A common biological basis of obesity and nicotine addiction
Contains fulltext : 128630.pdf (Publisher’s version ) (Open Access) Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked …
P-Wave Indices: Derivation of Reference Values from the Framingham Heart Study
P wave indices constitute an intermediate, phenotype reflecting the impact of ischemic, metabolic and inflammatory insults on atrial electrophysiology and morphology. Measured from the surface electrocardiogram (ECG), they reflect dimensions of atrial depolarization and are modified by conditions that alter atrial conduction, atrial refractoriness, or may result in a proarrhythmic substrate. The P wave indices of duration and dispersion have most commonly been measured. An array of studies have utilized these P wave indices to distinguish subjects with diverse cardiovascular and non-cardiovascular conditions and diseases from healthy reference groups.(1) Computerized software has more recen…
Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data.
Context Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease. Objective To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples. Design, Setting, and Participants Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nuc…
Duffy antigen receptor for chemokines (Darc) polymorphism regulates circulating concentrations of monocyte chemoattractant protein-1 and other inflammatory mediators
AbstractTo identify the genetic basis of circulating concentrations of monocyte chemoattractant protein-1 (MCP-1), we conducted genome-wide association analyses for MCP-1 in 3 independent cohorts (n = 9598). The strongest association was for serum MCP-1 with a nonsynonymous polymorphism, rs12075 (Asp42Gly) in DARC, the gene for Duffy antigen receptor for chemokines, a known vascular reservoir of proinflammatory cytokines (minor allele frequency, 45.6%; P < 1.0 * 10−323). This association was supported by family-based genetic linkage at a locus encompassing the DARC gene (genome-wide P = 8.0 * 10−13). Asp42Gly accounted for approximately 20% of the variability in serum MCP-1 concentration…
Relation of Multiple Inflammatory Biomarkers to Incident Atrial Fibrillation
Basic and clinical studies have suggested that inflammation predisposes to atrial fibrillation (AF). We assessed the association of 12 circulating inflammatory biomarkers (i.e., C-reactive protein, fibrinogen, interleukin-6, intercellular adhesion molecule-1, lipoprotein-associated phospholipase A2 [mass and activity], monocyte chemoattractant protein-1, myeloperoxidase, CD40 ligand, osteoprotegerin, P-selectin, and tumor necrosis factor receptor II) with incident AF in 2863 Framingham Offspring Study participants (mean age 60.7 years, SD = 9.4, 55% women). During follow-up (median 6 years), 148 participants (43% women) developed incident AF. In the multivariable proportional hazards models…
Clinical correlates of change in inflammatory biomarkers: The Framingham Heart Study
Objectives: Traditional clinical risk factors are associated with inflammation cross-sectionally, but associations of longitudinal variation in inflammatory biomarkers with corresponding changes in clinical risk factors are incompletely described. We sought to analyze clinical factors associated with change in inflammation in the community.Methods: We studied 3013 Framingham Offspring (n = 2735) and Omni Cohort (n = 278) participants (mean age 59 years, 55% women, 9% ethnic/racial minority) who attended two consecutive examination cycles (mean 6.7 years apart). We selected ten inflammatory biomarkers representing distinctive biological functions: C-reactive protein (CRP), intercellular adhe…
Relations of Metabolically Healthy and Unhealthy Obesity to Digital Vascular Function in Three Community‐Based Cohorts: A Meta‐Analysis
Background Microvascular dysfunction is a marker of early vascular disease that predicts cardiovascular events. Whether metabolically healthy obese individuals have impaired microvascular function remains unclear. The aim of this study was to evaluate the relation of obesity phenotypes stratified by metabolic status to microvascular function. Methods and Results We meta‐analyzed aggregate data from 3 large cohorts (Brazilian Longitudinal Study of Adult Health, the Framingham Heart Study, and the Gutenberg Heart Study; n=16 830 participants, age range 19–90, 51.3% men). Regression slopes between cardiovascular risk factors and microvascular function, measured by peripheral arterial tonometr…
Genome-wide association meta-analysis of PR interval identifies 47 novel loci associated with atrial and atrioventricular electrical activity
ABSTRACTElectrocardiographic PR interval measures atrial and atrioventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. We performed a genome-wide association study in over 92,000 individuals of European descent and identified 44 loci associated with PR interval (34 novel). Examination of the 44 loci revealed known and novel biological processes involved in cardiac atrial electrical activity, and genes in these loci were highly over-represented in several cardiac disease processes. Nearly half of the 61 independent index variants in the 44 loci were associated with atrial or blood transcript expression levels, or were i…
Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry
We conducted meta-analyses of genome-wide association studies (GWAS) for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a novel locus for AF (ZFHX3, rs2106261, risk ratio [RR]=1.19; P=2.3×10−7), an association that was replicated in the German AF Network (odds ratio=1.44; P=1.6×10−11). Combining the discovery and replication results, rs2106261 was significantly associated with AF (RR=1.25; P=1.8×10−15).
