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Showing papers by "Nilesh J. Samani published in 2014"


Journal ArticleDOI
Andrew R. Wood1, Tõnu Esko2, Jian Yang3, Sailaja Vedantam4  +441 moreInstitutions (132)
TL;DR: This article identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height, and all common variants together captured 60% of heritability.
Abstract: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

1,872 citations


Journal ArticleDOI
Jacy R Crosby1, Gina M. Peloso2, Gina M. Peloso3, Paul L. Auer4, David R. Crosslin5, Nathan O. Stitziel6, Leslie A. Lange7, Yingchang Lu8, Zheng-Zheng Tang7, He Zhang9, George Hindy10, Nicholas G. D. Masca11, Kathleen Stirrups12, Stavroula Kanoni12, Ron Do3, Ron Do2, Goo Jun9, Youna Hu9, Hyun Min Kang9, Chenyi Xue9, Anuj Goel13, Martin Farrall13, Stefano Duga14, Pier Angelica Merlini, Rosanna Asselta14, Domenico Girelli15, Oliviero Olivieri15, Nicola Martinelli15, Wu Yin16, Dermot F. Reilly16, Elizabeth K. Speliotes9, Caroline S. Fox17, Kristian Hveem18, Oddgeir L. Holmen19, Majid Nikpay20, Deborah N. Farlow3, Themistocles L. Assimes21, Nora Franceschini7, Jennifer G. Robinson22, Kari E. North7, Lisa W. Martin23, Mark A. DePristo3, Namrata Gupta3, Stefan A. Escher10, Jan-Håkan Jansson24, Natalie R. van Zuydam25, Colin N. A. Palmer25, Nicholas J. Wareham26, Werner Koch27, Thomas Meitinger27, Annette Peters, Wolfgang Lieb28, Raimund Erbel, Inke R. König29, Jochen Kruppa29, Franziska Degenhardt30, Omri Gottesman8, Erwin P. Bottinger8, Christopher J. O'Donnell17, Bruce M. Psaty5, Bruce M. Psaty31, Christie M. Ballantyne32, Christie M. Ballantyne33, Gonçalo R. Abecasis9, Jose M. Ordovas34, Jose M. Ordovas35, Olle Melander10, Hugh Watkins13, Marju Orho-Melander10, Diego Ardissino, Ruth J. F. Loos8, Ruth McPherson20, Cristen J. Willer9, Jeanette Erdmann29, Alistair S. Hall36, Nilesh J. Samani11, Panos Deloukas37, Panos Deloukas38, Panos Deloukas12, Heribert Schunkert27, James G. Wilson39, Charles Kooperberg40, Stephen S. Rich41, Russell P. Tracy42, Danyu Lin7, David Altshuler2, David Altshuler3, Stacey Gabriel3, Deborah A. Nickerson5, Gail P. Jarvik5, L. Adrienne Cupples43, L. Adrienne Cupples26, Alexander P. Reiner40, Alexander P. Reiner5, Eric Boerwinkle33, Sekar Kathiresan3, Sekar Kathiresan2 
TL;DR: Rare mutations that disrupt AP OC3 function were associated with lower levels of plasma triglycerides and APOC3, and carriers of these mutations were found to have a reduced risk of coronary heart disease.
Abstract: Background Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. Methods We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. Results An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10 − 20 ), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P = 8×10 − 10 ). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P = 4×10 − 6 ). Conclusions Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.)

877 citations


Journal ArticleDOI
TL;DR: Increased BMI in adults of European origin is associated with increased methylation at the HIF3A locus in blood cells and in adipose tissue, and perturbation of hypoxia inducible transcription factor pathways could have an important role in the response to increased weight in people.

690 citations


Journal ArticleDOI
01 Jun 2014-Heart
TL;DR: Non-adherence to blood pressure lowering therapy is common, particularly in patients with suboptimal blood pressure control and those referred for renal denervation, and high-performance liquid chromatography-tandem mass spectrometry urine analysis could be used to exclude non- adherence and better stratify further investigations and intervention.
Abstract: Objectives Non-adherence to therapy is an important cause of suboptimal blood pressure control but few practical tools exist to accurately and routinely detect it. We used a simple urine-based assay to evaluate the prevalence of antihypertensive treatment non-adherence and its impact on blood pressure in a specialist hypertension centre. Methods 208 hypertensive patients (125 new referrals, 66 follow-up patients with inadequate blood pressure control and 17 renal denervation referrals) underwent assessment of antihypertensive drug intake using highperformance liquid chromatography-tandem mass spectrometry (HP LC-MS/MS) urine analysis at the time of clinical appointment. A total of 40 most commonly prescribed antihypertensive medications (or their metabolites) were screened for in spot urine samples. Results Overall, 25% of patients were totally or partially non-adherent to antihypertensive treatment (total non-adherence 10.1%, partial non-adherence 14.9%). The highest prevalence of partial and total nonadherence was among follow-up patients with inadequate blood pressure control (28.8%) and those referred for consideration of renal denervation (23.5%), respectively. There was a linear relationship between blood pressure and the numerical difference in detected/ prescribed antihypertensive medications—every unit increase in this difference was associated with 3.0 (1.1) mm Hg, 3.1 (0.7) mm Hg and 1.9 (0.7) mm Hg increase in adjusted clinic systolic blood pressure, clinic diastolic blood pressure (DBP) and 24 h mean daytime DBP (p=0.0051, p=8.62×10 −6 , p=0.0057), respectively. Conclusions Non-adherence to blood pressure lowering therapy is common, particularly in patients with suboptimal blood pressure control and those referred for renal denervation. HP LC-MS/MS urine analysis could be used to exclude non-adherence and better stratify further investigations and intervention.

