Showing papers by "Christopher J. O'Donnell published in 2009"
TL;DR: The statistical update brings together the most up-to-date statistics on heart disease, stroke, other vascular diseases, and their risk factors and presents them in its Heart Disease and Stroke Statistical Update.
Abstract: We thank Drs Sean Coady, Eric L. Ding, Brian Eigel, Gregg C. Fonarow, Linda Geiss, Cherie James, Michael Mussolino, and Michael Wolz for their valuable comments and contributions. We acknowledge Tim Anderson and Tom Schneider for their editorial contributions, and Karen Modesitt for her administrative assistance.
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# Summary {#article-title-2}
Each year, the American Heart Association, in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together the most up-to-date statistics on heart disease, stroke, other vascular diseases, and their risk factors and presents them in its Heart Disease and Stroke Statistical Update. The Statistical Update is a valuable resource for researchers, clinicians, healthcare policy makers, media professionals, the lay …
5,019 citations
Massachusetts Institute of Technology1, Boston University2, Harvard University3, University of Michigan4, Merck & Co.5, University of Oxford6, National Institutes of Health7, French Institute of Health and Medical Research8, University of Eastern Finland9, University of Southern California10, National Institute for Health and Welfare11, Imperial College London12, University of Helsinki13, Lund University14, Wellcome Trust Sanger Institute15, Tufts University16, University of North Carolina at Chapel Hill17
TL;DR: The results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.
Abstract: Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.
1,358 citations
National Institutes of Health1, Johns Hopkins University2, University of Geneva3, University of Washington4, Erasmus University Rotterdam5, University of Texas Health Science Center at Houston6, University of Iceland7, Boston University8, Cedars-Sinai Medical Center9, Harvard University10, Group Health Cooperative11
TL;DR: A genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium identifies 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 × 10−7.
Abstract: Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 × 10(-7). The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 × 10(-8)) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.
1,333 citations
Christopher Newton-Cheh1, Christopher Newton-Cheh2, Toby Johnson3, Toby Johnson4 +359 more•Institutions (64)
TL;DR: In this paper, the association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2(P = 1 × 10-23), FGF5 (P=1 × 10 -21), SH2B3(P= 3 × 10−18), MTHFR(MTHFR), c10orf107(P), ZNF652(ZNF652), PLCD3 (P,P = 5 × 10 −9),
Abstract: Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
1,205 citations
Harvard University1, Broad Institute2, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico3, McMaster University4, McGill University5, University of Leicester6, University of Lübeck7, University of Pennsylvania8, Vanderbilt University9, University of Missouri–Kansas City10, University of Münster11, University of Verona12, Queen's University Belfast13, University of Washington14, Boston University15, University of Helsinki16, National Institute for Health and Welfare17, Lund University18, University of Cambridge19, Vita-Salute San Raffaele University20, University of Ferrara21, University of Turin22, Hebrew University of Jerusalem23, University of Girona24, University of Milan25, University of Leeds26, University of Regensburg27, Ludwig Maximilian University of Munich28, University of Kiel29, Wellcome Trust Sanger Institute30, University of Paris31, MedStar Washington Hospital Center32, deCODE genetics33, University of Iceland34
TL;DR: SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with my Cardiovascular Infarction risk.
Abstract: We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases and 3,075 controls We carried out replication in an independent sample with an effective sample size of up to 19,492 SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations1, 2, 3, 4 (9p21, 1p13 near CELSR2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR and 1p32 near PCSK9) We tested 554 common copy number polymorphisms (>1% allele frequency) and none met the pre-specified threshold for replication (P < 10-3) We identified 8,065 rare CNVs but did not detect a greater CNV burden in cases compared to controls, in genes compared to the genome as a whole, or at any individual locus SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with myocardial infarction risk
1,092 citations
TL;DR: In general, a novel risk marker should be evaluated in several phases, including initial proof of concept, prospective validation in independent populations, documentation of incremental information when added to standard risk markers, assessment of effects on patient management and outcomes, and ultimately, cost-effectiveness.
