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Find video protocols related to scientific articles indexed in Pubmed.
Origin of the y chromosome influences intrarenal vascular responsiveness to Angiotensin I and Angiotensin (1-7) in stroke-prone spontaneously hypertensive rats.
Hypertension
PUBLISHED: 09-08-2014
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The lineage of the Y chromosome accounts for up to 15 to 20 mm Hg in arterial pressure. Genes located on the Y chromosome from the spontaneously hypertensive rat (SHR) are associated with the renin-angiotensin system. Given the important role of the renin-angiotensin system in the renal regulation of fluid homeostasis and arterial pressure, we hypothesized that the origin of the Y chromosome influences arterial pressure via interaction between the intrarenal vasculature and the renin-angiotensin system. Sixteen-week-old normotensive rats (Wistar Kyoto [WKY]), spontaneously hypertensive stroke-prone rat (SHRSP), and 2 reciprocal Y consomic rat strains, 1 comprising the WKY autosomes and X chromosome with the Y chromosome from the hypertensive rat strain (WKY.SPGlaY) and vice versa (SP.WKYGlaY), were examined. SP.WKYGlaY had lower systolic blood pressure than SHRSP (195±5 versus 227±8 mm Hg; P<0.03), whereas WKY.SPGlaY had higher systolic blood pressure compared with WKY (157±3 versus 148±3 mm Hg; P<0.05), measured by radiotelemetry. Compared with WKY rats, SHRSP had higher plasma angiotensin(1-7) (Ang (1-7)):Ang II ratio (WKY: 0.13±0.01 versus SHRSP: 1.33±0.4; P<0.005), greater angiotensin II receptor type 2 and Mas receptor mRNA expression, and a blunted renal constrictor response to intrarenal Ang I and Ang(1-7) infusions. Introgression of the normotensive Y chromosome into the SHRSP background (SP.WKYGlaY) restored responses in the SHRSP to WKY levels, evidenced by a reduction in plasma Ang(1-7):Ang II ratio (SP.WKYGlaY: 0.24±0.02; P<0.01), angiotensin II receptor type 2, and Mas receptor mRNA expression and an increased vasoconstrictor response to intrarenal Ang I and Ang(1-7) infusion. This study demonstrates that the origin of the Y chromosome significantly impacts the renal vascular responsiveness and therefore may influence the long-term renal regulation of blood pressure.
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Allopurinol initiation and change in blood pressure in older adults with hypertension.
Hypertension
PUBLISHED: 08-18-2014
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Hypertension is a key risk factor for cardiovascular disease, and new treatments are needed. Uric acid reduction lowers blood pressure (BP) in adolescents, suggesting a direct pathophysiological role in the development of hypertension. Whether the same relationship is present in older adults is unknown. We explored change in BP after allopurinol initiation using data from the UK Clinical Practice Research Datalink. Data were extracted for patients with hypertension aged >65 years who were prescribed allopurinol with pretreatment and during treatment BP readings. Data from comparable controls were extracted. The change in BP in patients with stable BP medication was the primary outcome and was compared between groups. Regression analysis was used to adjust for potential confounding factors, and a propensity-matched sample was generated. Three hundred sixty-five patients who received allopurinol and 6678 controls were included. BP fell in the allopurinol group compared with controls (between-group difference in systolic and diastolic BP: 2.1 mm Hg; 95% confidence interval, -0.6 to 4.8; and 1.7 mm Hg; 95% confidence interval, 0.4-3.1, respectively). Allopurinol use was independently associated with a fall in both systolic and diastolic BP on regression analysis (P<0.001). Results were consistent in the propensity-matched sample. There was a trend toward greater fall in BP in the high-dose allopurinol group, but change in BP was not related to baseline uric acid level. Allopurinol use is associated with a small fall in BP in adults. Further studies of the effect of high-dose allopurinol in adults with hypertension are needed.
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Introgressed chromosome 2 quantitative trait loci restores aldosterone regulation and reduces response to salt in the stroke-prone spontaneously hypertensive rat.
J. Hypertens.
PUBLISHED: 08-02-2014
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The genetic contribution to salt-sensitivity in hypertension remains unclear. We have previously identified a quantitative trait locus on chromosome 2 in stroke-prone spontaneously hypertensive rats (SHRSPs) responsible for an increase in SBP in response to a salt challenge. This response is blunted in the congenic SHRSP strain with the Wistar-Kyoto (WKY) chromosome 2 region (10?cM) introgressed (SP.WKYGla2k). We aimed to discover the mechanisms that underlie the effects of this region on salt-handling in the SHRSP strain.
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Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data.
Michael V Holmes, Caroline E Dale, Luisa Zuccolo, Richard J Silverwood, Yiran Guo, Zheng Ye, David Prieto-Merino, Abbas Dehghan, Stella Trompet, Andrew Wong, Alana Cavadino, Dagmar Drogan, Sandosh Padmanabhan, Shanshan Li, Ajay Yesupriya, Maarten Leusink, Johan Sundström, Jaroslav A Hubacek, Hynek Pikhart, Daniel I Swerdlow, Andrie G Panayiotou, Svetlana A Borinskaya, Chris Finan, Sonia Shah, Karoline B Kuchenbaecker, Tina Shah, Jorgen Engmann, Lasse Folkersen, Per Eriksson, Fulvio Ricceri, Olle Melander, Carlotta Sacerdote, Dale M Gamble, Sruti Rayaprolu, Owen A Ross, Stela McLachlan, Olga Vikhireva, Ivonne Sluijs, Robert A Scott, Vera Adamkova, Leon Flicker, Frank M van Bockxmeer, Christine Power, Pedro Marques-Vidal, Tom Meade, Michael G Marmot, José M Ferro, Sofia Paulos-Pinheiro, Steve E Humphries, Philippa J Talmud, Irene Mateo Leach, Niek Verweij, Allan Linneberg, Tea Skaaby, Pieter A Doevendans, Maarten J Cramer, Pim van der Harst, Olaf H Klungel, Nicole F Dowling, Anna F Dominiczak, Meena Kumari, Andrew N Nicolaides, Cornelia Weikert, Heiner Boeing, Shah Ebrahim, Tom R Gaunt, Jackie F Price, Lars Lannfelt, Anne Peasey, Růžena Kubinova, Andrzej Pająk, Sofia Malyutina, Mikhail I Voevoda, Abdonas Tamosiunas, Anke H Maitland-van der Zee, Paul E Norman, Graeme J Hankey, Manuela M Bergmann, Albert Hofman, Oscar H Franco, Jackie Cooper, Jutta Palmen, Wilko Spiering, Pim A de Jong, Diana Kuh, Rebecca Hardy, André G Uitterlinden, M Arfan Ikram, Ian Ford, Elina Hyppönen, Osvaldo P Almeida, Nicholas J Wareham, Kay-Tee Khaw, Anders Hamsten, Lise Lotte N Husemoen, Anne Tjønneland, Janne S Tolstrup, Eric Rimm, Joline W J Beulens, W M Monique Verschuren, N Charlotte Onland-Moret, Marten H Hofker, S Goya Wannamethee, Peter H Whincup, Richard Morris, Astrid M Vicente, Hugh Watkins, Martin Farrall, J Wouter Jukema, James Meschia, L Adrienne Cupples, Stephen J Sharp, Myriam Fornage, Charles Kooperberg, Andrea Z LaCroix, James Y Dai, Matthew B Lanktree, David S Siscovick, Eric Jorgenson, Bonnie Spring, Josef Coresh, Yun R Li, Sarah G Buxbaum, Pamela J Schreiner, R Curtis Ellison, Michael Y Tsai, Sanjay R Patel, Susan Redline, Andrew D Johnson, Ron C Hoogeveen, Hakon Hakonarson, Jerome I Rotter, Eric Boerwinkle, Paul I W de Bakker, Mika Kivimäki, Folkert W Asselbergs, Naveed Sattar, Debbie A Lawlor, John Whittaker, George Davey Smith, Kenneth Mukamal, Bruce M Psaty, James G Wilson, Leslie A Lange, Ajna Hamidovic, Aroon D Hingorani, Børge G Nordestgaard, Martin Bobak, David A Leon, Claudia Langenberg, Tom M Palmer, Alex P Reiner, Brendan J Keating, Frank Dudbridge, Juan P Casas, .
BMJ
PUBLISHED: 07-12-2014
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To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease.
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Blood pressure and LDL-cholesterol targets for prevention of recurrent strokes and cognitive decline in the hypertensive patient: design of the European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment randomized trial.
J. Hypertens.
PUBLISHED: 07-01-2014
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The SBP values to be achieved by antihypertensive therapy in order to maximize reduction of cardiovascular outcomes are unknown; neither is it clear whether in patients with a previous cardiovascular event, the optimal values are lower than in the low-to-moderate risk hypertensive patients, or a more cautious blood pressure (BP) reduction should be obtained. Because of the uncertainty whether 'the lower the better' or the 'J-curve' hypothesis is correct, the European Society of Hypertension and the Chinese Hypertension League have promoted a randomized trial comparing antihypertensive treatment strategies aiming at three different SBP targets in hypertensive patients with a recent stroke or transient ischaemic attack. As the optimal level of low-density lipoprotein cholesterol (LDL-C) level is also unknown in these patients, LDL-C-lowering has been included in the design.
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Blood pressure and low-density lipoprotein-cholesterol lowering for prevention of strokes and cognitive decline: a review of available trial evidence.
J. Hypertens.
PUBLISHED: 07-01-2014
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It is well established by a large number of randomized controlled trials that lowering blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) by drugs are powerful means to reduce stroke incidence, but the optimal BP and LDL-C levels to be achieved are largely uncertain. Concerning BP targets, two hypotheses are being confronted: first, the lower the BP, the better the treatment outcome, and second, the hypothesis that too low BP values are accompanied by a lower benefit and even higher risk. It is also unknown whether BP lowering and LDL-C lowering have additive beneficial effects for the primary and secondary prevention of stroke, and whether these treatments can prevent cognitive decline after stroke.
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.