325 citations


Journal ArticleDOI
01 Jan 2014-Stroke
TL;DR: In this article, the authors conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases and found substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.
Abstract: BACKGROUND AND PURPOSE: Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. METHODS: Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype. RESULTS: Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10(-8)) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10(-7)) and ABO (PIS=2.6×10(-4)), as well as at HDAC9 (PLAS=2.32×10(-12)), 9p21 (PLAS=3.70×10(-6)), RAI1-PEMT-RASD1 (PLAS=2.69×10(-5)), EDNRA (PLAS=7.29×10(-4)), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10(-4)). CONCLUSIONS: Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.

317 citations


Journal ArticleDOI
TL;DR: The findings suggest the existence of dynamic, reversible site-specific methylation changes in response to cigarette smoking, which may contribute to the extended health risks associated with cigarette smoking.
Abstract: Smoking is a major risk factor in many diseases. Genome wide association studies have linked genes for nicotine dependence and smoking behavior to increased risk of cardiovascular, pulmonary, and malignant diseases. We conducted an epigenome wide association study in peripheral-blood DNA in 464 individuals (22 current smokers and 263 ex-smokers), using the Human Methylation 450 K array. Upon replication in an independent sample of 356 twins (41 current and 104 ex-smokers), we identified 30 probes in 15 distinct loci, all of which reached genome-wide significance in the combined analysis P < 5 × 10(-8). All but one probe (cg17024919) remained significant after adjusting for blood cell counts. We replicated all 9 known loci and found an independent signal at CPOX near GPR15. In addition, we found 6 new loci at PRSS23, AVPR1B, PSEN2, LINC00299, RPS6KA2, and KIAA0087. Most of the lead probes (13 out of 15) associated with cigarette smoking, overlapped regions of open chromatin (FAIRE and DNaseI hypersensitive sites) or/and H3K27Ac peaks (ENCODE data set), which mark regulatory elements. The effect of smoking on DNA methylation was partially reversible upon smoking cessation for longer than 3 months. We report the first statistically significant interaction between a SNP (rs2697768) and cigarette smoking on DNA methylation (cg03329539). We provide evidence that the metSNP for cg03329539 regulates expression of the CHRND gene located circa 95 Kb downstream of the methylation site. Our findings suggest the existence of dynamic, reversible site-specific methylation changes in response to cigarette smoking , which may contribute to the extended health risks associated with cigarette smoking.

292 citations


Journal ArticleDOI
Dan E. Arking1, Sara L. Pulit2, Sara L. Pulit3, Sara L. Pulit4  +257 moreInstitutions (73)
TL;DR: In this paper, the authors identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization.
Abstract: The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

283 citations


Journal ArticleDOI
Joris Deelen, Marian Beekman, Hae-Won Uh, Linda Broer, Kristin L. Ayers1, Qihua Tan, Yoichiro Kamatani2, Anna M. Bennet3, Riin Tamm4, Stella Trompet5, Daníel F. Guðbjartsson6, Friederike Flachsbart, Giuseppina Rose7, Alexander Viktorin3, Krista Fischer, Marianne Nygaard, Heather J. Cordell1, Paolina Crocco7, Erik B. van den Akker8, Stefan Böhringer, Quinta Helmer, Christopher P. Nelson9, Gary Saunders10, Maris Alver4, Karen Andersen-Ranberg, Marie E. Breen11, Ruud van der Breggen, Amke Caliebe12, Miriam Capri, Elisa Cevenini, Joanna Collerton13, Serena Dato7, Karen Davies13, Ian Ford, Jutta Gampe14, Paolo Garagnani, Eco J. C. de Geus15, Jennifer Harrow10, Diana van Heemst5, Bastiaan T. Heijmans, Femke-Anouska Heinsen, Jouke-Jan Hottenga16, Albert Hofman, Bernard Jeune, Palmi V. Jonsson17, Mark Lathrop15, Doris Lechner, Carmen Martin-Ruiz13, Susan E. McNerlan18, E. Mihailov19, Alberto Montesanto7, Simon P. Mooijaart5, A. Murphy11, Ellen A. Nohr20, Lavinia Paternoster21, Iris Postmus5, Fernando Rivadeneira22, Owen A. Ross11, Stefano Salvioli, Naveed Sattar23, Stefan Schreiber12, Hreinn Stefansson6, David J. Stott23, Henning Tiemeier22, André G. Uitterlinden22, Rudi G. J. Westendorp5, Gonneke Willemsen16, Nilesh J. Samani9, Pilar Galan24, Thorkild I. A. Sørensen25, Dorret I. Boomsma16, J. Wouter Jukema, Irene Maeve Rea11, Giuseppe Passarino7, Anton J. M. de Craen5, Kaare Christensen26, Almut Nebel, Kari Stefansson6, Andres Metspalu4, Patrik K. E. Magnusson3, Hélène Blanché2, Lene Christiansen, Thomas B. L. Kirkwood13, Cornelia M. van Duijn, Claudio Franceschi27, Jeanine J. Houwing-Duistermaat, P. Eline Slagboom 
TL;DR: The first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population is reported, with the minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure.
Abstract: The genetic contribution to the variation in human lifespan is ∼ 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥ 90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10(-36)), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.