Abstract: There is increasing interest in utilizing novel markers of cardiovascular disease risk, and consequently, there is a need to assess the value of their use. This scientific statement reviews current concepts of risk evaluation and proposes standards for the critical appraisal of risk assessment methods. An adequate evaluation of a novel risk marker requires a sound research design, a representative at-risk population, and an adequate number of outcome events. Studies of a novel marker should report the degree to which it adds to the prognostic information provided by standard risk markers. No single statistical measure provides all the information needed to assess a novel marker, so measures of both discrimination and accuracy should be reported. The clinical value of a marker should be assessed by its effect on patient management and outcomes. In general, a novel risk marker should be evaluated in several phases, including initial proof of concept, prospective validation in independent populations, documentation of incremental information when added to standard risk markers, assessment of effects on patient management and outcomes, and ultimately, cost-effectiveness.
1,070 citations
TL;DR: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and collaborating non-member studies or consortia provide an excellent framework for the identification of the genetic determinants of risk factors, subclinical-disease measures, and clinical events.
Abstract: Background— The primary aim of genome-wide association studies is to identify novel genetic loci associated with interindividual variation in the levels of risk factors, the degree of subclinical disease, or the risk of clinical disease. The requirement for large sample sizes and the importance of replication have served as powerful incentives for scientific collaboration.
Methods— The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium was formed to facilitate genome-wide association studies meta-analyses and replication opportunities among multiple large population-based cohort studies, which collect data in a standardized fashion and represent the preferred method for estimating disease incidence. The design of the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium includes 5 prospective cohort studies from the United States and Europe: the Age, Gene/Environment Susceptibility—Reykjavik Study, the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. With genome-wide data on a total of about 38 000 individuals, these cohort studies have a large number of health-related phenotypes measured in similar ways. For each harmonized trait, within-cohort genome-wide association study analyses are combined by meta-analysis. A prospective meta-analysis of data from all 5 cohorts, with a properly selected level of genome-wide statistical significance, is a powerful approach to finding genuine phenotypic associations with novel genetic loci.
Conclusions— The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and collaborating non-member studies or consortia provide an excellent framework for the identification of the genetic determinants of risk factors, subclinical-disease measures, and clinical events.
Received October 17, 2008; accepted December 17, 2008.
596 citations
Wellcome Trust Sanger Institute1, King's College London2, University of Cambridge3, University of Greifswald4, University of Lübeck5, University of Leicester6, University of Ottawa7, University of Pennsylvania8, University of Helsinki9, National Institutes of Health10, Broad Institute11, Harvard University12, European Bioinformatics Institute13, MedStar Washington Hospital Center14, Cambridge University Hospitals NHS Foundation Trust15, Imperial College London16, Children's Hospital of Philadelphia17, Leeds General Infirmary18, University of Regensburg19, GlaxoSmithKline20, Lund University21, Helsinki University Central Hospital22, Technische Universität München23, University of Kiel24, University of Washington25, Ludwig Maximilian University of Munich26, Queen Mary University of London27
TL;DR: A long-range haplotype at 12q24 associated with coronary artery disease and myocardial infarction is identified and it is shown that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.
Abstract: The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease and myocardial infarction in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.
504 citations
University of Lübeck1, University of Leicester2, University of Regensburg3, University of Leeds4, Harvard University5, French Institute of Health and Medical Research6, University of Washington7, Lund University8, National Institutes of Health9, Wellcome Trust Sanger Institute10, University of Milan11, Medical Research Council12, University of Pavia13, University of Mainz14, University of Kiel15, Medical University of Graz16, Heidelberg University17, Synlab Group18, Technische Universität München19, University of Cambridge20
TL;DR: A three-stage analysis of genome-wide SNP data in 1,222 German individuals with myocardial infarction and 1,298 controls is presented and suggestive association with a locus on 12q24.31 near HNF1A-C12orf43 is identified.
Abstract: We present a three-stage analysis of genome-wide SNP data in 1,222 German individuals with myocardial infarction and 1,298 controls, in silico replication in three additional genome-wide datasets of coronary artery disease (CAD) and subsequent replication in similar to 25,000 subjects. We identified one new CAD risk locus on 3q22.3 in MRAS (P = 7.44 x 10(-13); OR = 1.15, 95% CI = 1.11-1.19), and suggestive association with a locus on 12q24.31 near HNF1A-C12orf43 (P = 4.81 x 10(-7); OR = 1.08, 95% CI = 1.05-1.11).