Dan E Arking, Sara L Pulit, Lia Crotti, Pim van der Harst, Patricia B Munroe, Tamara T Koopmann, Nona Sotoodehnia, Elizabeth J Rossin, Michael Morley, Xinchen Wang, Andrew D Johnson, Alicia Lundby, Daniel F Gudbjartsson, Peter A Noseworthy, Mark Eijgelsheim, Yuki Bradford, Kirill V Tarasov, Marcus Dörr, Martina Müller-Nurasyid, Annukka M Lahtinen, Ilja M Nolte, Albert Vernon Smith, Joshua C Bis, Aaron Isaacs, Stephen J Newhouse, Daniel S Evans, Wendy S Post, Daryl Waggott, Leo-Pekka Lyytikäinen, Andrew A Hicks, Lewin Eisele, David Ellinghaus, Caroline Hayward, Pau Navarro, Sheila Ulivi, Toshiko Tanaka, David J Tester, Stéphanie Chatel, Stefan Gustafsson, Meena Kumari, Richard W Morris, Asa T Naluai, Sandosh Padmanabhan, Alexander Kluttig, Bernhard Strohmer, Andrie G Panayiotou, Maria Torres, Michael Knoflach, Jaroslav A Hubacek, Kamil Slowikowski, Soumya Raychaudhuri, Runjun D Kumar, Tamara B Harris, Lenore J Launer, Alan R Shuldiner, Alvaro Alonso, Joel S Bader, Georg Ehret, Hailiang Huang, W H Linda Kao, James B Strait, Peter W Macfarlane, Morris Brown, Mark J Caulfield, Nilesh J Samani, Florian Kronenberg, Johann Willeit, , J Gustav Smith, Karin H Greiser, Henriette Meyer zu Schwabedissen, Karl Werdan, Massimo Carella, Leopoldo Zelante, Susan R Heckbert, Bruce M Psaty, Jerome I Rotter, Ivana Kolčić, Ozren Polašek, Alan F Wright, Maura Griffin, Mark J Daly, David O Arnar, Hilma Holm, Unnur Thorsteinsdottir, Joshua C Denny, Dan M Roden, Rebecca L Zuvich, Valur Emilsson, Andrew S Plump, Martin G Larson, Christopher J O'Donnell, Xiaoyan Yin, Marco Bobbo, Adamo P d'Adamo, AnnaMaria Iorio, Gianfranco Sinagra, Angel Carracedo, Steven R Cummings, Michael A Nalls, Antti Jula, Kimmo K Kontula, Annukka Marjamaa, Lasse Oikarinen, Markus Perola, Kimmo Porthan, Raimund Erbel, Per Hoffmann, Karl-Heinz Jöckel, Hagen Kälsch, Markus M Nöthen, Marcel den Hoed, Ruth J F Loos, Dag S Thelle, Christian Gieger, Thomas Meitinger, Siegfried Perz, Annette Peters, Hanna Prucha, Moritz F Sinner, Melanie Waldenberger, Rudolf A de Boer, Lude Franke, Pieter A van der Vleuten, Britt Maria Beckmann, Eimo Martens, Abdennasser Bardai, Nynke Hofman, Arthur A M Wilde, Elijah R Behr, Chrysoula Dalageorgou, John R Giudicessi, Argelia Medeiros-Domingo, Julien Barc, Florence Kyndt, Vincent Probst, Alice Ghidoni, Roberto Insolia, Robert M Hamilton, Stephen W Scherer, Jeffrey Brandimarto, Kenneth Margulies, Christine E Moravec, Fabiola Del Greco M, Christian Fuchsberger, Jeffrey R O'Connell, Wai K Lee, Graham C M Watt, Harry Campbell, Sarah H Wild, Nour E El Mokhtari, Norbert Frey, Folkert W Asselbergs, Irene Mateo Leach, Gerjan Navis, Maarten P van den Berg, Dirk J van Veldhuisen, Manolis Kellis, Bouwe P Krijthe, Oscar H Franco, Albert Hofman, Jan A Kors, André G Uitterlinden, Jacqueline C M Witteman, Lyudmyla Kedenko, Claudia Lamina, Ben A Oostra, Gonçalo R Abecasis, Edward G Lakatta, Antonella Mulas, Marco Orrù, David Schlessinger, Manuela Uda, Marcello R P Markus, Uwe Völker, Harold Snieder, Timothy D Spector, Johan Arnlöv, Lars Lind, Johan Sundström, Ann-Christine Syvänen, Mika Kivimäki, Mika Kähönen, Nina Mononen, Olli T Raitakari, Jorma S Viikari, Vera Adamkova, Stefan Kiechl, María Brión, Andrew N Nicolaides, Bernhard Paulweber, Johannes Haerting, Anna F Dominiczak, Fredrik Nyberg, Peter H Whincup, Aroon D Hingorani, Jean-Jacques Schott, Connie R Bezzina, Erik Ingelsson, Luigi Ferrucci, Paolo Gasparini, James F Wilson, Igor Rudan, Andre Franke, Thomas W Mühleisen, Peter P Pramstaller, Terho J Lehtimäki, Andrew D Paterson, Afshin Parsa, Yongmei Liu, Cornelia M van Duijn, David S Siscovick, Vilmundur Gudnason, Yalda Jamshidi, Veikko Salomaa, Stephan B Felix, Serena Sanna, Marylyn D Ritchie, Bruno H Stricker, Kari Stefansson, Laurie A Boyer, Thomas P Cappola, Jesper V Olsen, Kasper Lage, Peter J Schwartz, Stefan Kääb, Aravinda Chakravarti, Michael J Ackerman, Arne Pfeufer, Paul I W de Bakker, Christopher Newton-Cheh.
Nat. Genet.
PUBLISHED: 05-29-2014
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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.
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Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing: a population-based study.
BMC Med. Genet.
PUBLISHED: 03-04-2014
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Familial hypercholesterolaemia (FH) is a common Mendelian condition which, untreated, results in premature coronary heart disease. An estimated 88% of FH cases are undiagnosed in the UK. We previously validated a method for FH mutation detection in a lipid clinic population using next generation sequencing (NGS), but this did not address the challenge of identifying index cases in primary care where most undiagnosed patients receive healthcare. Here, we evaluate the targeted use of NGS as a potential route to diagnosis of FH in a primary care population subset selected for hypercholesterolaemia.
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Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci.
Vinicius Tragante, Michael R Barnes, Santhi K Ganesh, Matthew B Lanktree, Wei Guo, Nora Franceschini, Erin N Smith, Toby Johnson, Michael V Holmes, Sandosh Padmanabhan, Konrad J Karczewski, Berta Almoguera, John Barnard, Jens Baumert, Yen-Pei Christy Chang, Clara C Elbers, Martin Farrall, Mary E Fischer, Tom R Gaunt, Johannes M I H Gho, Christian Gieger, Anuj Goel, Yan Gong, Aaron Isaacs, Marcus E Kleber, Irene Mateo Leach, Caitrin W McDonough, Matthijs F L Meijs, Olle Melander, Christopher P Nelson, Ilja M Nolte, Nathan Pankratz, Tom S Price, Jonathan Shaffer, Sonia Shah, Maciej Tomaszewski, Peter J van der Most, Erik P A van Iperen, Judith M Vonk, Kate Witkowska, Caroline O L Wong, Li Zhang, Amber L Beitelshees, Gerald S Berenson, Deepak L Bhatt, Morris Brown, Amber Burt, Rhonda M Cooper-DeHoff, John M Connell, Karen J Cruickshanks, Sean P Curtis, George Davey-Smith, Christian Delles, Ron T Gansevoort, Xiuqing Guo, Shen Haiqing, Claire E Hastie, Marten H Hofker, G Kees Hovingh, Daniel S Kim, Susan A Kirkland, Barbara E Klein, Ronald Klein, Yun R Li, Steffi Maiwald, Christopher Newton-Cheh, Eoin T O'Brien, N Charlotte Onland-Moret, Walter Palmas, Afshin Parsa, Brenda W Penninx, Mary Pettinger, Ramachandran S Vasan, Jane E Ranchalis, Paul M Ridker, Lynda M Rose, Peter Sever, Daichi Shimbo, Laura Steele, Ronald P Stolk, Barbara Thorand, Mieke D Trip, Cornelia M van Duijn, W Monique Verschuren, Cisca Wijmenga, Sharon Wyatt, J Hunter Young, Aeilko H Zwinderman, Connie R Bezzina, Eric Boerwinkle, Juan P Casas, Mark J Caulfield, Aravinda Chakravarti, Daniel I Chasman, Karina W Davidson, Pieter A Doevendans, Anna F Dominiczak, Garret A FitzGerald, John G Gums, Myriam Fornage, Hakon Hakonarson, Indrani Halder, Hans L Hillege, Thomas Illig, Gail P Jarvik, Julie A Johnson, John J P Kastelein, Wolfgang Koenig, Meena Kumari, Winfried März, Sarah S Murray, Jeffery R O'Connell, Albertine J Oldehinkel, James S Pankow, Daniel J Rader, Susan Redline, Muredach P Reilly, Eric E Schadt, Kandice Kottke-Marchant, Harold Snieder, Michael Snyder, Alice V Stanton, Martin D Tobin, André G Uitterlinden, Pim van der Harst, Yvonne T van der Schouw, Nilesh J Samani, Hugh Watkins, Andrew D Johnson, Alex P Reiner, Xiaofeng Zhu, Paul I W de Bakker, Daniel Levy, Folkert W Asselbergs, Patricia B Munroe, Brendan J Keating.
Am. J. Hum. Genet.
PUBLISHED: 02-20-2014
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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.
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Mendelian randomization of blood lipids for coronary heart disease.
Eur. Heart J.
PUBLISHED: 01-30-2014
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To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization.
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Gene-centric meta-analyses for central adiposity traits in up to 57,412 individuals of European descent confirm known loci and reveal several novel associations.
Hum. Mol. Genet.
PUBLISHED: 12-17-2013
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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 NHLBIs Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20 to 80. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ?50,000 cosmopolitan tagged SNPs across ?2,100 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<2.4x10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (?±SE,0.048±0.008, P=7.7x10(-9)) as was rs7302703-G in HOXC10 (?=0.044±0.008, P=2.9x10(-7)) and rs936108-C in PEMT (?=0.035±0.007, P=1.9x10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A near SHC1 (?=0.10±0.02, P=1.9x10(-6)), and rs1037575-A in ATBDB4 (?=0.046±0.01, P=2.2x10(-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.
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Family history of premature cardiovascular disease: blood pressure control and long-term mortality outcomes in hypertensive patients.
Eur. Heart J.
PUBLISHED: 12-15-2013
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Current guidelines recommend early referral and initiation of intensive cardiovascular (CV) risk reduction in individuals with a positive family history of coronary heart disease (CHD). We hypothesized that a family history of premature CHD and stroke [CV disease (CVD)] would lead to earlier referral of hypertensive patients to secondary care clinic, leading to better control of risk factors, mitigating the excess risk seen in these individuals.
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Validation of Uromodulin as a Candidate Gene for Human Essential Hypertension.
Hypertension
PUBLISHED: 12-09-2013
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A recent genome-wide association study identified a locus on chromosome 16 in the promoter region of the uromodulin (UMOD) gene that is associated with hypertension. Here, we examined the hypertension signal with functional studies in Umod knockout (KO) mice. Systolic blood pressure was significantly lower in KO versus wild-type (WT) mice under basal conditions (KO: 116.6±0.3 mm Hg versus WT: 136.2±0.4 mm Hg; P<0.0001). Administration of 2% NaCl did not alter systolic blood pressure in KO mice, whereas it increased in WT mice by ?33%, P<0.001. The average 24-hour urinary sodium excretion in the KO was greater than that of WT mice (P<0.001). Chronic renal function curves demonstrate a leftward shift in KO mice, suggesting that the relationship between UMOD and blood pressure is affected by sodium. Creatinine clearance was increased during salt loading with 2% NaCl in the KO mice, leading to augmented filtered Na(+) excretion and further Na(+) loss. The difference in sodium uptake that exists between WT and KO strains was explored at the molecular level. Urinary tumor necrosis factor-? levels were significantly higher in KO mice compared with WT mice (P<0.0001). Stimulation of primary thick ascending limb of the loop of Henle cells with exogenous tumor necrosis factor-? caused a reduction in NKCC2A expression (P<0.001) with a concurrent rise in the levels of UMOD mRNA (P<0.001). Collectively, we demonstrate that UMOD regulates sodium uptake in the thick ascending limb of the loop of Henle by modulating the effect of tumor necrosis factor-? on NKCC2A expression, making UMOD an important determinant of blood pressure control.
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Serum chloride is an independent predictor of mortality in hypertensive patients.
Hypertension
PUBLISHED: 08-26-2013
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Chloride (Cl-) is the major extracellular anion in the body, accompanying sodium (Na+), and is primarily derived from dietary sources. Data suggest that increased dietary Cl- intake increases blood pressure, yet paradoxically, higher serum Cl- appears associated with lower mortality and cardiovascular risk. This implies that serum Cl- also reflects risk pathways independent of blood pressure, serum Na+, and bicarbonate (HCO3-). We analyzed 12,968 hypertensive individuals followed up for 35 years, using Cox proportional hazards model to test whether baseline serum Cl- was an independent predictor of mortality. To distinguish the effect of Cl- from Na+ and HCO3-, we adjusted for these electrolytes and also performed the analysis stratified by Na+ /HCO3- and Cl- levels. Generalized estimating equation was used to determine the effect of baseline Cl- on follow-up blood pressure. The total time at risk was 19,7101 person-years. The lowest quintile of serum Cl- (<100 mEq/L) was associated with a 20% higher mortality (all-cause, cardiovascular and noncardiovascular) compared with the remainder of the subjects. A 1 mEq/L increase in serum Cl- was associated with a 1.5% (hazard ratio, 0.985; 95% confidence interval, 0.98-0.99) reduction in all-cause mortality, after adjustment for baseline confounding variables and Na+, K+ , and HCO3- levels. The group with Na+ > 135 and Cl- > 100 had the best survival, and compared with this group, the Na+ >135 and Cl- <100 group had significantly higher mortality (hazard ratio, 1.21; 95% confidence interval, 1.11-1.31). Low, not high Serum Cl- (<100 mEq/L), is associated with greater mortality risk independent of obvious confounders. Further studies are needed to elucidate the relation between Cl- and risk.
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Long-term and ultra long-term blood pressure variability during follow-up and mortality in 14,522 patients with hypertension.