Non-invasive peripheral vascular function, incident cardiovascular disease, and mortality in the general population
AIMS Evidence suggests that peripheral vascular function is related to cardiovascular disease (CVD) and mortality. We evaluated the associations of noninvasive measures of flow-mediated dilatation and peripheral arterial tonometry with incident CVD and mortality. METHODS AND RESULTS In a post-hoc analysis of the community-based Gutenberg Health Study, median age 55 years (25th/75th percentile 46/65) and 49.5% women, we measured brachial artery flow-mediated dilatation (N = 12,599) and fingertip peripheral arterial tonometry (N = 11,125). After a follow-up of up to 11.7 years, we observed 595 incident CVD events, 106 cardiac deaths, and 860 deaths in total. Survival curves showed decreased e…
Genome-wide association study of PR interval.
The electrocardiographic PR interval reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation (AF). To identify underlying common genetic variation, we meta-analyzed genome-wide association results for PR interval from seven community-based studies of European-ancestry individuals in the CHARGE consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N=28,517). Statistically significant loci (P<5×10-8) were tested for association with AF (N=5,741 cases). We identified nine loci associated with PR interval. At chromosome 3p22.2, we observed two independent associations in voltage gated sodium channel genes SCN10A and SCN5…
Common Genetic Variation in Relation to Brachial Vascular Dimensions and Flow-Mediated Vasodilation
Common Genetic Variation in Relation to Brachial Vascular Dimensions and Flow-Mediated Vasodilation
Validation of an atrial fibrillation risk algorithm in whites and African Americans.
Background We sought to validate a recently published risk algorithm for incident atrial fibrillation (AF) in independent cohorts and other racial groups. Methods We evaluated the performance of a Framingham Heart Study (FHS)-derived risk algorithm modified for 5-year incidence of AF in the FHS (n = 4764 participants) and 2 geographically and racially diverse cohorts in the age range 45 to 95 years: AGES (the Age, Gene/Environment Susceptibility-Reykjavik Study) (n = 4238) and CHS (the Cardiovascular Health Study) (n = 5410, of whom 874 [16.2%] were African Americans). The risk algorithm included age, sex, body mass index, systolic blood pressure, electrocardiographic PR interval, hypertens…
Multiple marker approach to risk stratification in patients with stable coronary artery disease
Aims Multimarker approaches for risk prediction in coronary artery disease have remained inconsistent. We assessed multiple biomarkers representing distinct pathophysiological pathways in relation to cardiovascular events in stable angina. Methods and results We investigated 12 biomarkers reflecting inflammation [C-reactive protein, growth-differentiation factor (GDF)-15, neopterin], lipid metabolism (apolipoproteins AI, B100), renal function (cystatin C, serum creatinine), and cardiovascular function and remodelling [copeptin, C-terminal-pro-endothelin-1, mid-regional-pro-adrenomedullin (MR-proADM), mid-regional-pro-atrial natriuretic peptide (MR-proANP), N-terminal-pro-B-type natriuretic …
Predicting atrial fibrillation – Authors' reply
Development of a Risk Score for Atrial Fibrillation in the Community; The Framingham Heart Study
Atrial fibrillation contributes to substantial increases in morbidity and mortality. We aimed to develop a risk score to predict individuals' absolute risk of developing the condition, and to provide a framework for researchers to assess new risk markers.We assessed 4764 participants in the Framingham Heart Study from 8044 examinations (55% women, 45-95 years of age) undertaken between June, 1968, and September, 1987. Thereafter, participants were monitored for the first event of atrial fibrillation for a maximum of 10 years. Multivariable Cox regression identified clinical risk factors associated with development of atrial fibrillation in 10 years. Secondary analyses incorporated routine e…
Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders
International audience; C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 1…
Genome-Wide Association Studies of the PR Interval in African Americans.