222 citations


Journal ArticleDOI
TL;DR: The results suggest genetic influences on a diverse set of both known and novel biological processes that contribute to CAD risk, and highlight potential novel targets for further mechanistic studies and therapeutic interventions.
Abstract: The majority of the heritability of coronary artery disease (CAD) remains unexplained, despite recent successes of genome-wide association studies (GWAS) in identifying novel susceptibility loci. Integrating functional genomic data from a variety of sources with a large-scale meta-analysis of CAD GWAS may facilitate the identification of novel biological processes and genes involved in CAD, as well as clarify the causal relationships of established processes. Towards this end, we integrated 14 GWAS from the CARDIoGRAM Consortium and two additional GWAS from the Ottawa Heart Institute (25,491 cases and 66,819 controls) with 1) genetics of gene expression studies of CAD-relevant tissues in humans, 2) metabolic and signaling pathways from public databases, and 3) data-driven, tissue-specific gene networks from a multitude of human and mouse experiments. We not only detected CAD-associated gene networks of lipid metabolism, coagulation, immunity, and additional networks with no clear functional annotation, but also revealed key driver genes for each CAD network based on the topology of the gene regulatory networks. In particular, we found a gene network involved in antigen processing to be strongly associated with CAD. The key driver genes of this network included glyoxalase I (GLO1) and peptidylprolyl isomerase I (PPIL1), which we verified as regulatory by siRNA experiments in human aortic endothelial cells. Our results suggest genetic influences on a diverse set of both known and novel biological processes that contribute to CAD risk. The key driver genes for these networks highlight potential novel targets for further mechanistic studies and therapeutic interventions.

187 citations


Journal ArticleDOI
TL;DR: This review article discusses the opportunities and challenges of MR studies for CAD, highlighting several examples that involved multiple biomarkers, including various lipid and inflammation traits as well as hypertension, diabetes mellitus, and obesity.
Abstract: Epidemiological research over the last 50 years has discovered a plethora of biomarkers (including molecules, traits or other diseases) that associate with coronary artery disease (CAD) risk. Even the strongest association detected in such observational research precludes drawing conclusions about the causality underlying the relationship between biomarker and disease. Mendelian randomization (MR) studies can shed light on the causality of associations, i.e whether, on the one hand, the biomarker contributes to the development of disease or, on the other hand, the observed association is confounded by unrecognized exogenous factors or due to reverse causation, i.e. due to the fact that prevalent disease affects the level of the biomarker. However, conclusions from a MR study are based on a number of important assumptions. A prerequisite for such studies is that the genetic variant employed affects significantly the biomarker under investigation but has no effect on other phenotypes that might confound the association between the biomarker and disease. If this biomarker is a true causal risk factor for CAD, genotypes of the variant should associate with CAD risk in the direction predicted by the association of the biomarker with CAD. Given a random distribution of exogenous factors in individuals carrying respective genotypes, groups represented by the genotypes are highly similar except for the biomarker of interest. Thus, the genetic variant converts into an unconfounded surrogate of the respective biomarker. This scenario is nicely exemplified for LDL cholesterol. Almost every genotype found to increase LDL cholesterol level by a sufficient amount has also been found to increase CAD risk. Pending a number of conditions that needed to be fulfilled by the genetic variant under investigation (e.g. no pleiotropic effects) and the experimental set-up of the study, LDL cholesterol can be assumed to act as the functional component that links genotypes and CAD risk and, more importantly, it can be assumed that any modulation of LDL cholesterol-by whatever mechanism-would have similar effects on disease risk. Therefore, MR analysis has tremendous potential for identifying therapeutic targets that are likely to be causal for CAD. This review article discusses the opportunities and challenges of MR studies for CAD, highlighting several examples that involved multiple biomarkers, including various lipid and inflammation traits as well as hypertension, diabetes mellitus, and obesity.