Hypertension
PUBLISHED: 08-19-2013
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Recent evidence indicates that long-term visit-to-visit blood pressure variability (BPV) may be an independent cardiovascular risk predictor. The implication of this variability in hypertension clinical practice is unclear. BPV as average real variability (ARV) was calculated in 14,522 treated patients with hypertension in 4 time frames: year 1 (Y1), years 2 to 5 (Y2-5), years 5 to 10 (Y5-10), and years >10 (Y10+) from first clinic visit. Cox proportional hazards models for cause-specific mortality were used in each time frame separately for long-term BPV, across time frames based on ultra long-term BPV, and within each time frame stratified by mean BP. ARV in systolic blood pressure (SBP), termed ARV(SBP), was higher in Y1 (21.3±11.9 mm Hg) in contrast to Y2-5 (17.7±9.9 mm Hg), Y5-10 (17.4±9.6 mm Hg), and Y10+ (16.8±8.5 mm Hg). In all time frames, ARV(SBP) was higher in women (P<0.01) and in older age (P<0.001), chronic kidney disease (P<0.01), and prevalent cardiovascular disease (P<0.01). Higher long-term and ultra long-term BPV values were associated with increased mortality (all-cause, cardiovascular, and noncardiovascular mortality; P for trend, <0.001). This relationship was also evident in subgroups with mean SBP<140 mm Hg in all time frames. Monitoring BPV in clinical practice may facilitate risk reduction strategies by identifying treated hypertensive individuals at high risk, especially those with BP within the normal range.
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Genomic association analysis of common variants influencing antihypertensive response to hydrochlorothiazide.
Hypertension
PUBLISHED: 06-10-2013
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To identify novel genes influencing blood pressure response to thiazide diuretic therapy for hypertension, we conducted genome-wide association meta-analyses of ?1.1 million single-nucleotide polymorphisms in a combined sample of 424 European Americans with primary hypertension treated with hydrochlorothiazide from the Pharmacogenomic Evaluation of Antihypertensive Responses study (n=228) and the Genetic Epidemiology of Responses to Antihypertensive study (n=196). Polymorphisms associated with blood pressure response at P<10(-5) were tested for replication of the associations in independent samples of hydrochlorothiazide-treated European hypertensives. The rs16960228 polymorphism in protein kinase C, ? replicated for same-direction association with diastolic blood pressure response in the Nordic Diltiazem study (n=420) and the Genetics of Drug Responsiveness in Essential Hypertension study (n=206), and the combined 4-study meta-analysis P value achieved genome-wide significance (P=3.3 × 10(-8)). Systolic or diastolic blood pressure responses were consistently greater in carriers of the rs16960228 A allele than in GG homozygotes (>4/4 mm Hg) across study samples. The rs2273359 polymorphism in the GNAS-EDN3 region also replicated for same-direction association with systolic blood pressure response in the Nordic Diltiazem study, and the combined 3-study meta-analysis P value approached genome-wide significance (P=5.5 × 10(-8)). The findings document clinically important effects of genetic variation at novel loci on blood pressure response to a thiazide diuretic, which may be a basis for individualization of antihypertensive drug therapy and identification of new drug targets.
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Serum uric acid level, longitudinal blood pressure, renal function, and long-term mortality in treated hypertensive patients.
Hypertension
PUBLISHED: 05-20-2013
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Uric acid may have a role in the development of hypertension and renal dysfunction. We explored the relationship among longitudinal blood pressure, renal function, and cardiovascular outcomes in a large cohort of patients with treated hypertension. We used data from the Glasgow Blood Pressure Clinic database. Patients with a baseline measure of serum uric acid and longitudinal measures of blood pressure and renal function were included. Mortality data were obtained from the General Register Office for Scotland. Generalized estimating equations were used to explore the relationship among quartiles of serum uric acid, blood pressure, and estimated glomerular filtration rate. Cox proportional hazard models were developed to assess mortality relationships. In total, 6984 patients were included. Serum uric acid level did not influence the longitudinal changes in systolic or diastolic blood pressure but was related to change in glomerular filtration rate. In comparison with patients in the first quartile of serum uric acid, the relative decrease in glomerular filtration rate in the fourth was 10.7 (95% confidence interval, 7.9-13.6 mL/min per 1.73 m(2)) in men and 12.2 (95% confidence interval, 9.2-15.2 mL/min per 1.73 m(2)) in women. All-cause and cardiovascular mortality differed across quartiles of serum uric acid in women only (P<0.001; hazard ratios for all-cause mortality 1.38 [95% confidence interval, 1.14-1.67] for the fourth quartile of serum uric acid compared with the first). Serum uric acid level was not associated with longitudinal blood pressure control in adults with treated hypertension but was related to decline in renal function and mortality in women.
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Pharmacogenomic association of nonsynonymous SNPs in SIGLEC12, A1BG, and the selectin region and cardiovascular outcomes.
Hypertension
PUBLISHED: 05-20-2013
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We sought to identify novel pharmacogenetic markers associated with cardiovascular outcomes in patients with hypertension on antihypertensive therapy. We genotyped a 1:4 case:control cohort (n=1345) on the Illumina HumanCVD Beadchip from the INternational VErapamil SR-Trandolapril STudy (INVEST), where participants were randomized to a ?-blocker strategy or a calcium channel blocker strategy. Genome-spanning single nucleotide polymorphism (SNP)×treatment interaction analyses of nonsynonymous SNPs were conducted in white and Hispanic race/ethnic groups. Top hits from whites were tested in Hispanics for consistency. A genetic risk score was constructed from the top 3 signals and tested in the Nordic Diltiazem study. SIGLEC12 rs16982743 and A1BG rs893184 had a significant interaction with treatment strategy for adverse cardiovascular outcomes (INVEST whites and Hispanics combined interaction P=0.0038 and 0.0036, respectively). A genetic risk score, including rs16982743, rs893184, and rs4525 in F5, was significantly associated with treatment-related adverse cardiovascular outcomes in whites and Hispanics from the INVEST study and in the Nordic Diltiazem study (meta-analysis interaction P=2.39×10(-5)). In patients with a genetic risk score of 0 or 1, calcium channel blocker treatment was associated with lower risk (odds ratio [95% confidence interval]=0.60 [0.42-0.86]), and in those with a genetic risk score of 2 to 3, calcium channel blocker treatment was associated with higher risk (odds ratio [95% confidence interval]=1.31 [1.08-1.59]). These results suggest that cardiovascular outcomes may differ based on SIGLEC12, A1BG, F5 genotypes, and antihypertensive treatment strategy. These specific genetic associations and our risk score provide insight into a potential approach to personalized antihypertensive treatment selection.
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Interaction between chromosome 2 and 3 regulates pulse pressure in the stroke-prone spontaneously hypertensive rat.
Hypertension
PUBLISHED: 05-06-2013
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In an F2 cross between stroke-prone spontaneously hypertensive (SHRSP) and Wistar Kyoto (WKY) rats, we previously identified blood pressure quantitative trait loci (QTL) on rat chromosome (RNO) 2 and a pulse pressure QTL on RNO3. The aims of this study were to confirm the QTL on RNO3 and to investigate interaction between RNO2 and RNO3 loci through the generation and phenotypic assessment of single RNO3 congenic (SP.WKY(Gla)3a) and bicongenic (SP.WKY(Gla)2a/3a) strains. Hemodynamic profiling, vascular function, and renal histology were examined in these newly generated strains along with the previously reported RNO2 congenic strain (SP.WKY(Gla)2a). Our results demonstrate significant equivalent reduction in systolic, diastolic, and pulse pressure phenotypes in SP.WKY(Gla)3a and SP.WKY(Gla)2a rats, whereas greater reductions were observed with the SP.WKY(Gla)2a/3a bicongenic strain achieving blood pressure levels similar to normotensive WKY rats. Epistasis was observed between pulse pressure QTL on RNO2 and 3 at baseline and during 1% salt challenge. Vascular function and renal pathology studies indicate that QTL on RNO3 are responsible for salt-induced kidney pathology, whereas QTL on RNO2 seem to have greater impact on vascular function. RNO3 congenic and bicongenic strains have confirmed the importance of SHRSP alleles in the RNO3 congenic interval on pulse pressure variability and end-organ damage. These strains will allow interrogation of complex gene-gene and gene-environment interactions contributing to salt-sensitive hypertension and renal pathology in the SHRSP rat.
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Blood pressure response to patterns of weather fluctuations and effect on mortality.
Hypertension
PUBLISHED: 05-06-2013
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Very few studies have looked at longitudinal intraindividual blood pressure responses to weather conditions. There are no data to suggest that specific response to changes in weather will have an impact on survival. We analyzed >169 000 clinic visits of 16 010 Glasgow Blood Pressure Clinic patients with hypertension. Each clinic visit was mapped to the mean West of Scotland monthly weather (temperature, sunshine, rainfall) data. Percentage change in blood pressure was calculated between pairs of consecutive clinic visits, where the weather alternated between 2 extreme quartiles (Q(1)-Q(4) or Q(4)-Q(1)) or remained in the same quartile (Q(n)-Q(n)) of each weather parameter. Subjects were also categorized into 2 groups depending on whether their blood pressure response in Q(1)-Q(4) or Q(4)-Q(1) were concordant or discordant to Q(n)-Q(n). Generalized estimating equations and Cox proportional hazards model were used to model the effect on longitudinal blood pressure and mortality, respectively. Q(n)-Q(n) showed a mean 2% drop in blood pressure consistently, whereas Q(4)-Q(1) showed a mean 2.1% and 1.6% rise in systolic and diastolic blood pressure, respectively. However, Q(1)-Q(4) did not show significant changes in blood pressure. Temperature-sensitive subjects had significantly higher mortality (1.35 [95% confidence interval, 1.06-1.71]; P=0.01) and higher follow-up systolic blood pressure (1.85 [95% confidence interval, 0.24-3.46]; P=0.02) compared with temperature-nonsensitive subjects. Blood pressure response to temperature may be one of the underlying mechanisms that determine long-term blood pressure variability. Knowing a patients blood pressure response to weather can help reduce unnecessary antihypertensive treatment modification, which may in turn increase blood pressure variability and, thus, risk.
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Combined sequence-based and genetic mapping analysis of complex traits in outbred rats.
Nat. Genet.
PUBLISHED: 04-25-2013
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Genetic mapping on fully sequenced individuals is transforming understanding of the relationship between molecular variation and variation in complex traits. Here we report a combined sequence and genetic mapping analysis in outbred rats that maps 355 quantitative trait loci for 122 phenotypes. We identify 35 causal genes involved in 31 phenotypes, implicating new genes in models of anxiety, heart disease and multiple sclerosis. The relationship between sequence and genetic variation is unexpectedly complex: at approximately 40% of quantitative trait loci, a single sequence variant cannot account for the phenotypic effect. Using comparable sequence and mapping data from mice, we show that the extent and spatial pattern of variation in inbred rats differ substantially from those of inbred mice and that the genetic variants in orthologous genes rarely contribute to the same phenotype in both species.
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Acetaminophen use and change in blood pressure in a hypertensive population.
J. Hypertens.
PUBLISHED: 04-17-2013
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Recent data suggest that self-reported acetaminophen use is associated with increased risk of cardiovascular events and a rise in arterial blood pressure (BP). We investigated the association between acetaminophen use and BP in a large cohort of patients with hypertension using verified prescription data.
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Cardiovascular risk factors associated with the metabolic syndrome are more prevalent in people reporting chronic pain: results from a cross-sectional general population study.
Pain
PUBLISHED: 04-04-2013
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To explore whether chronic pain is associated with cardiovascular risk factors and identify whether increased distribution or intensity of pain is associated with cardiovascular risk, participants in Generation Scotland: The Scottish Family Health study completed pain questionnaires recording the following: presence of chronic pain, distribution of pain, and intensity of chronic pain. Blood pressure, lipids, blood glucose, smoking history, waist-hip ratio, and body mass index were recorded; Framingham 10-year coronary heart disease (CHD) risk scores were calculated and a diagnosis of metabolic syndrome derived. Associations between chronic pain and cardiovascular risk were explored. Of 13,328 participants, 1100 (8.3%) had high CHD risk. Chronic pain was reported by 5209 (39%), 1294 (9.7%) reported widespread chronic pain, and 707 (5.3%) reported high-intensity chronic pain. In age- and gender-adjusted analyses, chronic pain was associated with elevated CHD risk scores (odds ratio 1.11, 95% confidence interval 1.01-1.23) and the metabolic syndrome (odds ratio 1.42, 95% confidence interval 1.24-1.62). Multivariate analyses identified dyslipidaemia, age, gender, smoking, obesity, and high waist-hip ratio as independently associated with chronic pain. Within the chronic pain subgroup, widespread pain did not confer any additional cardiovascular disease risk. However, cardiovascular disease risk factors contributing to metabolic syndrome were more prevalent in those reporting high-intensity chronic pain. This large population-based study has demonstrated that chronic pain, and in particular high-intensity chronic pain, is associated with an increased prevalence of cardiovascular risk factors and metabolic syndrome. The 10-year CHD risk score and metabolic syndrome correlate well with increased pain intensity, but not with widespread pain.
