those with and without secondary precipitants, though heart failure risk was reduced (n=294/1107 at risk, HR 0.74, 95%CI 0.56–0.97).
Conclusions
AF recurs in most individuals, including those diagnosed with secondary precipitants. Long-term AF-related stroke and mortality risks were similar between individuals with and without secondary AF precipitants. Future studies may determine whether increased arrhythmia surveillance or adherence to general AF management principles in patients with reversible AF precipitants will reduce morbidity.
doi:10.1161/CIRCULATIONAHA.114.014058
PMCID: PMC4430386  PMID: 25769640
atrial fibrillation; atrial flutter; risk factors; stroke; heart failure; epidemiology
25.  Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure 
PLoS Genetics  2016;12(5):e1006034.
Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.
Author Summary
In this study, we applied a genome-wide mapping approach to study molecular determinants of mortality in subjects with heart failure. We identified a genetic variant on chromosome 5q22 that was associated with mortality in this group and observed that this variant conferred increased function of an enhancer region active in multiple tissues. We further observed association of the genetic variant with a DNA methylation signature in blood that in turn is associated with allergy and expression of the gene TSLP (Thymic stromal lymphoprotein) in blood. Knockdown of the transcription factor predicted to bind the enhancer region also resulted in lower TSLP expression. The TSLP gene encodes a cytokine that induces release of T-cell attracting chemokines from monocytes, promotes T helper type 2 cell responses, enhances maturation of dendritic cells and activates mast cells. Development of TSLP inhibiting therapeutics are underway and currently in phase III clinical trials for asthma and allergy. These findings provide novel genetic leads to factors that influence mortality in patients with heart failure and in the longer term may result in novel therapies.
doi:10.1371/journal.pgen.1006034
PMCID: PMC4858216  PMID: 27149122

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