163 citations


Journal ArticleDOI
Vinicius Tragante1, Michael R. Barnes2, Santhi K. Ganesh3, Matthew B. Lanktree4, Wei Guo5, Nora Franceschini6, Erin N. Smith7, Toby Johnson2, Michael V. Holmes8, Sandosh Padmanabhan9, Konrad J. Karczewski10, Berta Almoguera8, John Barnard11, Jens Baumert, Yen Pei C. Chang12, Clara C. Elbers1, Martin Farrall13, Mary E. Fischer14, Tom R. Gaunt15, Johannes M.I.H. Gho1, Christian Gieger, Anuj Goel13, Yan Gong16, Aaron Isaacs17, Marcus E. Kleber18, Irene Mateo Leach19, Caitrin W. McDonough16, Matthijs F.L. Meijs1, Olle Melander20, Christopher P. Nelson21, Christopher P. Nelson22, Ilja M. Nolte19, Nathan Pankratz23, Thomas S. Price, Jonathan A. Shaffer24, Sonia Shah25, Maciej Tomaszewski22, Peter J. van der Most19, Erik P A Van Iperen, Judith M. Vonk19, Kate Witkowska2, Caroline O. L. Wong2, Li Zhang11, Amber L. Beitelshees12, Gerald S. Berenson26, Deepak L. Bhatt27, Morris Brown28, Amber A. Burt29, Rhonda M. Cooper-DeHoff16, John M. C. Connell30, Karen J. Cruickshanks14, Sean P. Curtis31, George Davey-Smith15, Christian Delles9, Ron T. Gansevoort19, Xiuqing Guo32, Shen Haiqing12, Claire E. Hastie9, Marten H. Hofker1, Marten H. Hofker19, G. Kees Hovingh, Daniel Seung Kim29, Susan Kirkland33, Barbara E.K. Klein14, Ronald Klein14, Yun Li8, Steffi Maiwald, Christopher Newton-Cheh27, Eoin O'Brien34, N. Charlotte Onland-Moret1, Walter Palmas24, Afshin Parsa12, Brenda W.J.H. Penninx35, Mary Pettinger36, Ramachandran S. Vasan37, Jane E. Ranchalis29, Paul M. Ridker27, Lynda M. Rose27, Peter S. Sever38, Daichi Shimbo24, Laura Steele8, Ronald P. Stolk19, Barbara Thorand, Mieke D. Trip, Cornelia M. van Duijn17, W M Monique Verschuren1, Cisca Wijmenga19, Sharon B. Wyatt39, J. Hunter Young40, Aeilko H. Zwinderman, Connie R. Bezzina41, Eric Boerwinkle42, Juan P. Casas43, Mark J. Caulfield2, Aravinda Chakravarti40, Daniel I. Chasman27, Karina W. Davidson24, Pieter A. Doevendans1, Anna F. Dominiczak9, Garret A. FitzGerald8, John G. Gums16, Myriam Fornage42, Hakon Hakonarson8, Indrani Halder44, Hans L. Hillege19, Thomas Illig45, Gail P. Jarvik38, Julie A. Johnson16, John J.P. Kastelein, Wolfgang Koenig46, Meena Kumari25, Winfried März47, Sarah S. Murray7, Jeffrey R. O'Connell12, Albertine J. Oldehinkel19, James S. Pankow23, Daniel J. Rader8, Susan Redline27, Muredach P. Reilly8, Eric E. Schadt48, Kandice Kottke-Marchant11, Harold Snieder19, Michael Snyder10, Alice Stanton49, Martin D. Tobin22, André G. Uitterlinden17, Pim van der Harst19, Yvonne T. van der Schouw1, Nilesh J. Samani22, Nilesh J. Samani21, Hugh Watkins13, Andrew D. Johnson, Alexander P. Reiner36, Xiaofeng Zhu5, Paul I.W. de Bakker50, Daniel Levy, Folkert W. Asselbergs25, Folkert W. Asselbergs1, Patricia B. Munroe2, Brendan J. Keating8 
TL;DR: The findings extend the understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification and provide support for a putative role in hypertension of several genes.
Abstract: Blood pressure (BP) is a heritable risk factor for cardiovascular disease To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis We replicated findings in an independent set of 68,368 individuals of European ancestry Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2 Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules In summary, we identified previously unknown loci associated with BP Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification

Journal ArticleDOI
TL;DR: The aim of this study was to determine longitudinal leucocyte telomere length dynamics and identify factors associated with temporal changes in telomeres length.
Abstract: ObjectivesHuman age-dependent telomere attrition and telomere shortening are associated with several age-associated diseases and poorer overall survival. The aim of this study was to determine longitudinal leucocyte telomere length dynamics and identify factors associated with temporal changes in telomere length. Design and MethodsLeucocyte telomere length was measured by quantitative polymerase chain reaction in 8074 participants from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study, an ongoing community-based prospective cohort study initiated in 1997. Follow-up data were available at two time-points up to 2007. Leucocyte telomere length was measured, on between one and three separate occasions, in a total of 16783 DNA samples. Multilevel growth models were created to identify the factors that influence leucocyte telomere dynamics. ResultsWe observed an average attrition rate of 0.470.16 relative telomere length units (RTLUs) per year in the study population aged 48 (range 39-60) years at baseline. Annual telomere attrition rate increased with age (P ConclusionsSmoking and variables linked to the metabolic syndrome are modifiable lifestyle factors that accelerate telomere attrition in humans. The higher rate of cellular ageing may mediate the link between smoking and the metabolic syndrome to an increased risk of several age-associated diseases.

Journal ArticleDOI
TL;DR: This paper identified a new SNP associated with glioma risk, rs1920116 (near TERC), that reached genome-wide significance (Pcombined = 8.3 × 10(-9)) in a meta-analysis of genomewide association studies.
Abstract: Glioma, the most common central nervous system cancer in adults, has poor prognosis. Here we identify a new SNP associated with glioma risk, rs1920116 (near TERC), that reached genome-wide significance (Pcombined = 8.3 × 10(-9)) in a meta-analysis of genome-wide association studies (GWAS) of high-grade glioma and replication data (1,644 cases and 7,736 controls). This region has previously been associated with mean leukocyte telomere length (LTL). We therefore examined the relationship between LTL and both this new risk locus and other previously established risk loci for glioma using data from a recent GWAS of LTL (n = 37,684 individuals). Alleles associated with glioma risk near TERC and TERT were strongly associated with longer LTL (P = 5.5 × 10(-20) and 4.4 × 10(-19), respectively). In contrast, risk-associated alleles near RTEL1 were inconsistently associated with LTL, suggesting the presence of distinct causal alleles. No other risk loci for glioma were associated with LTL. The identification of risk alleles for glioma near TERC and TERT that also associate with telomere length implicates telomerase in gliomagenesis.

04 Dec 2014
TL;DR: The results indicate a genetic architecture for human height that is characterized by a very large but finite number of causal variants, including mTOR, osteoglycin and binding of hyaluronic acid.
Abstract: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate–related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Journal ArticleDOI
TL;DR: The results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.
Abstract: Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated age ...