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Impaired renal function impacts negatively on vascular stiffness in patients with coronary artery disease.
BMC Nephrol
PUBLISHED: 03-18-2013
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Chronic kidney disease (CKD) and coronary artery disease (CAD) are independently associated with increased vascular stiffness. We examined whether renal function contributes to vascular stiffness independently of CAD status.
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Pedigree and genotyping quality analyses of over 10,000 DNA samples from the Generation Scotland: Scottish Family Health Study.
BMC Med. Genet.
PUBLISHED: 03-14-2013
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Generation Scotland: Scottish Family Health Study (GS:SFHS) is a family-based biobank of 24,000 participants with rich phenotype and DNA available for genetic research. This paper describes the laboratory results from genotyping 32 single nucleotide polymorphisms (SNPs) on DNA from over 10,000 participants who attended GS:SFHS research clinics. The analysis described here was undertaken to test the quality of genetic information available to researchers. The success rate of each marker genotyped (call rate), minor allele frequency and adherence to Mendelian inheritance are presented. The few deviations in marker transmission in the 925 parent-child trios analysed were assessed as to whether they were likely to be miscalled genotypes, data or sample handling errors, or pedigree inaccuracies including non-paternity.
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An MRI-histological study of white matter in stroke-free SHRSP.
J. Cereb. Blood Flow Metab.
PUBLISHED: 02-13-2013
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Hypertension is associated with cerebral small vessel disease (SVD) and with diffuse white matter hyperintensities (WMH) on T2-weighted magnetic resonance imaging (MRI). We tested whether stroke-prone spontaneously hypertensive rats (SHRSP), a model of chronic hypertension, exhibit WMH. Male SHRSP (age 10 months) without stroke symptoms were compared with age-matched male WKY rats. Stroke-prone spontaneously hypertensive rats exhibited no WMH on MRI scans (T2, T2*, diffusion tensor imaging) and no neuropathological lesions. While leptomeningeal arteries exhibited fibrohyaline wall thickening, with decreased smooth muscle actin relative to WKY, deep penetrating arterioles within the caudate nuclei had no vasculopathy. We conclude that WMH are not an obligate feature of stroke-free SHRSP aged up to 10 months.
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Mitochondrial reactive oxygen species enhance AMP-activated protein kinase activation in the endothelium of patients with coronary artery disease and diabetes.
Clin. Sci.
PUBLISHED: 01-29-2013
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The aim of the present study was to determine whether the endothelial dysfunction associated with CAD (coronary artery disease) and T2D (Type 2 diabetes mellitus) is concomitant with elevated mtROS (mitochondrial reactive oxygen species) production in the endothelium and establish if this, in turn, regulates the activity of endothelial AMPK (AMP-activated protein kinase). We investigated endothelial function, mtROS production and AMPK activation in saphenous veins from patients with advanced CAD. Endothelium-dependent vasodilation was impaired in patients with CAD and T2D relative to those with CAD alone. Levels of mitochondrial H(2)O(2) and activity of AMPK were significantly elevated in primary HSVECs (human saphenous vein endothelial cells) from patients with CAD and T2D compared with those from patients with CAD alone. Incubation with the mitochondria-targeted antioxidant, MitoQ(10) significantly reduced AMPK activity in HSVECs from patients with CAD and T2D but not in cells from patients with CAD alone. Elevated mtROS production in the endothelium of patients with CAD and T2D increases AMPK activation, supporting a role for the kinase in defence against oxidative stress. Further investigation is required to determine whether pharmacological activators of AMPK will prove beneficial in the attenuation of endothelial dysfunction in patients with CAD and T2D.
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Genome sequencing reveals loci under artificial selection that underlie disease phenotypes in the laboratory rat.
Cell
PUBLISHED: 01-25-2013
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Large numbers of inbred laboratory rat strains have been developed for a range of complex disease phenotypes. To gain insights into the evolutionary pressures underlying selection for these phenotypes, we sequenced the genomes of 27 rat strains, including 11 models of hypertension, diabetes, and insulin resistance, along with their respective control strains. Altogether, we identified more than 13 million single-nucleotide variants, indels, and structural variants across these rat strains. Analysis of strain-specific selective sweeps and gene clusters implicated genes and pathways involved in cation transport, angiotensin production, and regulators of oxidative stress in the development of cardiovascular disease phenotypes in rats. Many of the rat loci that we identified overlap with previously mapped loci for related traits in humans, indicating the presence of shared pathways underlying these phenotypes in rats and humans. These data represent a step change in resources available for evolutionary analysis of complex traits in disease models.
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Angiotensin-(1-9) attenuates cardiac fibrosis in the stroke-prone spontaneously hypertensive rat via the angiotensin type 2 receptor.
Hypertension
PUBLISHED: 12-19-2011
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The renin-angiotensin system regulates cardiovascular physiology via angiotensin II engaging the angiotensin type 1 or type 2 receptors. Classic actions are type 1 receptor mediated, whereas the type 2 receptor may counteract type 1 receptor activity. Angiotensin-converting enzyme 2 metabolizes angiotensin II to angiotensin-(1-7) and angiotensin I to angiotensin-(1-9). Angiotensin-(1-7) antagonizes angiotensin II actions via the receptor Mas. Angiotensin-(1-9) was shown recently to block cardiomyocyte hypertrophy via the angiotensin type 2 receptor. Here, we investigated in vivo effects of angiotensin-(1-9) via the angiotensin type 2 receptor. Angiotensin-(1-9) (100 ng/kg per minute) with or without the angiotensin type 2 receptor antagonist PD123 319 (100 ng/kg per minute) or PD123 319 alone was infused via osmotic minipump for 4 weeks into stroke-prone spontaneously hypertensive rats. We measured blood pressure by radiotelemetry and cardiac structure and function by echocardiography. Angiotensin-(1-9) did not affect blood pressure or left ventricular mass index but reduced cardiac fibrosis by 50% (P<0.01) through modulating collagen I expression, reversed by PD123 319 coinfusion. In addition, angiotensin-(1-9) inhibited fibroblast proliferation in vitro in a PD123 319-sensitive manner. Aortic myography revealed that angiotensin-(1-9) significantly increased contraction to phenylephrine compared with controls after N-nitro-l-arginine methyl ester treatment, an effect abolished by PD123 319 coinfusion (area under the curve: angiotensin-(1-9) N-nitro-l-arginine methyl ester=98.9±11.8%; control+N-nitro-l-arginine methyl ester=74.0±10.4%; P<0.01), suggesting that angiotensin-(1-9) improved basal NO bioavailability in an angiotensin type 2 receptor-sensitive manner. In summary, angiotensin-(1-9) reduced cardiac fibrosis and altered aortic contraction via the angiotensin type 2 receptor supporting a direct role for angiotensin-(1-9) in the renin-angiotensin system.
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Genomewide association study using a high-density single nucleotide polymorphism array and case-control design identifies a novel essential hypertension susceptibility locus in the promoter region of endothelial NO synthase.
Hypertension
PUBLISHED: 12-19-2011
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Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37-1.73]; combined P=2.58 · 10(-13)). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25-1.44; P=1.032 · 10(-14)). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16-3.66) for systolic and 1.40 (95% CI: 0.25-2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus.
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Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.
, Georg B Ehret, Patricia B Munroe, Kenneth M Rice, Murielle Bochud, Andrew D Johnson, Daniel I Chasman, Albert V Smith, Martin D Tobin, Germaine C Verwoert, Shih-Jen Hwang, Vasyl Pihur, Peter Vollenweider, Paul F O'Reilly, Najaf Amin, Jennifer L Bragg-Gresham, Alexander Teumer, Nicole L Glazer, Lenore Launer, Jing Hua Zhao, Yurii Aulchenko, Simon Heath, Siim Sõber, Afshin Parsa, Jian'an Luan, Pankaj Arora, Abbas Dehghan, Feng Zhang, Gavin Lucas, Andrew A Hicks, Anne U Jackson, John F Peden, Toshiko Tanaka, Sarah H Wild, Igor Rudan, Wilmar Igl, Yuri Milaneschi, Alex N Parker, Cristiano Fava, John C Chambers, Ervin R Fox, Meena Kumari, Min Jin Go, Pim van der Harst, Wen Hong Linda Kao, Marketa Sjögren, D G Vinay, Myriam Alexander, Yasuharu Tabara, Sue Shaw-Hawkins, Peter H Whincup, Yongmei Liu, Gang Shi, Johanna Kuusisto, Bamidele Tayo, Mark Seielstad, Xueling Sim, Khanh-Dung Hoang Nguyen, Terho Lehtimäki, Giuseppe Matullo, Ying Wu, Tom R Gaunt, N Charlotte Onland-Moret, Matthew N Cooper, Carl G P Platou, Elin Org, Rebecca Hardy, Santosh Dahgam, Jutta Palmen, Veronique Vitart, Peter S Braund, Tatiana Kuznetsova, Cuno S P M Uiterwaal, Adebowale Adeyemo, Walter Palmas, Harry Campbell, Barbara Ludwig, Maciej Tomaszewski, Ioanna Tzoulaki, Nicholette D Palmer, Thor Aspelund, Melissa Garcia, Yen-Pei C Chang, Jeffrey R O'Connell, Nanette I Steinle, Diederick E Grobbee, Dan E Arking, Sharon L Kardia, Alanna C Morrison, Dena Hernandez, Samer Najjar, Wendy L McArdle, David Hadley, Morris J Brown, John M Connell, Aroon D Hingorani, Ian N M Day, Debbie A Lawlor, John P Beilby, Robert W Lawrence, Robert Clarke, Jemma C Hopewell, Halit Ongen, Albert W Dreisbach, Yali Li, J Hunter Young, Joshua C Bis, Mika Kähönen, Jorma Viikari, Linda S Adair, Nanette R Lee, Ming-Huei Chen, Matthias Olden, Cristian Pattaro, Judith A Hoffman Bolton, Anna Köttgen, Sven Bergmann, Vincent Mooser, Nish Chaturvedi, Timothy M Frayling, Muhammad Islam, Tazeen H Jafar, Jeanette Erdmann, Smita R Kulkarni, Stefan R Bornstein, Jürgen Gräßler, Leif Groop, Benjamin F Voight, Johannes Kettunen, Philip Howard, Andrew Taylor, Simonetta Guarrera, Fulvio Ricceri, Valur Emilsson, Andrew Plump, Inês Barroso, Kay-Tee Khaw, Alan B Weder, Steven C Hunt, Yan V Sun, Richard N Bergman, Francis S Collins, Lori L Bonnycastle, Laura J Scott, Heather M Stringham, Leena Peltonen, Markus Perola, Erkki Vartiainen, Stefan-Martin Brand, Jan A Staessen, Thomas J Wang, Paul R Burton, María Soler Artigas, Yanbin Dong, Harold Snieder, Xiaoling Wang, Haidong Zhu, Kurt K Lohman, Megan E Rudock, Susan R Heckbert, Nicholas L Smith, Kerri L Wiggins, Ayo Doumatey, Daniel Shriner, Gudrun Veldre, Margus Viigimaa, Sanjay Kinra, Dorairaj Prabhakaran, Vikal Tripathy, Carl D Langefeld, Annika Rosengren, Dag S Thelle, Anna Maria Corsi, Andrew Singleton, Terrence Forrester, Gina Hilton, Colin A McKenzie, Tunde Salako, Naoharu Iwai, Yoshikuni Kita, Toshio Ogihara, Takayoshi Ohkubo, Tomonori Okamura, Hirotsugu Ueshima, Satoshi Umemura, Susana Eyheramendy, Thomas Meitinger, H-Erich Wichmann, Yoon Shin Cho, Hyung-Lae Kim, Jong-Young Lee, James Scott, Joban S Sehmi, Weihua Zhang, Bo Hedblad, Peter Nilsson, George Davey Smith, Andrew Wong, Narisu Narisu, Alena Stančáková, Leslie J Raffel, Jie Yao, Sekar Kathiresan, Christopher J O'Donnell, Stephen M Schwartz, M Arfan Ikram, W T Longstreth, Thomas H Mosley, Sudha Seshadri, Nick R G Shrine, Louise V Wain, Mario A Morken, Amy J Swift, Jaana Laitinen, Inga Prokopenko, Paavo Zitting, Jackie A Cooper, Steve E Humphries, John Danesh, Asif Rasheed, Anuj Goel, Anders Hamsten, Hugh Watkins, Stephan J L Bakker, Wiek H van Gilst, Charles S Janipalli, K Radha Mani, Chittaranjan S Yajnik, Albert Hofman, Francesco U S Mattace-Raso, Ben A Oostra, Ayse Demirkan, Aaron Isaacs, Fernando Rivadeneira, Edward G Lakatta, Marco Orrù, Angelo Scuteri, Mika Ala-Korpela, Antti J Kangas, Leo-Pekka Lyytikäinen, Pasi Soininen, Taru Tukiainen, Peter Würtz, Rick Twee-Hee Ong, Marcus Dörr, Heyo K Kroemer, Uwe Völker, Henry Völzke, Pilar Galán, Serge Hercberg, Mark Lathrop, Diana Zelenika, Panos Deloukas, Massimo Mangino, Tim D Spector, Guangju Zhai, James F Meschia, Michael A Nalls, Pankaj Sharma, Janos Terzic, M V Kranthi Kumar, Matthew Denniff, Ewa Zukowska-Szczechowska, Lynne E Wagenknecht, F Gerald R Fowkes, Fadi J Charchar, Peter E H Schwarz, Caroline Hayward, Xiuqing Guo, Charles Rotimi, Michiel L Bots, Eva Brand, Nilesh J Samani, Ozren Polašek, Philippa J Talmud, Fredrik Nyberg, Diana Kuh, Maris Laan, Kristian Hveem, Lyle J Palmer, Yvonne T van der Schouw, Juan P Casas, Karen L Mohlke, Paolo Vineis, Olli Raitakari, Santhi K Ganesh, Tien Y Wong, E Shyong Tai, Richard S Cooper, Markku Laakso, Dabeeru C Rao, Tamara B Harris, Richard W Morris, Anna F Dominiczak, Mika Kivimäki, Michael G Marmot, Tetsuro Miki, Danish Saleheen, Giriraj R Chandak, Josef Coresh, Gerjan Navis, Veikko Salomaa, Bok-Ghee Han, Xiaofeng Zhu, Jaspal S Kooner, Olle Melander, Paul M Ridker, Stefania Bandinelli, Ulf B Gyllensten, Alan F Wright, James F Wilson, Luigi Ferrucci, Martin Farrall, Jaakko Tuomilehto, Peter P Pramstaller, Roberto Elosua, Nicole Soranzo, Eric J G Sijbrands, David Altshuler, Ruth J F Loos, Alan R Shuldiner, Christian Gieger, Pierre Meneton, André G Uitterlinden, Nicholas J Wareham, Vilmundur Gudnason, Jerome I Rotter, Rainer Rettig, Manuela Uda, David P Strachan, Jacqueline C M Witteman, Anna-Liisa Hartikainen, Jacques S Beckmann, Eric Boerwinkle, Ramachandran S Vasan, Michael Boehnke, Martin G Larson, Marjo-Riitta Järvelin, Bruce M Psaty, Gonçalo R Abecasis, Aravinda Chakravarti, Paul Elliott, Cornelia M van Duijn, Christopher Newton-Cheh, Daniel Levy, Mark J Caulfield, Toby Johnson.