497 citations
TL;DR: A meta-analysis of three genome-wide association studies in 13,685 individuals of European ancestry offers insights into myocardial repolarization and suggests candidate genes that could predispose to sudden cardiac death and drug-induced arrhythmias.
Abstract: QT interval duration, reflecting myocardial repolarization on the electrocardiogram, is a heritable risk factor for sudden cardiac death and drug-induced arrhythmias. We conducted a meta-analysis of three genome-wide association studies in 13,685 individuals of European ancestry from the Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study, as part of the QTGEN consortium. We observed associations at P < 5 x 10(-8) with variants in NOS1AP, KCNQ1, KCNE1, KCNH2 and SCN5A, known to be involved in myocardial repolarization and mendelian long-QT syndromes. Associations were found at five newly identified loci, including 16q21 near NDRG4 and GINS3, 6q22 near PLN, 1p36 near RNF207, 16p13 near LITAF and 17q12 near LIG3 and RFFL. Collectively, the 14 independent variants at these 10 loci explain 5.4-6.5% of the variation in QT interval. These results, together with an accompanying paper, offer insights into myocardial repolarization and suggest candidate genes that could predispose to sudden cardiac death and drug-induced arrhythmias.
411 citations
Johns Hopkins University1, National Institutes of Health2, University of Vermont3, Erasmus University Rotterdam4, Wellcome Trust Sanger Institute5, King's College London6, Boston University7, University of Washington8, University of Iceland9, University of Greifswald10, Geneva College11, University of Cambridge12, University of Texas Health Science Center at Houston13, Cedars-Sinai Medical Center14, Leiden University15, Leiden University Medical Center16, Harvard University17
TL;DR: This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in ery throatcyte measures, and identifies 23 loci significantly associated with these traits.
Abstract: Measurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 x 10(-8) to 7 x 10(-86)). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.
TL;DR: This database provides access to a full gene-annotated GWAS database which could be used for further querying, analyses or integration with other genomic information, and finds considerable heterogeneity in information available from GWAS suggesting the wider community could benefit from standardization and centralization of results reporting.
Abstract: The number of genome-wide association studies (GWAS) is growing rapidly leading to the discovery and replication of many new disease loci. Combining results from multiple GWAS datasets may potentially strengthen previous conclusions and suggest new disease loci, pathways or pleiotropic genes. However, no database or centralized resource currently exists that contains anywhere near the full scope of GWAS results. We collected available results from 118 GWAS articles into a database of 56,411 significant SNP-phenotype associations and accompanying information, making this database freely available here. In doing so, we met and describe here a number of challenges to creating an open access database of GWAS results. Through preliminary analyses and characterization of available GWAS, we demonstrate the potential to gain new insights by querying a database across GWAS. Using a genomic bin-based density analysis to search for highly associated regions of the genome, positive control loci (e.g., MHC loci) were detected with high sensitivity. Likewise, an analysis of highly repeated SNPs across GWAS identified replicated loci (e.g., APOE, LPL). At the same time we identified novel, highly suggestive loci for a variety of traits that did not meet genome-wide significant thresholds in prior analyses, in some cases with strong support from the primary medical genetics literature (SLC16A7, CSMD1, OAS1), suggesting these genes merit further study. Additional adjustment for linkage disequilibrium within most regions with a high density of GWAS associations did not materially alter our findings. Having a centralized database with standardized gene annotation also allowed us to examine the representation of functional gene categories (gene ontologies) containing one or more associations among top GWAS results. Genes relating to cell adhesion functions were highly over-represented among significant associations (p < 4.6 × 10-14), a finding which was not perturbed by a sensitivity analysis. We provide access to a full gene-annotated GWAS database which could be used for further querying, analyses or integration with other genomic information. We make a number of general observations. Of reported associated SNPs, 40% lie within the boundaries of a RefSeq gene and 68% are within 60 kb of one, indicating a bias toward gene-centricity in the findings. We found considerable heterogeneity in information available from GWAS suggesting the wider community could benefit from standardization and centralization of results reporting.