Journal ArticleDOI
TL;DR: LTL is confirmed to be a marker of prospective mortality in middle and highly advanced age and this association could not be explained by the association of LTL with various immune-related markers.
Abstract: Background: Human leukocyte telomere length (LTL) decreases with age and shorter LTL has previously been associated with increased prospective mortality. However, it is not clear whether LTL merely marks the health status of an individual by its association with parameters of immune function, for example, or whether telomere shortening also contributes causally to lifespan variation in humans. Methods: We measured LTL in 870 nonagenarian siblings (mean age 93 years), 1580 of their offspring and 725 spouses thereof (mean age 59 years) from the Leiden Longevity Study (LLS). Results: We found that shorter LTL is associated with increased prospective mortality in middle (30-80 years; hazard ratio (HR) = 0.75, P = 0.001) and highly advanced age (≥90 years; HR = 0.92, P = 0.028), and show that this association cannot be explained by the association of LTL with the immune-related markers insulin-like growth factor 1 to insulin-like growth factor binding protein 3 molar ratio, C-reactive protein, interleukin 6, cytomegalovirus serostatus or white blood cell counts. We found no difference in LTL between the middle-aged LLS offspring and their spouses (β = 0.006, P = 0.932). Neither did we observe an association of LTL-associated genetic variants with mortality in a prospective meta-analysis of multiple cohorts (n = 8165). Conclusions: We confirm LTL to be a marker of prospective mortality in middle and highly advanced age and additionally show that this association could not be explained by the association of LTL with various immune-related markers. Furthermore, the approaches performed here do not further support the hypothesis that LTL variation contributes to the genetic propensity for longevity.

Journal ArticleDOI
TL;DR: It is demonstrated that blood vasculatures in the adipose tissues experience continuous changes during aging and VEGF is a key angiogenic factor controlling microvessel numbers and functions and has therapeutic implications for treatment of obesity and diabetes with anti-VEGF-based antiangiogenic drugs.
Abstract: Mechanisms underlying age-related obesity and insulin resistance are generally unknown. Here, we report age-related adipose vascular changes markedly modulated fat mass, adipocyte functions, blood lipid composition, and insulin sensitivity. Notably, VEGF expression levels in various white adipose tissues (WATs) underwent changes uninterruptedly in different age populations. Anti-VEGF and anti- VEGF receptor 2 treatment in different age populations showed marked variations of vascular regression, with midaged mice exhibiting modest sensitivity. Interestingly, anti-VEGF treatment produced opposing effects on WAT adipocyte sizes in different age populations and affected vascular density and adipocyte sizes in brown adipose tissue. Consistent with changes of vasculatures and adipocyte sizes, anti-VEGF treatment increased insulin sensitivity in young and old mice but had no effects in the midaged group. Surprisingly, anti-VEGF treatment significantly improved insulin sensitivity in midaged obese mice fed a high-fat diet. Our findings demonstrate that adipose vasculatures show differential responses to anti-VEGF treatment in various age populations and have therapeutic implications for treatment of obesity and diabetes with anti-VEGF-based antiangiogenic drugs.

Journal ArticleDOI
TL;DR: By identification of a novel signal in telomere pathway genes, this study provides new molecular insight into the underlying mechanism that may regulate telomeres length and its association with human aging and cardiometabolic pathophysiology.
Abstract: Background— Telomere length is a heritable trait, and short telomere length has been associated with multiple chronic diseases. We investigated the relationship of relative leukocyte telomere length with cardiometabolic risk and performed the first genome-wide association study and meta-analysis to identify variants influencing relative telomere length in a population of Sikhs from South Asia. Methods and Results— Our results revealed a significant independent association of shorter relative telomere length with type 2 diabetes mellitus and heart disease. Our discovery genome-wide association study (n=1616) was followed by stage 1 replication of 25 top signals ( P –6 ) in an additional Sikhs (n=2397). On combined discovery and stage 1 meta-analysis (n= 4013), we identified a novel relative telomere length locus at chromosome 16q21 represented by an intronic variant (rs74019828) in the CSNK2A2 gene (β=−0.38; P =4.5×10 −8 ). We further tested 3 top variants by genotyping in UK cardiovascular disease (UKCVD) (whites n=2952) for stage 2. Next, we performed in silico replication of 139 top signals ( P –5 ) in UK Twin, Nurses Heart Study, Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, and MD Anderson Cancer Controls (n=10 033) and joint meta-analysis (n=16 998). The observed signal in CSNK2A2 was confined to South Asians and could not be replicated in whites because of significant difference in allele frequencies ( P Conclusions— By identification of a novel signal in telomere pathway genes, our study provides new molecular insight into the underlying mechanism that may regulate telomere length and its association with human aging and cardiometabolic pathophysiology.