Nature
PUBLISHED: 07-28-2011
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Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (?140?mm?Hg systolic blood pressure or? ?90?mm?Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
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Blood pressure loci identified with a gene-centric array.
Toby Johnson, Tom R Gaunt, Stephen J Newhouse, Sandosh Padmanabhan, Maciej Tomaszewski, Meena Kumari, Richard W Morris, Ioanna Tzoulaki, Eoin T O'Brien, Neil R Poulter, Peter Sever, Denis C Shields, Simon Thom, Sasiwarang G Wannamethee, Peter H Whincup, Morris J Brown, John M Connell, Richard J Dobson, Philip J Howard, Charles A Mein, Abiodun Onipinla, Sue Shaw-Hawkins, Yun Zhang, George Davey Smith, Ian N M Day, Debbie A Lawlor, Alison H Goodall, , F Gerald Fowkes, Gonçalo R Abecasis, Paul Elliott, Vesela Gateva, Peter S Braund, Paul R Burton, Christopher P Nelson, Martin D Tobin, Pim van der Harst, Nicola Glorioso, Hani Neuvrith, Erika Salvi, Jan A Staessen, Andrea Stucchi, Nabila Devos, Xavier Jeunemaitre, Pierre-Francois Plouin, Jean Tichet, Peeter Juhanson, Elin Org, Margus Putku, Siim Sõber, Gudrun Veldre, Margus Viigimaa, Anna Levinsson, Annika Rosengren, Dag S Thelle, Claire E Hastie, Thomas Hedner, Wai K Lee, Olle Melander, Björn Wahlstrand, Rebecca Hardy, Andrew Wong, Jackie A Cooper, Jutta Palmen, Li Chen, Alexandre F R Stewart, George A Wells, Harm-Jan Westra, Marcel G M Wolfs, Robert Clarke, Maria Grazia Franzosi, Anuj Goel, Anders Hamsten, Mark Lathrop, John F Peden, Udo Seedorf, Hugh Watkins, Willem H Ouwehand, Jennifer Sambrook, Jonathan Stephens, Juan-Pablo Casas, Fotios Drenos, Michael V Holmes, Mika Kivimäki, Sonia Shah, Tina Shah, Philippa J Talmud, John Whittaker, Chris Wallace, Christian Delles, Maris Laan, Diana Kuh, Steve E Humphries, Fredrik Nyberg, Daniele Cusi, Robert Roberts, Christopher Newton-Cheh, Lude Franke, Alice V Stanton, Anna F Dominiczak, Martin Farrall, Aroon D Hingorani, Nilesh J Samani, Mark J Caulfield, Patricia B Munroe.
Am. J. Hum. Genet.
PUBLISHED: 06-15-2011
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Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.
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Urinary proteomics in cardiovascular disease: Achievements, limits and hopes.
Proteomics Clin Appl
PUBLISHED: 04-27-2011
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Cardiovascular disease (CVD) is the major cause of mortality and morbidity worldwide. Diagnosis of CVD and risk stratification of patients with CVD remains challenging despite the availability of a wealth of non-invasive and invasive tests. Clinical proteomics analyses a large number of peptides and proteins in biofluids. For clinical applications, the urinary proteome appears particularly attractive due to the relative low complexity compared with the plasma proteome and the noninvasive collection of urine. In this article, we review the results from pilot studies into urinary proteomics of coronary artery disease and discuss the potential of urinary proteomics in the context of pathogenesis of CVD.
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Association between ADRA1A gene and the metabolic syndrome: candidate genes and functional counterpart in the PAMELA population.
J. Hypertens.
PUBLISHED: 04-27-2011
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There is currently uncertainty about whether metabolic syndrome has a common underlying process. We performed a gene-centric association study of metabolic syndrome in 98 major cardiometabolic genes in the large, well phenotyped Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study. We followed this with functional studies to elucidate a possible mechanism for the top association signal.
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miR-21 and miR-214 are consistently modulated during renal injury in rodent models.
Am. J. Pathol.
PUBLISHED: 04-01-2011
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Transforming growth factor (TGF)-? is one of the main fibrogenic cytokines that drives the pathophysiology of progressive renal scarring. MicroRNAs (miRNAs) are endogenous non-coding RNAs that post-transcriptionally regulate gene expression. We examined the role of TGF-?-induced expression of miR-21, miRNAs in cell culture models and miRNA expression in relevant models of renal disease. In vitro, TGF-? changed expression of miR-21, miR-214, and miR-145 in rat mesangial cells (CRL-2753) and miR-214, miR-21, miR-30c, miR-200b, and miR-200c during induction of epithelial-mesenchymal transition in rat tubular epithelial cells (NRK52E). miR-214 expression was robustly modulated in both cell types, whereas in tubular epithelial cells miR-21 was increased and miR-200b and miR-200c were decreased by 58% and 48%, respectively, in response to TGF-?. TGF-? receptor-1 was found to be a target of miR-200b/c and was down-regulated after overexpression of miR-200c. To assess the differential expression of these miRNAs in vivo, we used the anti-Thy1.1 mesangial glomerulonephritis model and the unilateral ureteral obstruction model in which TGF-? plays a role and also a genetic model of hypertension, the stroke-prone spontaneously hypertensive rat with and without salt loading. The expressions of miR-214 and miR-21 were significantly increased in all in vivo models, showing a possible miRNA signature of renal damage despite differing causes.
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Sphingosine-1-phosphate-induced inflammation involves receptor tyrosine kinase transactivation in vascular cells: upregulation in hypertension.
Hypertension
PUBLISHED: 03-07-2011
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Sphingosine-1-phosphate (S1P), a multifunctional phospholipid, regulates vascular cell function. Whether S1P influences vascular inflammatory responses, particularly in hypertension, is unclear. We tested the hypothesis that S1P is a proinflammatory mediator signaling through receptor tyrosine kinase transactivation and that responses are amplified in vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats (SHRSPs), a model in which we demonstrated Edg1 (S1P1 receptor) to be a candidate gene for salt-sensitive hypertension. Vascular smooth muscle cell from Wistar-Kyoto rats and SHRSPs were studied. S1P receptor subtypes, S1P1 and S1P2, were similarly expressed in Wistar-Kyoto rats and SHRSPs. S1P induced phosphorylation of epidermal growth factor receptor and platelet-derived growth factor and activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase, with amplified effects in SHRSPs versus Wistar-Kyoto rats. Inhibition of epidermal growth factor receptor and platelet-derived growth factor (with AG1478 and AG1296, respectively) abolished S1P-induced phosphorylation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase in Wistar-Kyoto rats with variable effects in SHRSPs. Vascular smooth muscle cell inflammation was evaluated by expression of adhesion molecules and functional responses assessed by monocyte adhesion. S1P stimulated expression of intercellular adhesion molecule 1 and vascular cell adhesion protein 1 and promoted monocyte adhesion, particularly in SHRSP cells. S1P-mediated inflammation was blunted by AG1478 and AG1296 in SHRSP cells. VPC23019, a S1P1 receptor antagonist, inhibited S1P-induced mitogen-activated protein kinase phosphorylation, intercellular adhesion molecule 1 and vascular cell adhesion protein 1 expression, and monocyte adhesion. Our data indicate that molecular processes underlying vascular inflammation and cell adhesion in SHRSPs involve S1P/S1P1 receptors and phosphorylation of receptor tyrosine kinases. We identify a novel pathway linking S1P/S1P1 receptors to specific proinflammatory signaling pathways through epidermal growth factor receptor and platelet-derived growth factor transactivation, a process that is upregulated in SHRSPs. Such molecular events may contribute to vascular inflammation in hypertension.
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Evaluation of how gene-job strain interaction affects blood pressure in the PAMELA study.
Psychosom Med
PUBLISHED: 03-01-2011
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To see whether there is interaction between single nucleotide polymorphisms (SNPs) belonging to candidate genes for hypertension and job strain and its components (job demand and job control) in an accurately phenotyped Italian cohort (Pressioni Arteriose Monitorate E Loro Associazioni).
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Urinary proteomics for prediction of preeclampsia.
Hypertension
PUBLISHED: 01-03-2011
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Preeclampsia is a major determinant of fetal and maternal morbidity and mortality. We used a proteomic strategy to identify urinary biomarkers that predict preeclampsia before the onset of disease. We prospectively collected urine samples from women throughout pregnancy. Samples from gestational weeks 12 to 16 (n=45), 20 (n=50), and 28 (n=18) from women who subsequently had preeclampsia develop were matched to controls (n=86, n=49, and n=17, respectively). We performed capillary electrophoresis online coupled to micro-time-of-flight mass spectrometry. Disease-specific peptide patterns were generated using support vector machine-based software. Candidate biomarkers were sequenced by liquid chromatography-tandem mass spectrometry. From comparison with nonpregnant controls, we defined a panel of 284 pregnancy-specific proteomic biomarkers. Subsequently, we developed a model of 50 biomarkers from specimens obtained at week 28 that was associated with future preeclampsia (classification factor in cases, 1.032 ± 0.411 vs controls, -1.038 ± 0.432; P<0.001). Classification factor increased markedly from week 12 to 16 to 28 in women who subsequently had preeclampsia develop (n=16; from -0.392 ± 0.383 to 1.070 ± 0.383; P<0.001) and decreased slightly in controls (n=16; from -0.647 ± 0.437 to -1.024 ± 0.433; P=0.043). Among the biomarkers are fibrinogen alpha chain, collagen alpha chain, and uromodulin fragments. The markers appear to predict preeclampsia at gestational week 28 with good confidence but not reliably at earlier time points (weeks 12-16 and 20). After prospective validation in other cohorts, these markers may contribute to better prediction, monitoring, and accurate diagnosis of preeclampsia.
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Genome-wide association studies will unlock the genetic basis of hypertension: pro side of the argument.