Boston University1, Erasmus University Rotterdam2, University of North Carolina at Chapel Hill3, Uppsala University4, National Institutes of Health5, University of Maryland, Baltimore6, Cedars-Sinai Medical Center7, Washington University in St. Louis8, University of Iceland9, Mayo Clinic10, University of Texas Health Science Center at Houston11, Johns Hopkins University12, University of Minnesota13, University of Washington14, University of Edinburgh15, University of Zagreb16, Harvard University17, Yeshiva University18
TL;DR: It is established that common variants in NRXN3 are associated with WC, BMI, and obesity, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder.
Abstract: Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4610 27 )]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3610 28 for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4610 26 , 0.024 z-score units (0.10 kg/m 2 ) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07–1.19; p = 3.2610 25 per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.
TL;DR: Pericardial fat is correlated with cardiovascular magnetic resonance measures, but the association is not independent of or stronger than other ectopic fat stores or proxy measures of visceral adiposity.
Abstract: Background— Pericardial fat has been implicated in the pathogenesis of obesity-related cardiovascular disease. Whether the associations of pericardial fat and measures of cardiac structure and function are independent of the systemic effects of obesity and visceral adiposity has not been fully explored. Methods and Results— Participants from the Framingham Heart Study (n=997; 54.4% women) underwent chest and abdominal computed tomography and cardiovascular magnetic resonance imaging between 2002 and 2005. Pericardial fat, intrathoracic fat, and visceral adipose tissue quantified from multidetector computed tomography, along with body mass index and waist circumference, were examined in relation to cardiovascular magnetic resonance measures of left ventricular (LV) mass, LV end-diastolic volume, and left atrial dimension. In women, pericardial fat (r=0.20 to 0.35, P<0.001), intrathoracic fat (r=0.25 to 0.37, P<0.001), visceral adipose tissue (r=0.24 to 0.45, P<0.001), body mass index (r=0.36 to 0.53, P<0.0...
TL;DR: Phylloquinone supplementation slows the progression of CAC in healthy older adults with preexisting CAC, independent of its effect on total MGP concentrations.
TL;DR: Variability in biomarkers of vitamin K status was attributed to nongenetic factors, whereas plasma 25(OH)D was found to be significantly heritable.
Abstract: To assess the genetic and nongenetic correlates of circulating measures of vitamins K and D status in a community-based sample of men and women. A cross-sectional study of 1762 participants of the Framingham Offspring Study (919 women; mean age 59 years). Vitamin K status was measured as plasma phylloquinone and serum percent undercarboxylated osteocalcin (ucOC), and vitamin D was measured using plasma 25-hydroxyvitamin D (25(OH)D). Associations between vitamin K status and vitamin D status with biologically plausible nongenetic factors were assessed using stepwise regression. Heritability and linkage were determined using Sequential Oligogenic Linkage Analysis Routines (SOLAR). Nongenetic factors accounted for 20.1 and 12.3% of the variability in plasma phylloquinone in men and women respectively, with triglycerides and phylloquinone intake being the primary correlates. In men 12.2% and in women 14.6% of the variability in %ucOC was explained by nongenetic factors in our models. Heritability estimates for these vitamin K status biomarkers were nonsignificant. Season, vitamin D intake, high-density lipoprotein (HDL) cholesterol and waist circumference explained 24.7% (men) and 24.2% (women) of the variability in plasma 25(OH)D. Of the three vitamins examined, only 25(OH)D was significantly heritable (heritability estimate=28.8%, P<0.01), but linkage analysis of 25(OH)D did not achieve genome-wide significance. Variability in biomarkers of vitamin K status was attributed to nongenetic factors, whereas plasma 25(OH)D was found to be significantly heritable. Further studies are warranted to investigate genetic loci influencing vitamin D status.
TL;DR: One of the largest genetic studies of bilirubin to date confirms the substantial genetic influence of UGT1A1 variants, consistent with past linkage and association studies, and provides strong evidence of a role for allelic variation in SLCO1B1.