Journal ArticleDOI
Sachiko Yoneyama1, Yiran Guo2, Yiran Guo3, Matthew B. Lanktree4, Michael R. Barnes5, Michael R. Barnes6, Clara C. Elbers7, Konrad J. Karczewski8, Sandosh Padmanabhan9, Florianne Bauer7, Jens Baumert, Amber L. Beitelshees10, Gerald S. Berenson11, Jolanda M. A. Boer, Gregory L. Burke12, Brian E. Cade13, Wei Chen11, Rhonda M. Cooper-DeHoff14, Tom R. Gaunt15, Christian Gieger, Yan Gong14, Mathias Gorski16, Nancy L. Heard-Costa17, Toby Johnson6, Michael J. LaMonte18, Caitrin W. McDonough14, Keri L. Monda19, Keri L. Monda1, N. Charlotte Onland-Moret7, Christopher P. Nelson20, Christopher P. Nelson21, Jeffrey R. O'Connell10, Jose M. Ordovas22, Inga Peter23, Annette Peters, Jonathan A. Shaffer24, Haiqinq Shen10, Erin N. Smith25, Liz Speilotes13, Liz Speilotes26, Liz Speilotes27, Fridtjof Thomas28, Barbara Thorand, W. M. Monique Verschuren, Sonia S. Anand4, Sonia S. Anand29, Anna F. Dominiczak9, Karina W. Davidson24, Robert A. Hegele30, Iris M. Heid16, Marten H. Hofker31, Gordon S. Huggins22, Thomas Illig32, Julie A. Johnson14, Susan Kirkland33, Wolfgang König34, Taimour Y. Langaee14, Jeanne M. McCaffery35, Jeanne M. McCaffery36, Olle Melander37, Braxton D. Mitchell10, Patricia B. Munroe6, Sarah S. Murray38, George J. Papanicolaou39, Susan Redline13, Muredach P. Reilly3, Nilesh J. Samani20, Nilesh J. Samani21, Nicholas J. Schork38, Nicholas J. Schork40, Yvonne T. van der Schouw7, Daichi Shimbo24, Alan R. Shuldiner10, Alan R. Shuldiner41, Martin D. Tobin20, Cisca Wijmenga31, Salim Yusuf4, Salim Yusuf29, Hakon Hakonarson3, Leslie A. Lange1, Ellen W. Demerath42, Caroline S. Fox17, Kari E. North1, Alexander P. Reiner43, Brendan J. Keating3, Kira C. Taylor44 
TL;DR: Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue, supporting an already established sexual dimorphism of central adiposity-related genetic variants.
Abstract: Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.

Journal ArticleDOI
TL;DR: Common COMT polymorphisms were associated with incident CVD, and this association was modified by randomized allocation to aspirin or vitamin E.
Abstract: Objective— Catechol- O -methyltransferase (COMT), a key enzyme in catecholamine metabolism, is implicated in cardiovascular, sympathetic, and endocrine pathways. This study aimed to confirm preliminary association of COMT genetic variation with incident cardiovascular disease (CVD). It further aimed to evaluate whether aspirin, a commonly used CVD prevention agent, modified the potential association of COMT with incident CVD. Approach and Results— We examined COMT polymorphism rs4680 (MAF [minor allele frequency], 0.47), encoding a nonsynonymous methionine-to-valine substitution, in the Women’s Genome Health Study (WGHS), a large population-based cohort of women with randomized allocation to aspirin or vitamin E when compared with placebo and 10-year follow-up. Rs4680 effects were confirmed with COMT polymorphism rs4818 and also examined in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis/The Coronary Artery Disease Genetics Consortium, consortia for genome-wide association studies of coronary artery disease. Among WGHS women allocated to placebo (135 events/n=5811), the rs4680 valine allele was protective against incident CVD relative to the methionine (hazard ratio [HR; 95% confidence interval {CI}], 0.66 [0.51–0.84]; P =0.0007); an association also observed in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis and The Coronary Artery Disease Genetics Consortium (combined P =2.4×10 −5 ). In the WGHS, the rs4680 association was abolished by randomized allocation to aspirin, such that valine/valine women experienced higher CVD rates with aspirin allocation when compared with placebo (HR [95% CI], 1.85 [1.05–3.25]; P =0.033), whereas methionine/methionine women experienced lower rates (HR [95% CI], 0.60 [0.39–0.93]; P =0.023). Allocation to vitamin E also conferred higher but nonsignificant CVD rates on valine/valine (HR [95% CI], 1.50 [0.83–2.70]; P =0.180) when compared with significantly lower rates on methionine/methionine (HR [95% CI], 0.53 [0.34–0.84]; P =0.006) women. Rs4818 results were similar. Conclusions— Common COMT polymorphisms were associated with incident CVD, and this association was modified by randomized allocation to aspirin or vitamin E. Replication of these findings is required.

Journal ArticleDOI
04 Aug 2014-Heart
TL;DR: R2I2 and PERS each independently and in combination, identify patients with ICM that are at high risk of developing ventricular arrhythmias (VA) and represent promising risk markers for SCD discrimination.
Abstract: Objective To improve prediction of sudden cardiac death (SCD) in patients with ischaemic cardiomyopathy (ICM). Electrical heterogeneity is known to contribute to risk of SCD. We have previously developed Regional Restitution Instability Index (R2I2), an ECG-based biomarker, which quantifies cardiac electrical instability by measuring heterogeneity in electrical restitution, and demonstrated its potential utility for risk stratification in a retrospective analysis of patients with ICM. Here, we examined R2I2 in a prospective ICM cohort and also tested the predictive value of another ECG-based biomarker, Peak ECG Restitution Slope (PERS). Methods Prospective, blinded, observational study of 60 patients with ICM undergoing implantable cardioverter defibrillator risk stratification. R2I2 was calculated from an electrophysiological study (EPS) using ECG surrogates for action potential duration and diastolic interval. R2I2 quantifies inter-lead electrical restitution heterogeneity. PERS was the peak restitution curve slope taken as a mean across the 12 ECG leads. Endpoints were ventricular arrhythmia (VA)/SCD. Results Over median follow-up of 22 months, 16 (26.6%) patients achieved endpoint. R2I2 was significantly higher in these patients compared with those without an event (mean±SEM: 1.11±0.09 vs 0.84±0.04, p=0.003) as was PERS (median(IQR): 1.35(0.60) vs 1.08(0.52), p=0.014). R2I2≥1.03, the cut-off used in our previous study, identified patients with a significantly higher risk of VA/SCD independent of EPS result, LVEF or QRS duration with a relative risk of 6.5 (p=0.008). Patients positive for R2I2 and PERS had a relative risk of VA/SCD 21.6 times that of those negative for R2I2 and PERS (p Conclusions R2I2 and PERS each independently and in combination, identify patients with ICM that are at high risk of developing ventricular arrhythmias (VA). R2I2/PERS represent promising risk markers for SCD discrimination. Trial registration number ClinicalTrials.gov Identifier: NCT01944514.