Hypertension
PUBLISHED: 11-10-2010
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This brief commentary is based on the debate that took part in May 2010 in New York. We describe the initial difficulties experienced in early genome-wide association studies of blood pressure and hypertension, as well as strategic developments, including large meta-analyses and sampling from the extremes of blood pressure distribution. The reasons for negative attitudes toward the genome-wide association studies include their nonhypothesis-driven character and the need for very large sample sizes. Nevertheless, we describe published successes, which include 13 single nucleotide polymorphisms/loci associated with blood pressure and hypertension at P < 5 x 10??, which fulfill the criteria of genome-wide significance. We conclude by suggesting a way forward, which will include resequencing to aid fine mapping and the identification of causal variants, even bigger meta-analyses, and, most importantly, appropriate functional studies leading to clinically useful applications.
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Vascular-targeting antioxidant therapy in a model of hypertension and stroke.
J. Cardiovasc. Pharmacol.
PUBLISHED: 09-15-2010
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Oxidative stress is implicated in the pathogenesis of hypertension and stroke. Superoxide is produced by NAD(P)H oxidase in the vasculature and reduces nitric oxide bioavailability, which leads to increased blood pressure. The objective of this study was to determine whether targeting an antioxidant peptide to the vasculature would increase the antioxidant effect and reduce systolic blood pressure (SBP) in a model of genetic hypertension, the stroke-prone spontaneously hypertensive rat. Vascular-targeting peptides CRPPR and CSGMARTKC were identified by phage display in mice. These peptides retain their selectivity across species and target the aorta (CRPPR) and cardiac vasculature (CSGMARTKC) in the stroke-prone spontaneously hypertensive rat. These vascular-targeting peptides were linked to the antioxidant peptide gp91ds, which selectively inhibits assembly of NAD(P)H oxidase, thereby reducing superoxide production. SBP was determined for 1 week before treatment followed by 3 weeks of study duration before euthanasia. SBP in the control animals increased from 178.1 ± 4.1 mmHg to 201.6 ± 9.0 mmHg. The SBP of the animals treated with gp91ds alone, HIV-tat-gp91ds, and CSGMARTKC-gp91ds increased from 177.8 ± 3.5 mmHg, 179.8 ± 4.7 mmHg, and 177.9 ± 5.2 mmHg, respectively, to 201.6 ± 10.8 mmHg, 200.3 ± 11.7 mmHg and 205.7 ± 10.9 mmHg, respectively. This increase in SBP was significantly attenuated in animals receiving CRPPR-gp91ds (maximum SBP 187.5 mmHg ± 5.2, *P , 0.001 versus other treatment groups and control group). Additionally, animals treated with CRPPR-gp91ds, CSGMARTKC-gp91ds, and gp91ds alone showed significantly improved nitric oxide bioavailability determined by large vessel myography. Therefore, targeting an antioxidant to the aortic vasculature in vivo using peptides can significantly improve nitric oxide bioavailability and attenuate the time-dependent and progressive increase in SBP in the stroke-prone spontaneously hypertensive rat. This study has demonstrated the importance and potential benefit of targeting a biologically active peptide in the context of a preclinical model of endothelial dysfunction and hypertension.
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Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height.
Matthew B Lanktree, Yiran Guo, Muhammed Murtaza, Joseph T Glessner, Swneke D Bailey, N Charlotte Onland-Moret, Guillaume Lettre, Halit Ongen, Ramakrishnan Rajagopalan, Toby Johnson, Haiqing Shen, Christopher P Nelson, Norman Klopp, Jens Baumert, Sandosh Padmanabhan, Nathan Pankratz, James S Pankow, Sonia Shah, Kira Taylor, John Barnard, Bas J Peters, Cliona M Maloney, Maximilian T Lobmeyer, Alice Stanton, M Hadi Zafarmand, Simon P R Romaine, Amar Mehta, Erik P A van Iperen, Yan Gong, Tom S Price, Erin N Smith, Cecilia E Kim, Yun R Li, Folkert W Asselbergs, Larry D Atwood, Kristian M Bailey, Deepak Bhatt, Florianne Bauer, Elijah R Behr, Tushar Bhangale, Jolanda M A Boer, Bernhard O Boehm, Jonathan P Bradfield, Morris Brown, Peter S Braund, Paul R Burton, Cara Carty, Hareesh R Chandrupatla, Wei Chen, John Connell, Chrysoula Dalgeorgou, Anthonius de Boer, Fotios Drenos, Clara C Elbers, James C Fang, Caroline S Fox, Edward C Frackelton, Barry Fuchs, Clement E Furlong, Quince Gibson, Christian Gieger, Anuj Goel, Diederik E Grobbee, Claire Hastie, Philip J Howard, Guan-Hua Huang, W Craig Johnson, Qing Li, Marcus E Kleber, Barbara E K Klein, Ronald Klein, Charles Kooperberg, Bonnie Ky, Andrea LaCroix, Paul Lanken, Mark Lathrop, Mingyao Li, Vanessa Marshall, Olle Melander, Frank D Mentch, Nuala J Meyer, Keri L Monda, Alexandre Montpetit, Gurunathan Murugesan, Karen Nakayama, Dave Nondahl, Abiodun Onipinla, Suzanne Rafelt, Stephen J Newhouse, F George Otieno, Sanjey R Patel, Mary E Putt, Santiago Rodriguez, Radwan N Safa, Douglas B Sawyer, Pamela J Schreiner, Claire Simpson, Suthesh Sivapalaratnam, Sathanur R Srinivasan, Christine Suver, Gary Swergold, Nancy K Sweitzer, Kelly A Thomas, Barbara Thorand, Nicholas J Timpson, Sam Tischfield, Martin Tobin, Maciej Tomaszewski, Maciej Tomaszweski, W M Monique Verschuren, Chris Wallace, Bernhard Winkelmann, Haitao Zhang, Dongling Zheng, Li Zhang, Joseph M Zmuda, Robert Clarke, Anthony J Balmforth, John Danesh, Ian N Day, Nicholas J Schork, Paul I W de Bakker, Christian Delles, David Duggan, Aroon D Hingorani, Joel N Hirschhorn, Marten H Hofker, Steve E Humphries, Mika Kivimäki, Debbie A Lawlor, Kandice Kottke-Marchant, Jessica L Mega, Braxton D Mitchell, David A Morrow, Jutta Palmen, Susan Redline, Denis C Shields, Alan R Shuldiner, Patrick M Sleiman, George Davey Smith, Martin Farrall, Yalda Jamshidi, David C Christiani, Juan P Casas, Alistair S Hall, Pieter A Doevendans, Jason D Christie, Gerald S Berenson, Sarah S Murray, Thomas Illig, Gerald W Dorn, Thomas P Cappola, Eric Boerwinkle, Peter Sever, Daniel J Rader, Muredach P Reilly, Mark Caulfield, Philippa J Talmud, Eric Topol, James C Engert, Kai Wang, Anna Dominiczak, Anders Hamsten, Sean P Curtis, Roy L Silverstein, Leslie A Lange, Marc S Sabatine, Mieke Trip, Danish Saleheen, John F Peden, Karen J Cruickshanks, Winfried März, Jeffrey R O'Connell, Olaf H Klungel, Cisca Wijmenga, Anke Hilse Maitland-van der Zee, Eric E Schadt, Julie A Johnson, Gail P Jarvik, George J Papanicolaou, , Struan F A Grant, Patricia B Munroe, Kari E North, Nilesh J Samani, Wolfgang Koenig, Tom R Gaunt, Sonia S Anand, Yvonne T van der Schouw, Nicole Soranzo, Garret A FitzGerald, Alex Reiner, Robert A Hegele, Hakon Hakonarson, Brendan J Keating.
Am. J. Hum. Genet.
PUBLISHED: 09-14-2010
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Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.
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Urinary proteomic diagnosis of coronary artery disease: identification and clinical validation in 623 individuals.
J. Hypertens.
PUBLISHED: 09-03-2010
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We studied the urinary proteome in a total of 623 individuals with and without coronary artery disease (CAD) in order to characterize multiple biomarkers that enable prediction of the presence of CAD.
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Recommendations for biomarker identification and qualification in clinical proteomics.
Sci Transl Med
PUBLISHED: 08-27-2010
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Clinical proteomics has yielded some early positive results-the identification of potential disease biomarkers-indicating the promise for this analytical approach to improve the current state of the art in clinical practice. However, the inability to verify some candidate molecules in subsequent studies has led to skepticism among many clinicians and regulatory bodies, and it has become evident that commonly encountered shortcomings in fundamental aspects of experimental design mainly during biomarker discovery must be addressed in order to provide robust data. In this Perspective, we assert that successful studies generally use suitable statistical approaches for biomarker definition and confirm results in independent test sets; in addition, we describe a brief set of practical and feasible recommendations that we have developed for investigators to properly identify and qualify proteomic biomarkers, which could also be used as reporting requirements. Such recommendations should help put proteomic biomarker discovery on the solid ground needed for turning the old promise into a new reality.
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Naturally occurring human urinary peptides for use in diagnosis of chronic kidney disease.
Mol. Cell Proteomics
PUBLISHED: 07-08-2010
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Because of its availability, ease of collection, and correlation with physiology and pathology, urine is an attractive source for clinical proteomics/peptidomics. However, the lack of comparable data sets from large cohorts has greatly hindered the development of clinical proteomics. Here, we report the establishment of a reproducible, high resolution method for peptidome analysis of naturally occurring human urinary peptides and proteins, ranging from 800 to 17,000 Da, using samples from 3,600 individuals analyzed by capillary electrophoresis coupled to MS. All processed data were deposited in an Structured Query Language (SQL) database. This database currently contains 5,010 relevant unique urinary peptides that serve as a pool of potential classifiers for diagnosis and monitoring of various diseases. As an example, by using this source of information, we were able to define urinary peptide biomarkers for chronic kidney diseases, allowing diagnosis of these diseases with high accuracy. Application of the chronic kidney disease-specific biomarker set to an independent test cohort in the subsequent replication phase resulted in 85.5% sensitivity and 100% specificity. These results indicate the potential usefulness of capillary electrophoresis coupled to MS for clinical applications in the analysis of naturally occurring urinary peptides.
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Predictive response-relevant clustering of expression data provides insights into disease processes.
Nucleic Acids Res.
PUBLISHED: 06-22-2010
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This article describes and illustrates a novel method of microarray data analysis that couples model-based clustering and binary classification to form clusters of `response-relevant genes; that is, genes that are informative when discriminating between the different values of the response. Predictions are subsequently made using an appropriate statistical summary of each gene cluster, which we call the `meta-covariate representation of the cluster, in a probit regression model. We first illustrate this method by analysing a leukaemia expression dataset, before focusing closely on the meta-covariate analysis of a renal gene expression dataset in a rat model of salt-sensitive hypertension. We explore the biological insights provided by our analysis of these data. In particular, we identify a highly influential cluster of 13 genes--including three transcription factors (Arntl, Bhlhe41 and Npas2)-that is implicated as being protective against hypertension in response to increased dietary sodium. Functional and canonical pathway analysis of this cluster using Ingenuity Pathway Analysis implicated transcriptional activation and circadian rhythm signalling, respectively. Although we illustrate our method using only expression data, the method is applicable to any high-dimensional datasets. Expression data are available at ArrayExpress (accession number E-MEXP-2514) and code is available at http://www.dcs.gla.ac.uk/inference/metacovariateanalysis/.
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Gene expression profiling in whole blood of patients with coronary artery disease.
Clin. Sci.
PUBLISHED: 06-10-2010
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Owing to the dynamic nature of the transcriptome, gene expression profiling is a promising tool for discovery of disease-related genes and biological pathways. In the present study, we examined gene expression in whole blood of 12 patients with CAD (coronary artery disease) and 12 healthy control subjects. Furthermore, ten patients with CAD underwent whole-blood gene expression analysis before and after the completion of a cardiac rehabilitation programme following surgical coronary revascularization. mRNA and miRNA (microRNA) were isolated for expression profiling. Gene expression analysis identified 365 differentially expressed genes in patients with CAD compared with healthy controls (175 up- and 190 down-regulated in CAD), and 645 in CAD rehabilitation patients (196 up- and 449 down-regulated post-rehabilitation). Biological pathway analysis identified a number of canonical pathways, including oxidative phosphorylation and mitochondrial function, as being significantly and consistently modulated across the groups. Analysis of miRNA expression revealed a number of differentially expressed miRNAs, including hsa-miR-140-3p (control compared with CAD, P=0.017), hsa-miR-182 (control compared with CAD, P=0.093), hsa-miR-92a and hsa-miR-92b (post- compared with pre-exercise, P<0.01). Global analysis of predicted miRNA targets found significantly reduced expression of genes with target regions compared with those without: hsa-miR-140-3p (P=0.002), hsa-miR-182 (P=0.001), hsa-miR-92a and hsa-miR-92b (P=2.2x10-16). In conclusion, using whole blood as a surrogate tissue in patients with CAD, we have identified differentially expressed miRNAs, differentially regulated genes and modulated pathways which warrant further investigation in the setting of cardiovascular function. This approach may represent a novel non-invasive strategy to unravel potentially modifiable pathways and possible therapeutic targets in cardiovascular disease.