Abstract: Variation in serum bilirubin is associated with altered cardiovascular disease risk and drug metabolism. We aimed to identify genetic contributors to variability in serum bilirubin levels by combining results from three genome-wide association studies (Framingham heart study, n = 3424; Rotterdam study, n = 3847; Age, Gene, Environment and Susceptibility-Reykjavik, n = 2193). Meta-analysis showed strong replication for a genetic influence on serum bilirubin levels of the UGT1A1 locus (P < 5 x 10(-324)) and a 12p12.2 locus. The peak signal in the 12p12.2 region was a non-synonymous SNP in SLCO1B1 (rs4149056, P = 6.7 x 10(-13)), which gives rise to a valine to alanine amino acid change leading to reduced activity for a hepatic transporter with known affinity for bilirubin. There were also suggestive associations with several other loci. The top variants in UGT1A1 and SLCO1B1 explain approximately 18.0 and approximately 1.0% of the variation in total serum bilirubin levels, respectively. In a conditional analysis adjusted for individual genotypes for the top UGT1A1 variant, the top SLCO1B1 variant remained highly significant (P = 7.3 x 10(-13)), but no other variants achieved genome-wide significance. In one of the largest genetic studies of bilirubin to date (n = 9464), we confirm the substantial genetic influence of UGT1A1 variants, consistent with past linkage and association studies, and additionally provide strong evidence of a role for allelic variation in SLCO1B1. Given the involvement of bilirubin in a number of physiological and disease processes, and the roles for UGT1A1 and SLCO1B1 in drug metabolism, these genetic findings have potential clinical importance. In analyses for association with gallbladder disease or gallstones, top bilirubin SNPs in UGT1A1 and SLCO1B1 were not associated.
Boston University1, National Institutes of Health2, University of Washington3, Erasmus University Rotterdam4, University of Lübeck5, University of Mainz6, University of Greifswald7, Medical University of Graz8, United States Department of Veterans Affairs9, Uppsala University10, Mayo Clinic11, Martin Luther University of Halle-Wittenberg12, Cedars-Sinai Medical Center13, Karolinska Institutet14, University of Alabama at Birmingham15, University of Maryland, Baltimore16, Technische Universität München17, Group Health Cooperative18, Ludwig Maximilian University of Munich19
TL;DR: 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size were identified, but such findings explained a very small proportion of variance.
Abstract: 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-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n=4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10-7to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort. Main Outcome Measures: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size. Results: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1%of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance). Conclusions: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.
TL;DR: Over the past 40 years, rates of AMI-ECG have declined by 50%, whereas rates ofAMI-marker have doubled, offering an explanation for the apparently steady national AMI rates in the face of improvements in primary prevention.
Abstract: Background— Whereas the prevalence of coronary heart disease risk factors has declined over the past decades in the United States, acute myocardial infarction (AMI) rates have been steady. We hypothesized that this paradox is due partly to the advent of increasingly sensitive biomarkers for AMI diagnosis. Methods and Results— In Framingham Heart Study participants over 4 decades, we compared the incidence and survival rates of initial AMI diagnosis by ECG (AMI-ECG) regardless of biomarkers with those based exclusively on infarction biomarkers (AMI-marker). We used Poisson regression to calculate annual incidence rates of first AMI over 4 decades (1960 to 1969, 1970 to 1979, 1980 to 1989, and 1990 to 1999) and compared rates of AMI-ECG with rates of AMI-marker. Cox proportional-hazards analysis was used to compare AMI case fatality over 4 decades. In 9824 persons (54% women; follow-up, 212 539 person-years; age, 40 to 89 years), 941 AMIs occurred, including 639 AMI-ECG and 302 AMI-marker events. From 1960 ...
TL;DR: Nearly one-third of the sample has abdominal subcutaneous obesity, and >40% have visceral obesity, which may misclassify individuals in terms of VAT and metabolic risk.