Journal ArticleDOI
15 Jul 2014-Heart
TL;DR: STEMI complicated by resuscitated CA merits careful monitoring in the early period postevent, particularly in patients surviving to discharge, and in contemporary practice there is no impact of resuscitatedCA on longer-term prognosis.
Abstract: Objectives To determine whether resuscitated cardiac arrest (CA) complicating ST elevation myocardial infarction (STEMI) impacts outcome, particularly in patients surviving to discharge. Background Resuscitated CA complicating STEMI is associated with increased inpatient mortality. The impact on later prognosis is unclear. Methods We analysed data from the UK Myocardial Ischaemia National Audit Project for STEMI patients admitted during January 2008–March 2010. We used survival analyses to assess the independent impact of resuscitated CA during the index episode on inhospital, 30 days, 1 year and medium term all-cause mortality. Results Of 48 749 STEMI patients, 5308 (10.9%) were recorded as having a CA. Of these, 1557 (29.3%) died on the day of CA. In survivors, after covariate adjustment, resuscitated CA was associated with increased risk of death during the index admission (HR 4.05 (3.69 to 4.45) p Conclusions STEMI complicated by resuscitated CA merits careful monitoring in the early period postevent. In contemporary practice, there is no impact of resuscitated CA on longer-term prognosis.

Journal ArticleDOI
TL;DR: The data suggest that the previously identified association between haplogroup I and coronary artery disease is not likely mediated by unfavourable profile of sex steroids or heightened aggression early in life.

Journal ArticleDOI
TL;DR: This study suggests that high leptin levels are associated with short RTL, and appeared to be determined by a single study and when the outlier study was removed, this association disappeared.
Abstract: Oxidative stress and inflammation are major contributors to accelerated age-related relative telomere length (RTL) shortening. Both conditions are strongly linked to leptin and adiponectin, the most prominent adipocyte-derived protein hormones. As high leptin levels and low levels of adiponectin have been implicated in inflammation, one expects adiponectin to be positively associated with RTL while leptin should be negatively associated. Within the ENGAGE consortium, we investigated the association of RTL with adiponectin and leptin in seven independent cohorts with a total of 11,448 participants. We performed partial correlation analysis on Z-transformed RTL and LN-transformed leptin/adiponectin, adjusting for age and sex. In extended models we adjusted for body mass index (BMI) and C-reactive protein (CRP). Adiponectin showed a borderline significant association with RTL. This appeared to be determined by a single study and when the outlier study was removed, this association disappeared. The association between RTL and leptin was highly significant (r = -0.05; p = 1.81 × 10(-7)). Additional adjustment for BMI or CRP did not change the results. Sex-stratified analysis revealed no difference between men and women. Our study suggests that high leptin levels are associated with short RTL.

Journal ArticleDOI
TL;DR: The evidence does not support a causal role for sPLA2-V in CHD and a novel approach for single-nucleotide polymorphism selection for this modified Mendelian randomization analysis showed no association between rs525380 (the lead single-molecule polymorphism for PLA2G5 expression, a surrogate for s PLA2- V levels) and CHD events.
Abstract: Background— Secretory phospholipase A2 (sPLA2) enzymes are considered to play a role in atherosclerosis. sPLA2 activity encompasses several sPLA2 isoenzymes, including sPLA2-V. Although observational studies show a strong association between elevated sPLA2 activity and CHD, no assay to measure sPLA2-V levels exists, and the only evidence linking the sPLA2-V isoform to atherosclerosis progression comes from animal studies. In the absence of an assay that directly quantifies sPLA2-V levels, we used PLA2G5 mRNA levels in a novel, modified Mendelian randomization approach to investigate the hypothesized causal role of sPLA2-V in coronary heart disease (CHD) pathogenesis. Methods and Results— Using data from the Advanced Study of Aortic Pathology, we identified the single-nucleotide polymorphism in PLA2G5 showing the strongest association with PLA2G5 mRNA expression levels as a proxy for sPLA2-V levels. We tested the association of this SNP with sPLA2 activity and CHD events in 4 prospective and 14 case–control studies with 27 230 events and 70 500 controls. rs525380C>A showed the strongest association with PLA2G5 mRNA expression ( P =5.1×10−6). There was no association of rs525380C>A with plasma sPLA2 activity (difference in geometric mean of sPLA2 activity per rs525380 A-allele 0.4% (95% confidence intervals [−0.9%, 1.6%]; P =0.56). In meta-analyses, the odds ratio for CHD per A-allele was 1.02 (95% confidence intervals [0.99, 1.04]; P =0.20). Conclusions— This novel approach for single-nucleotide polymorphism selection for this modified Mendelian randomization analysis showed no association between rs525380 (the lead single-nucleotide polymorphism for PLA2G5 expression, a surrogate for sPLA2-V levels) and CHD events. The evidence does not support a causal role for sPLA2-V in CHD.