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Urinary collagen fragments are significantly altered in diabetes: a link to pathophysiology.
PLoS ONE
PUBLISHED: 06-04-2010
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The pathogenesis of diabetes mellitus (DM) is variable, comprising different inflammatory and immune responses. Proteome analysis holds the promise of delivering insight into the pathophysiological changes associated with diabetes. Recently, we identified and validated urinary proteomics biomarkers for diabetes. Based on these initial findings, we aimed to further validate urinary proteomics biomarkers specific for diabetes in general, and particularity associated with either type 1 (T1D) or type 2 diabetes (T2D).
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Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension.
PLoS Genet.
PUBLISHED: 05-25-2010
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Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5 region of Uromodulin (UMOD; rs13333226, combined P value of 3.6 × 10?¹¹). The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R.?=?0.923, 95% CI 0.860-0.991; p?=?0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p?=?0.004; after eGFR adjustment: 0.89 [0.83-0.96], p?=?0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.
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Preeclampsia and future maternal health.
J. Hypertens.
PUBLISHED: 05-15-2010
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Preeclampsia is a multisystem disorder that complicates 3-8% of pregnancies in the Western world, and is a major source of morbidity and mortality worldwide. Although it is a disease unique to pregnancy, evidence has mounted in recent years that preeclampsia has important implications for future maternal health, in particular cardiovascular health. In this review we examine epidemiological evidence for this relationship, and examine potential mechanisms such as insulin resistance, genetic factors and endothelial dysfunction that may explain the relationship. In addition we explore potential future avenues of research into the field, such as genomics, proteomics and metabolomics.
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Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction.
Nona Sotoodehnia, Aaron Isaacs, Paul I W de Bakker, Marcus Dörr, Christopher Newton-Cheh, Ilja M Nolte, Pim van der Harst, Martina Müller, Mark Eijgelsheim, Alvaro Alonso, Andrew A Hicks, Sandosh Padmanabhan, Caroline Hayward, Albert Vernon Smith, Ozren Polašek, Steven Giovannone, Jingyuan Fu, Jared W Magnani, Kristin D Marciante, Arne Pfeufer, Sina A Gharib, Alexander Teumer, Man Li, Joshua C Bis, Fernando Rivadeneira, Thor Aspelund, Anna Köttgen, Toby Johnson, Kenneth Rice, Mark P S Sie, Ying A Wang, Norman Klopp, Christian Fuchsberger, Sarah H Wild, Irene Mateo Leach, Karol Estrada, Uwe Völker, Alan F Wright, Folkert W Asselbergs, Jiaxiang Qu, Aravinda Chakravarti, Moritz F Sinner, Jan A Kors, Astrid Petersmann, Tamara B Harris, Elsayed Z Soliman, Patricia B Munroe, Bruce M Psaty, Ben A Oostra, L Adrienne Cupples, Siegfried Perz, Rudolf A de Boer, André G Uitterlinden, Henry Völzke, Timothy D Spector, Fang-Yu Liu, Eric Boerwinkle, Anna F Dominiczak, Jerome I Rotter, Gé van Herpen, Daniel Levy, H-Erich Wichmann, Wiek H van Gilst, Jacqueline C M Witteman, Heyo K Kroemer, W H Linda Kao, Susan R Heckbert, Thomas Meitinger, Albert Hofman, Harry Campbell, Aaron R Folsom, Dirk J van Veldhuisen, Christine Schwienbacher, Christopher J O'Donnell, Claudia Beu Volpato, Mark J Caulfield, John M Connell, Lenore Launer, Xiaowen Lu, Lude Franke, Rudolf S N Fehrmann, Gerard te Meerman, Harry J M Groen, Rinse K Weersma, Leonard H van den Berg, Cisca Wijmenga, Roel A Ophoff, Gerjan Navis, Igor Rudan, Harold Snieder, James F Wilson, Peter P Pramstaller, David S Siscovick, Thomas J Wang, Vilmundur Gudnason, Cornelia M van Duijn, Stephan B Felix, Glenn I Fishman, Yalda Jamshidi, Bruno H Ch Stricker, Nilesh J Samani, Stefan Kääb, Dan E Arking.
Nat. Genet.
PUBLISHED: 05-03-2010
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The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
Hana Lango Allen, Karol Estrada, Guillaume Lettre, Sonja I Berndt, Michael N Weedon, Fernando Rivadeneira, Cristen J Willer, Anne U Jackson, Sailaja Vedantam, Soumya Raychaudhuri, Teresa Ferreira, Andrew R Wood, Robert J Weyant, Ayellet V Segrè, Elizabeth K Speliotes, Eleanor Wheeler, Nicole Soranzo, Ju-Hyun Park, Jian Yang, Daniel Gudbjartsson, Nancy L Heard-Costa, Joshua C Randall, Lu Qi, Albert Vernon Smith, Reedik Mägi, Tomi Pastinen, Liming Liang, Iris M Heid, Jian'an Luan, Gudmar Thorleifsson, Thomas W Winkler, Michael E Goddard, Ken Sin Lo, Cameron Palmer, Tsegaselassie Workalemahu, Yurii S Aulchenko, Asa Johansson, M Carola Zillikens, Mary F Feitosa, Tonu Esko, Toby Johnson, Shamika Ketkar, Peter Kraft, Massimo Mangino, Inga Prokopenko, Devin Absher, Eva Albrecht, Florian Ernst, Nicole L Glazer, Caroline Hayward, Jouke-Jan Hottenga, Kevin B Jacobs, Joshua W Knowles, Zoltan Kutalik, Keri L Monda, Ozren Polašek, Michael Preuss, Nigel W Rayner, Neil R Robertson, Valgerdur Steinthorsdottir, Jonathan P Tyrer, Benjamin F Voight, Fredrik Wiklund, Jianfeng Xu, Jing Hua Zhao, Dale R Nyholt, Niina Pellikka, Markus Perola, John R B Perry, Ida Surakka, Mari-Liis Tammesoo, Elizabeth L Altmaier, Najaf Amin, Thor Aspelund, Tushar Bhangale, Gabrielle Boucher, Daniel I Chasman, Constance Chen, Lachlan Coin, Matthew N Cooper, Anna L Dixon, Quince Gibson, Elin Grundberg, Ke Hao, M Juhani Junttila, Lee M Kaplan, Johannes Kettunen, Inke R König, Tony Kwan, Robert W Lawrence, Douglas F Levinson, Mattias Lorentzon, Barbara McKnight, Andrew P Morris, Martina Müller, Julius Suh Ngwa, Shaun Purcell, Suzanne Rafelt, Rany M Salem, Erika Salvi, Serena Sanna, Jianxin Shi, Ulla Sovio, John R Thompson, Michael C Turchin, Liesbeth Vandenput, Dominique J Verlaan, Veronique Vitart, Charles C White, Andreas Ziegler, Peter Almgren, Anthony J Balmforth, Harry Campbell, Lorena Citterio, Alessandro De Grandi, Anna Dominiczak, Jubao Duan, Paul Elliott, Roberto Elosua, Johan G Eriksson, Nelson B Freimer, Eco J C Geus, Nicola Glorioso, Shen Haiqing, Anna-Liisa Hartikainen, Aki S Havulinna, Andrew A Hicks, Jennie Hui, Wilmar Igl, Thomas Illig, Antti Jula, Eero Kajantie, Tuomas O Kilpeläinen, Markku Koiranen, Ivana Kolčić, Seppo Koskinen, Peter Kovacs, Jaana Laitinen, Jianjun Liu, Marja-Liisa Lokki, Ana Marušić, Andrea Maschio, Thomas Meitinger, Antonella Mulas, Guillaume Paré, Alex N Parker, John F Peden, Astrid Petersmann, Irene Pichler, Kirsi H Pietiläinen, Anneli Pouta, Martin Ridderstråle, Jerome I Rotter, Jennifer G Sambrook, Alan R Sanders, Carsten Oliver Schmidt, Juha Sinisalo, Jan H Smit, Heather M Stringham, G Bragi Walters, Elisabeth Widén, Sarah H Wild, Gonneke Willemsen, Laura Zagato, Lina Zgaga, Paavo Zitting, Helene Alavere, Martin Farrall, Wendy L McArdle, Mari Nelis, Marjolein J Peters, Samuli Ripatti, Joyce B J van Meurs, Katja K Aben, Kristin G Ardlie, Jacques S Beckmann, John P Beilby, Richard N Bergman, Sven Bergmann, Francis S Collins, Daniele Cusi, Martin den Heijer, Gudny Eiriksdottir, Pablo V Gejman, Alistair S Hall, Anders Hamsten, Heikki V Huikuri, Carlos Iribarren, Mika Kähönen, Jaakko Kaprio, Sekar Kathiresan, Lambertus Kiemeney, Thomas Kocher, Lenore J Launer, Terho Lehtimäki, Olle Melander, Tom H Mosley, Arthur W Musk, Markku S Nieminen, Christopher J O'Donnell, Claes Ohlsson, Ben Oostra, Lyle J Palmer, Olli Raitakari, Paul M Ridker, John D Rioux, Aila Rissanen, Carlo Rivolta, Heribert Schunkert, Alan R Shuldiner, David S Siscovick, Michael Stumvoll, Anke Tönjes, Jaakko Tuomilehto, Gert-Jan van Ommen, Jorma Viikari, Andrew C Heath, Nicholas G Martin, Grant W Montgomery, Michael A Province, Manfred Kayser, Alice M Arnold, Larry D Atwood, Eric Boerwinkle, Stephen J Chanock, Panos Deloukas, Christian Gieger, Henrik Grönberg, Per Hall, Andrew T Hattersley, Christian Hengstenberg, Wolfgang Hoffman, G Mark Lathrop, Veikko Salomaa, Stefan Schreiber, Manuela Uda, Dawn Waterworth, Alan F Wright, Themistocles L Assimes, Inês Barroso, Albert Hofman, Karen L Mohlke, Dorret I Boomsma, Mark J Caulfield, L Adrienne Cupples, Jeanette Erdmann, Caroline S Fox, Vilmundur Gudnason, Ulf Gyllensten, Tamara B Harris, Richard B Hayes, Marjo-Riitta Järvelin, Vincent Mooser, Patricia B Munroe, Willem H Ouwehand, Brenda W Penninx, Peter P Pramstaller, Thomas Quertermous, Igor Rudan, Nilesh J Samani, Timothy D Spector, Henry Völzke, Hugh Watkins, James F Wilson, Leif C Groop, Talin Haritunians, Frank B Hu, Robert C Kaplan, Andres Metspalu, Kari E North, David Schlessinger, Nicholas J Wareham, David J Hunter, Jeffrey R O'Connell, David P Strachan, H-Erich Wichmann, Ingrid B Borecki, Cornelia M van Duijn, Eric E Schadt, Unnur Thorsteinsdottir, Leena Peltonen, André G Uitterlinden, Peter M Visscher, Nilanjan Chatterjee, Ruth J F Loos, Michael Boehnke, Mark I McCarthy, Erik Ingelsson, Cecilia M Lindgren, Gonçalo R Abecasis, Kari Stefansson, Timothy M Frayling, Joel N Hirschhorn.
Nature
PUBLISHED: 04-23-2010
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Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P?
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Meta-analysis and imputation refines the association of 15q25 with smoking quantity.