Abstract: OBJECTIVE — The prevalence of abdominal obesity exceeds that of general obesity. We sought to determine the prevalence of abdominal subcutaneous and visceral obesity and to characterize the different patterns of fat distribution in a community-based sample. RESEARCH DESIGN AND METHODS — Participants from the Framingham Heart Study (n 3,348, 48% women, mean age 52 years) underwent multidetector computed tomography; subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes were assessed. Sex-specific high SAT and VAT definitions were based on 90th percentile cut points from a healthy referent sample. Metabolic risk factors were examined in subgroups with elevated SAT and VAT. RESULTS — The prevalence of high SAT was 30% (women) and 31% (men) and that for high VAT was 44% (women) and 42% (men). Overall, 27.8% of the sample was discordant for high SAT and high VAT: 19.9% had SAT less than but VAT equal to or greater than the 90th percentile, and 7.9% had SAT greater than but VAT less than the 90th percentile. The prevalence of metabolic syndrome was higher among women and men with SAT less than the 90th percentile and high VAT than in those with high SAT but VAT less than the 90th percentile, despite lower BMI and waist circumference. Findings were similar for hypertension, elevated triglycerides, and low HDL cholesterol. CONCLUSIONS — Nearly one-third of our sample has abdominal subcutaneous obesity, and 40% have visceral obesity. Clinical measures of BMI and waist circumference may misclassify individuals in terms of VAT and metabolic risk. Diabetes Care 32:481–485, 2009
TL;DR: This study elegantly demonstrates how Mendelian randomization can be used to improve the evidence for causality from observational studies and highlights the advantages and limitations of such an approach.
Abstract: Despite several observational studies showing that lipoprotein(a), or Lp(a), is associated with myocardial infarction (MI)1, 2, only circumstantial evidence exists regarding the causal nature of this association. Observational epidemiological studies, even with a sound prospective design, can provide hints to disease pathogenesis when the effect size is modest but cannot provide definitive evidence for causal relationships. Much of the current understanding of the causal factors in cardiovascular disease, such as the role of LDL, has been confirmed by randomized clinical trials (RCT)3, 4. However, RCTs are not always feasible. In the case of Lp(a), the modest effect size and the lack of specific Lp(a) lowering therapy are major obstacles to obtaining causal evidence for its role in cardiovascular disease. In this issue of JAMA, Kamstrup and colleagues 5 provide insights using a “Mendelian randomization” approach and provide evidence for the causal role of Lp(a) in MI. This study elegantly demonstrates how Mendelian randomization can be used to improve the evidence for causality from observational studies and highlights the advantages and limitations of such an approach.
TL;DR: Standardized semiautomatic CT-based volumetric quantification of periaortic adipose tissue is feasible and highly reproducible and association with anthropometric measures of obesity, and abdominal adipose tissues was determined.
Abstract: Background: Perivascular adipose tissue may be associated with the amount of local atherosclerosis We developed a novel and reproducible method to standardize volumetric quantification of periaortic adipose tissue by computed tomography (CT) and determined the association with anthropometric measures of obesity, and abdominal adipose tissue Methods: Measurements of adipose tissue were performed in a random subset of participants from the Framingham Heart Study (n ¼ 100) who underwent multidetector CT of the thorax (ECG triggering, 25 mm slice thickness) and the abdomen (helical CT acquisition, 25 mm slice thickness) Abdominal periaortic adipose tissue (AAT) was defined by a 5 mm cylindrical region of interest around the aortic wall; thoracic periaortic adipose tissue (TAT) was defined by anatomic landmarks TAT and AAT were defined as any voxel between � 195 and � 45 HU and volumes were measured using dedicated semiautomatic software Measurement reproducibility and association with anthropometric measures of obesity, and abdominal adipose tissue were determined Results: The intra- and inter-observer reproducibility for both AAT and TAT was excellent (ICC: 097 and 097; 099 and 098, respectively) Similarly, the relative intra- and inter-observer difference was small for both AAT (� 185±128% and 785±608%; respectively) and TAT (356±083% and � 456±085%, respectively) Both AAT and TAT were highly correlated with visceral abdominal fat (r ¼ 065 and 077, Po00001 for both) and moderately correlated with subcutaneous abdominal fat (r ¼ 039 and 042, Po00001 and P ¼ 0009), waist circumference (r ¼ 049 and 057, Po00001 for both) and body mass index (r ¼ 047 and 058, Po00001 for both) Conclusion: Standardized semiautomatic CT-based volumetric quantification of periaortic adipose tissue is feasible and highly reproducible Further investigation is warranted regarding associations of periaortic adipose tissue with other body fat deposits, cardiovascular risk factors and clinical outcomes International Journal of Obesity (2009) 33, 226–232; doi:101038/ijo2008267; published online 13 January 2009
TL;DR: Adherence to recommended dietary guidelines and physical activity are associated with lower SAT and VAT volumes, however, both smoking and high alcohol intake are differentially associated with VAT volumes.