28 Aug 2014
TL;DR: The integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
Abstract: The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8–10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval–associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

Journal ArticleDOI
31 Jan 2014-PLOS ONE
TL;DR: Moderate changes in obesity measures tracked with a significant deterioration in measures of pro-atherogenic dyslipidaemia at both personal and population level, predominantly driven by factors not measureable directly through either BMI or waist circumference.
Abstract: Objective: The impact of fast changes in obesity indices on other measures of metabolic health is poorly defined in the general population. Using the Polish accession to the European Union as a model of political and social transformation we examined how an expected rapid increase in body mass index (BMI) and waist circumference relates to changes in lipid profile, both at the population and personal level. Methods: Through primary care centres in 444 Polish cities, two cross-sectional nationwide population-based surveys (LIPIDOGRAM 2004 and LIPIDOGRAM 2006) examined 15,404 and 15,453 adult individuals in 2004 and 2006, respectively. A separate prospective sample of 1,840 individuals recruited in 2004 had a follow-up in 2006 (LIPIDOGRAM PLUS). Results: Two years after Polish accession to European Union, mean population BMI and waist circumference increased by 0.6% and 0.9%, respectively. This tracked with a 7.6% drop in HDL-cholesterol and a 2.1% increase in triglycerides (all p,0.001) nationwide. The direction and magnitude of the population changes were replicated at the personal level in LIPIDOGRAM PLUS (0.7%, 0.3%, 8.6% and 1.8%, respectively). However, increases in BMI and waist circumference were both only weakly associated with HDL-cholesterol and triglycerides changes prospectively. The relation of BMI to the magnitude of change in both lipid fractions was comparable to that of waist circumference. Conclusions: Moderate changes in obesity measures tracked with a significant deterioration in measures of pro-atherogenic dyslipidaemia at both personal and population level. These associations were predominantly driven by factors not measureable directly through either BMI or waist circumference.

Journal ArticleDOI
TL;DR: The results suggest that dense genotyping of genes, in pathways known to influence BP, could add to candidate-gene and Genome Wide Association studies in further explaining BP heritability.
Abstract: Background— Blood pressure (BP) is highly heritable, but our understanding of the genetic causes underlying variations in BP is incomplete. In this study, we explored whether novel loci associated with BP could be identified using a genecentric approach in 3 community-based cohorts with accurate BP measurements. Methods and Results— Genotyping of 1857 single nucleotide polymorphisms (SNPs) in 91 ion channel genes was performed in a discovery cohort (n=358). Thirty-four SNPs associated with BP traits ( P ≤0.01) were followed up in an independent population (n=387); significant SNPs from this analysis were looked up in another independent population (n=1010) and meta-analyzed. Repeated clinic and ambulatory measurements were available for all but the discovery cohort (clinic only). Association analyses were performed, with systolic, diastolic, and pulse pressures as quantitative traits, adjusting for age and sex. Quantile–quantile plots indicated that the genecentric approach resulted in an inflation of association signals. Of the 29 SNPs taken forward from the discovery cohort, 2 SNPs were associated with BP phenotypes with the same direction of effect, with experiment-wide significance, in follow-up cohort I. These were rs2228291, in the chloride channel gene CLCN2 , and rs10513488, in the potassium channel gene KCNAB1 . Both associations were subsequently replicated in follow-up cohort II. Conclusions— Using a genecentric design and 3 well-phenotyped populations, this study identified 2 previously unreported, biologically plausible, genetic associations with BP. These results suggest that dense genotyping of genes, in pathways known to influence BP, could add to candidate-gene and Genome Wide Association studies in further explaining BP heritability.

Journal ArticleDOI
01 Jun 2014-Heart
TL;DR: Downstream cGMP/PKG is likely to play a prominent role in this anti-hypertrophic effect in rIC, suggesting a broader cardioprotective role for rIC.
Abstract: Introduction Remote ischaemic conditioning (rIC) has mainly been implicated in protection from ischemia/reperfusion injury. Using a model of endothelin-1 (ET-1) driven cardiomyocyte hypertrophy, we have previously shown that rIC attenuates ET-1 induced hypertrophy via PKCe translocation and AMPKα phosphorylation, suggesting a broader cardioprotective role for rIC. Here we investigate downstream mechanisms in this process. Methods Blood was taken from healthy volunteers after 3 cycles of 5 min of upper arm cuff inflation/deflation and then centrifuged. The resulting rIC-serum was applied to H9c2 cardiomyoblasts in culture for 30 min. Cells were treated with ET-1 to stimulate hypertrophy. Cell area was determined using immunofluorescence after 48 h and protein levels were detected using Western blotting after 30 min and 48 h. Compound-C was used to inhibit AMP-activated protein kinase alpha (AMPKα), L-NAME to inhibit nitric oxide synthase (NOS) and 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) to inhibit NO-activation of soluble guanylate cyclase (sGC). Results ET-1 increased cell surface area by ~44% from 1.41 × 10 4 ± 0.08 μm 2 in control cells to 2.03 × 10 4 ± 0.07 μm 2 in ET-1 treated cells (n = 4–8, 500–1000 cells per treatment, p 4 ± 0.06 μm 2 , p 4 ± 0.08 μm 2 , p 4 ± 0.08 μm 2 , p Conclusions and Implications The PKCe/AMPKα/eNOS pathway is important in rIC attenuation of ET-1 induced cardiomyoblast hypertrophy. Downstream cGMP/PKG is likely to play a prominent role in this anti-hypertrophic effect and further experiments are planned to test this hypothesis.