The PR interval on the electrocardiogram reflects atrial and atrioventricular nodal conduction time. The PR interval is heritable, provides important information about arrhythmia risk, and has been suggested to differ among human races. Genome-wide association (GWA) studies have identified common genetic determinants of the PR interval in individuals of European and Asian ancestry, but there is a general paucity of GWA studies in individuals of African ancestry. We performed GWA studies in African American individuals from four cohorts (n = 6,247) to identify genetic variants associated with PR interval duration. Genotyping was performed using the Affymetrix 6.0 microarray. Imputation was p…
Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia
Increased systemic levels of myeloperoxidase (MPO) are associated with the risk of coronary artery disease (CAD). To identify the genetic factors that are associated with circulating MPO levels, we carried out a genome-wide association study (GWAS) and a gene-centric analysis in subjects of European ancestry and African Americans (AAs). A locus on chromosome 1q31.1 containing the complement factor H (CFH) gene was strongly associated with serum MPO levels in 9305 subjects of European ancestry (lead SNP rs800292; P = 4.89 × 10(-41)) and in 1690 AA subjects (rs505102; P = 1.05 × 10(-8)). Gene-centric analyses in 8335 subjects of European ancestry additionally identified two rare M…
Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function
BACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication …
Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium
Background Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting. Methods We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10−6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up. Res…
P wave duration and risk of longitudinal atrial fibrillation in persons ≥ 60 years old (from the Framingham Heart Study).
Long-term risk prediction is a priority for the prevention of atrial fibrillation (AF). P wave indices are electrocardiographic measurements describing atrial conduction. The role of P wave indices in the prospective determination of AF and mortality risk has had limited assessment. We quantified by digital caliper the P wave indices of maximum duration and dispersion in 1,550 Framingham Heart Study participants ≥ 60 years old (58% women) from single-channel electrocardiograms recorded from 1968 through 1971. We examined the association of selected P wave indices and long-term outcomes using Cox proportional hazards regression incorporating age, gender, body mass index, systolic blood press…
Large-Scale Candidate Gene Analysis in Whites and African Americans Identifies IL6R Polymorphism in Relation to Atrial Fibrillation The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe) Project
Background— The genetic background of atrial fibrillation (AF) in whites and African Americans is largely unknown. Genes in cardiovascular pathways have not been systematically investigated. Methods and Results— We examined a panel of approximately 50 000 common single-nucleotide polymorphisms (SNPs) in 2095 cardiovascular candidate genes and AF in 3 cohorts with participants of European (n=18 524; 2260 cases) or African American descent (n=3662; 263 cases) in the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource. Results in whites were followed up in the German Competence Network for AF (n=906, 468 cases). The top result was assessed in relation to incident i…
Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation o…
Insulin resistance and atrial fibrillation (from the Framingham Heart Study)
Diabetes mellitus and obesity are increasing in prevalence and are associated with an elevated risk of atrial fibrillation (AF). Given the aging of the United States population, AF is projected to concomitantly increase in prevalence in the upcoming decades. Both diabetes and obesity are associated with insulin resistance. Whether insulin resistance is an intermediate step for the development of AF is uncertain. We hypothesized that insulin resistance is associated with an increased risk of incident AF. We examined the association of insulin resistance with incident AF using multivariate Cox proportional hazards regression analysis adjusting for the established AF risk factors (i.e., age, g…
Meta-Analysis of Genome-Wide Association Studies in >80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels
Background— C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels. Methods and Results— We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in p…
Association of Common Variants in NPPA and NPPB with Circulating Natriuretic Peptides and Blood Pressure
We examined the association of common variants at the NPPA-NPPB locus with circulating concentrations of the natriuretic peptides, which have blood pressure-lowering properties. We genotyped SNPs at the NPPA-NPPB locus in 14,743 individuals of European ancestry, and identified associations of plasma atrial natriuretic peptide with rs5068 (P = 8 x 10(-70)), rs198358 (P = 8 x 10(-30)) and rs632793 (P = 2 x 10(-10)), and of plasma B-type natriuretic peptide with rs5068 (P = 3 x 10(-12)), rs198358 (P = 1 x 10(-25)) and rs632793 (P = 2 x 10(-68)). In 29,717 individuals, the alleles of rs5068 and rs198358 that showed association with increased circulating natriuretic peptide concentrations were a…