Abstract: OBJECTIVE— The purpose of this study was to assess the relationship between lifestyle factors and abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in a community-based setting.
RESEARCH DESIGN AND METHODS— Cross-sectional associations between lifestyle factors (dietary quality, physical activity, smoking, and alcohol consumption) and SAT and VAT volumes were examined in 2,926 Framingham Heart Study participants (48.6% women, aged 50 ± 10 years).
RESULTS— Diets consistent with the 2005 Dietary Guidelines Adherence Index and greater physical activity were inversely associated with SAT and VAT (P 7 drinks/week) had lower SAT (2,869 ± 106 cm3) than those who consumed less alcohol (3,184 ± 44 cm3, P = 0.006); significant differences in VAT were not observed (P = 0.18). In men, high amounts of alcohol intake (>14 drinks/week) were associated with higher VAT (2,272 ± 59 cm3) compared with intake of ≤14 drinks/week (2,139 ± 25 cm3, P = 0.04), whereas SAT did not differ (P = 0.91). An increasing number of healthy lifestyle factors were associated with lower SAT and VAT volumes (all P < 0.003).
CONCLUSIONS— Adherence to recommended dietary guidelines and physical activity are associated with lower SAT and VAT volumes. However, both smoking and high alcohol intake are differentially associated with VAT volumes. Further research to uncover the putative mechanisms is warranted.
TL;DR: In this article, the authors identify common variants influencing circulation fibrinogen levels, which is both central to blood coagulation and an acute-phase reactant, and they use this information to predict the levels of fibrusogen in patients.
Abstract: Background— Fibrinogen is both central to blood coagulation and an acute-phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels. Methods and Results— We cond...
TL;DR: Adiponectin and resistin are correlated with fat depots cross-sectionally, but none of the adipokines can serve as surrogates for theFat depots, and Relations between VAT, SAT, and cardiometabolic risk factors were not fully explained by adiponect in or resistin concentrations.
Abstract: Objective: To test the association of regional fat depots with circulating adiponectin and resistin concentrations, and to assess the potential mediating effect of adipokines on associations between abdominal fat depots and cardiometabolic risk factors. Research Design and Methods: Participants from the Framingham Heart Study Offspring cohort (n = 916, 55% women; mean age 59 years) free of CVD underwent computed tomography measurement of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), pericardial fat, and intra-thoracic fat volumes and assays of circulating adiponectin and resistin. Results: VAT, SAT, pericardial fat, and intra-thoracic fat were negatively correlated with adiponectin (r = −0.19 to −0.34, p Conclusions: Adiponectin and resistin are correlated with fat depots cross-sectionally, but none of the adipokines can serve as surrogates for the fat depots. Relations between VAT, SAT, and cardiometabolic risk factors were not fully explained by adiponectin or resistin concentrations.
TL;DR: VAT, but not SAT was associated with FMD% after adjusting for clinical covariates and there was little incremental increase in the proportion of variability explained by VAT as compared to SAT, above and beyond traditional risk factors.
Abstract: Endothelial dysfunction may link obesity to cardiovascular disease (CVD). We tested the hypothesis that visceral abdominal tissue (VAT) as compared with subcutaneous adipose tissue (SAT) is more related to endothelium-dependent vasodilation. Among Framingham Offspring and Third Generation cohorts (n = 3,020, mean age 50 years, 47% women), we used multivariable linear regression adjusted for CVD and its risk factors to relate computed tomography (CT)-assessed VAT and SAT, BMI, and waist circumference (WC), with brachial artery measures. In multivariable-adjusted models, BMI, WC, VAT, and SAT were positively related to baseline artery diameter and baseline mean flow velocity (all P < 0.001), but not hyperemic mean flow velocity. In multivariable-adjusted models, BMI (P = 0.002), WC (P = 0.001), and VAT (P = 0.01), but not SAT (P = 0.24) were inversely associated with percentage of flow-mediated dilation (FMD%). However, there was little incremental increase in the proportion of variability explained by VAT (R(2) = 0.266) as compared to SAT (R(2) = 0.265), above and beyond traditional risk factors. VAT, but not SAT was associated with FMD% after adjusting for clinical covariates. Nevertheless, the differential association with VAT as compared to SAT was minimal.
TL;DR: A role for MGP genetic variants in coronary atherosclerosis among men that is not reflected in serum MGP concentrations is suggested, despite the fact that genetic variation in MGP was associated with serum M GP concentrations.
Abstract: Matrix Gla protein (MGP) is a key regulator of vascular calcification. Genetic variation at the MGP locus could modulate the development of coronary artery calcification (CAC). Our aim was to examine the cross-sectional association between MGP single nucleotide polymorphisms (SNPs) [rs1800802 (T-138C), rs1800801 (G-7A), and rs4236 (Ala102Thr)] and CAC. CAC was measured by multidetector computed tomography (MDCT), in older men and women of European descent, (n=386; 60 to 80 y of age). Serum MGP was measured by radioimmunoassay. Linear, Tobit and Ordinal regression analyses all revealed that in men, homozygous carriers of the minor allele of rs1800802, rs1800801, or rs4236 (minor allele frequency: 21, 38, and 40%, respectively) were associated with a decreased quantity of CAC, relative to major allele carriers. This association was not found in women. Although genetic variation in MGP was associated with serum MGP concentrations, there were no associations between serum MGP and CAC. The results of this study suggest a role for MGP genetic variants in coronary atherosclerosis among men that is not reflected in serum MGP concentrations.
TL;DR: The general measures of obesity and measures of central abdominal fat are related to the coronary aortic calcium and abdominal aorti calcium levels, however, these cross-sectional associations are attenuated by cardiovascular disease risk factors, possibly because they mediate the association between adiposity measures and subclinical cardiovascular disease.
Abstract: Body fat distribution might be differentially associated with subclinical cardiovascular disease. We examined whether the body mass index, waist circumference, and subcutaneous and visceral adipose tissue are associated with the prevalence of either coronary or abdominal aortic calcium in the Framingham Heart Study. Participants (n = 3,130, mean age 52 years, 49% women) free of clinical cardiovascular disease from the Framingham Heart Study underwent multidetector computed tomographic assessment to quantify the subcutaneous and visceral fat volume and coronary and abdominal aortic calcification. Coronary artery calcification and abdominal aortic calcium were examined in relation to the body mass index, waist circumference, subcutaneous adipose tissue, and visceral adipose tissue in age-, gender-, and multivariate-adjusted models. All measures of adiposity were associated with coronary aortic calcium in the age- and gender-adjusted models (all p 0.14). The body mass index, waist circumference, and visceral adipose tissue (but not the subcutaneous adipose tissue) were associated with abdominal aortic calcification in the age- and gender-adjusted models (all p 0.23). Similar findings were observed in the quartile-based analyses. In conclusion, the general measures of obesity and measures of central abdominal fat are related to the coronary aortic calcium and abdominal aortic calcium levels. However, these cross-sectional associations are attenuated by cardiovascular disease risk factors, possibly because they mediate the association between adiposity measures and subclinical cardiovascular disease.
TL;DR: The new test statistic exploits all available information about the association, while, by virtue of its design, it maintains the same robustness against population admixture as traditional family-based approaches that are based exclusively on the within-family information.
Abstract: For genome-wide association studies in family-based designs, we propose a new, universally applicable approach. The new test statistic exploits all available information about the association, while, by virtue of its design, it maintains the same robustness against population admixture as traditional family-based approaches that are based exclusively on the within-family information. The approach is suitable for the analysis of almost any trait type, e.g. binary, continuous, time-to-onset, multivariate, etc., and combinations of those. We use simulation studies to verify all theoretically derived properties of the approach, estimate its power, and compare it with other standard approaches. We illustrate the practical implications of the new analysis method by an application to a lung-function phenotype, forced expiratory volume in one second (FEV1) in 4 genome-wide association studies.
TL;DR: The studies suggest that UGT1A1 may be the major gene with strong effects on bilirubin levels and the TA-repeat polymorphism might be the key polymorphism within the gene controlling bilirUBin levels.