Jason Z Liu, Federica Tozzi, Dawn M Waterworth, Sreekumar G Pillai, Pierandrea Muglia, Lefkos Middleton, Wade Berrettini, Christopher W Knouff, Xin Yuan, Gérard Waeber, Peter Vollenweider, Martin Preisig, Nicholas J Wareham, Jing Hua Zhao, Ruth J F Loos, Inês Barroso, Kay-Tee Khaw, Scott Grundy, Philip Barter, Robert Mahley, Antero Kesäniemi, Ruth McPherson, John B Vincent, John Strauss, James L Kennedy, Anne Farmer, Peter McGuffin, Richard Day, Keith Matthews, Per Bakke, Amund Gulsvik, Susanne Lucae, Marcus Ising, Tanja Brueckl, Sonja Horstmann, H-Erich Wichmann, Rajesh Rawal, Norbert Dahmen, Claudia Lamina, Ozren Polašek, Lina Zgaga, Jennifer Huffman, Susan Campbell, Jaspal Kooner, John C Chambers, Mary Susan Burnett, Joseph M Devaney, Augusto D Pichard, Kenneth M Kent, Lowell Satler, Joseph M Lindsay, Ron Waksman, Stephen Epstein, James F Wilson, Sarah H Wild, Harry Campbell, Veronique Vitart, Muredach P Reilly, Mingyao Li, Liming Qu, Robert Wilensky, William Matthai, Hakon H Hakonarson, Daniel J Rader, Andre Franke, Michael Wittig, Arne Schäfer, Manuela Uda, Antonio Terracciano, Xiangjun Xiao, Fabio Busonero, Paul Scheet, David Schlessinger, David St Clair, Dan Rujescu, Gonçalo R Abecasis, Hans Jörgen Grabe, Alexander Teumer, Henry Völzke, Astrid Petersmann, Ulrich John, Igor Rudan, Caroline Hayward, Alan F Wright, Ivana Kolčić, Benjamin J Wright, John R Thompson, Anthony J Balmforth, Alistair S Hall, Nilesh J Samani, Carl A Anderson, Tariq Ahmad, Christopher G Mathew, Miles Parkes, Jack Satsangi, Mark Caulfield, Patricia B Munroe, Martin Farrall, Anna Dominiczak, Jane Worthington, Wendy Thomson, Steve Eyre, Anne Barton, , Vincent Mooser, Clyde Francks, Jonathan Marchini.
Nat. Genet.
PUBLISHED: 03-18-2010
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Smoking is a leading global cause of disease and mortality. We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 x 10(-19)) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.
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Genetic loci influencing kidney function and chronic kidney disease.
John C Chambers, Weihua Zhang, Graham M Lord, Pim van der Harst, Debbie A Lawlor, Joban S Sehmi, Daniel P Gale, Mark N Wass, Kourosh R Ahmadi, Stephan J L Bakker, Jacqui Beckmann, Henk J G Bilo, Murielle Bochud, Morris J Brown, Mark J Caulfield, John M C Connell, H Terence Cook, Ioana Cotlarciuc, George Davey Smith, Ranil de Silva, Guohong Deng, Olivier Devuyst, Lambert D Dikkeschei, Nada Dimković, Mark Dockrell, Anna Dominiczak, Shah Ebrahim, Thomas Eggermann, Martin Farrall, Luigi Ferrucci, Jürgen Floege, Nita G Forouhi, Ron T Gansevoort, Xijin Han, Bo Hedblad, Jaap J Homan van der Heide, Bouke G Hepkema, Maria Hernandez-Fuentes, Elina Hyppönen, Toby Johnson, Paul E de Jong, Nanne Kleefstra, Vasiliki Lagou, Marta Lapsley, Yun Li, Ruth J F Loos, Jian'an Luan, Karin Luttropp, Céline Maréchal, Olle Melander, Patricia B Munroe, Louise Nordfors, Afshin Parsa, Leena Peltonen, Brenda W Penninx, Esperanza Perucha, Anneli Pouta, Inga Prokopenko, Paul J Roderick, Aimo Ruokonen, Nilesh J Samani, Serena Sanna, Martin Schalling, David Schlessinger, Georg Schlieper, Marc A J Seelen, Alan R Shuldiner, Marketa Sjögren, Johannes H Smit, Harold Snieder, Nicole Soranzo, Timothy D Spector, Peter Stenvinkel, Michael J E Sternberg, Ramasamyiyer Swaminathan, Toshiko Tanaka, Lielith J Ubink-Veltmaat, Manuela Uda, Peter Vollenweider, Chris Wallace, Dawn Waterworth, Klaus Zerres, Gérard Waeber, Nicholas J Wareham, Patrick H Maxwell, Mark I McCarthy, Marjo-Riitta Järvelin, Vincent Mooser, Gonçalo R Abecasis, Liz Lightstone, James Scott, Gerjan Navis, Paul Elliott, Jaspal S Kooner.
Nat. Genet.
PUBLISHED: 03-15-2010
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Using genome-wide association, we identify common variants at 2p12-p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10(-10) to 10(-15)). Of these, rs10206899 (near NAT8, 2p12-p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 x 10(-5) and P = 3.6 x 10(-4), respectively). Our findings provide insight into metabolic, solute and drug-transport pathways underlying susceptibility to chronic kidney disease.
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Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls.
, Nick Craddock, Matthew E Hurles, Niall Cardin, Richard D Pearson, Vincent Plagnol, Samuel Robson, Damjan Vukcevic, Chris Barnes, Donald F Conrad, Eleni Giannoulatou, Chris Holmes, Jonathan L Marchini, Kathy Stirrups, Martin D Tobin, Louise V Wain, Chris Yau, Jan Aerts, Tariq Ahmad, T Daniel Andrews, Hazel Arbury, Anthony Attwood, Adam Auton, Stephen G Ball, Anthony J Balmforth, Jeffrey C Barrett, Inês Barroso, Anne Barton, Amanda J Bennett, Sanjeev Bhaskar, Katarzyna Blaszczyk, John Bowes, Oliver J Brand, Peter S Braund, Francesca Bredin, Gerome Breen, Morris J Brown, Ian N Bruce, Jaswinder Bull, Oliver S Burren, John Burton, Jake Byrnes, Sian Caesar, Chris M Clee, Alison J Coffey, John M C Connell, Jason D Cooper, Anna F Dominiczak, Kate Downes, Hazel E Drummond, Darshna Dudakia, Andrew Dunham, Bernadette Ebbs, Diana Eccles, Sarah Edkins, Cathryn Edwards, Anna Elliot, Paul Emery, David M Evans, Gareth Evans, Steve Eyre, Anne Farmer, I Nicol Ferrier, Lars Feuk, Tomas Fitzgerald, Edward Flynn, Alistair Forbes, Liz Forty, Jayne A Franklyn, Rachel M Freathy, Polly Gibbs, Paul Gilbert, Omer Gokumen, Katherine Gordon-Smith, Emma Gray, Elaine Green, Chris J Groves, Detelina Grozeva, Rhian Gwilliam, Anita Hall, Naomi Hammond, Matt Hardy, Pile Harrison, Neelam Hassanali, Husam Hebaishi, Sarah Hines, Anne Hinks, Graham A Hitman, Lynne Hocking, Eleanor Howard, Philip Howard, Joanna M M Howson, Debbie Hughes, Sarah Hunt, John D Isaacs, Mahim Jain, Derek P Jewell, Toby Johnson, Jennifer D Jolley, Ian R Jones, Lisa A Jones, George Kirov, Cordelia F Langford, Hana Lango-Allen, G Mark Lathrop, James Lee, Kate L Lee, Charlie Lees, Kevin Lewis, Cecilia M Lindgren, Meeta Maisuria-Armer, Julian Maller, John Mansfield, Paul Martin, Dunecan C O Massey, Wendy L McArdle, Peter McGuffin, Kirsten E McLay, Alex Mentzer, Michael L Mimmack, Ann E Morgan, Andrew P Morris, Craig Mowat, Simon Myers, William Newman, Elaine R Nimmo, Michael C O'Donovan, Abiodun Onipinla, Ifejinelo Onyiah, Nigel R Ovington, Michael J Owen, Kimmo Palin, Kirstie Parnell, David Pernet, John R B Perry, Anne Phillips, Dalila Pinto, Natalie J Prescott, Inga Prokopenko, Michael A Quail, Suzanne Rafelt, Nigel W Rayner, Richard Redon, David M Reid, Renwick, Susan M Ring, Neil Robertson, Ellie Russell, David St Clair, Jennifer G Sambrook, Jeremy D Sanderson, Helen Schuilenburg, Carol E Scott, Richard Scott, Sheila Seal, Sue Shaw-Hawkins, Beverley M Shields, Matthew J Simmonds, Debbie J Smyth, Elilan Somaskantharajah, Katarina Spanova, Sophia Steer, Jonathan Stephens, Helen E Stevens, Millicent A Stone, Zhan Su, Deborah P M Symmons, John R Thompson, Wendy Thomson, Mary E Travers, Clare Turnbull, Armand Valsesia, Mark Walker, Neil M Walker, Chris Wallace, Margaret Warren-Perry, Nicholas A Watkins, John Webster, Michael N Weedon, Anthony G Wilson, Matthew Woodburn, B Paul Wordsworth, Allan H Young, Eleftheria Zeggini, Nigel P Carter, Timothy M Frayling, Charles Lee, Gil McVean, Patricia B Munroe, Aarno Palotie, Stephen J Sawcer, Stephen W Scherer, David P Strachan, Chris Tyler-Smith, Matthew A Brown, Paul R Burton, Mark J Caulfield, Alastair Compston, Martin Farrall, Stephen C L Gough, Alistair S Hall, Andrew T Hattersley, Adrian V S Hill, Christopher G Mathew, Marcus Pembrey, Jack Satsangi, Michael R Stratton, Jane Worthington, Panos Deloukas, Audrey Duncanson, Dominic P Kwiatkowski, Mark I McCarthy, Willem Ouwehand, Miles Parkes, Nazneen Rahman, John A Todd, Nilesh J Samani, Peter Donnelly.
Nature
PUBLISHED: 03-05-2010
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Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohns disease, HLA for Crohns disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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Biological, clinical and population relevance of 95 loci for blood lipids.
Tanya M Teslovich, Kiran Musunuru, Albert V Smith, Andrew C Edmondson, Ioannis M Stylianou, Masahiro Koseki, James P Pirruccello, Samuli Ripatti, Daniel I Chasman, Cristen J Willer, Christopher T Johansen, Sigrid W Fouchier, Aaron Isaacs, Gina M Peloso, Maja Barbalic, Sally L Ricketts, Joshua C Bis, Yurii S Aulchenko, Gudmar Thorleifsson, Mary F Feitosa, John Chambers, Marju Orho-Melander, Olle Melander, Toby Johnson, Xiaohui Li, Xiuqing Guo, Mingyao Li, Yoon Shin Cho, Min Jin Go, Young Jin Kim, Jong-Young Lee, Taesung Park, Kyunga Kim, Xueling Sim, Rick Twee-Hee Ong, Damien C Croteau-Chonka, Leslie A Lange, Joshua D Smith, Kijoung Song, Jing Hua Zhao, Xin Yuan, Jian'an Luan, Claudia Lamina, Andreas Ziegler, Weihua Zhang, Robert Y L Zee, Alan F Wright, Jacqueline C M Witteman, James F Wilson, Gonneke Willemsen, H-Erich Wichmann, John B Whitfield, Dawn M Waterworth, Nicholas J Wareham, Gérard Waeber, Peter Vollenweider, Benjamin F Voight, Veronique Vitart, André G Uitterlinden, Manuela Uda, Jaakko Tuomilehto, John R Thompson, Toshiko Tanaka, Ida Surakka, Heather M Stringham, Tim D Spector, Nicole Soranzo, Johannes H Smit, Juha Sinisalo, Kaisa Silander, Eric J G Sijbrands, Angelo Scuteri, James Scott, David Schlessinger, Serena Sanna, Veikko Salomaa, Juha Saharinen, Chiara Sabatti, Aimo Ruokonen, Igor Rudan, Lynda M Rose, Robert Roberts, Mark Rieder, Bruce M Psaty, Peter P Pramstaller, Irene Pichler, Markus Perola, Brenda W J H Penninx, Nancy L Pedersen, Cristian Pattaro, Alex N Parker, Guillaume Paré, Ben A Oostra, Christopher J O'Donnell, Markku S Nieminen, Deborah A Nickerson, Grant W Montgomery, Thomas Meitinger, Ruth McPherson, Mark I McCarthy, Wendy McArdle, David Masson, Nicholas G Martin, Fabio Marroni, Massimo Mangino, Patrik K E Magnusson, Gavin Lucas, Robert Luben, Ruth J F Loos, Marja-Liisa Lokki, Guillaume Lettre, Claudia Langenberg, Lenore J Launer, Edward G Lakatta, Reijo Laaksonen, Kirsten O Kyvik, Florian Kronenberg, Inke R König, Kay-Tee Khaw, Jaakko Kaprio, Lee M Kaplan, Asa Johansson, Marjo-Riitta Järvelin, A Cecile J W Janssens, Erik Ingelsson, Wilmar Igl, G Kees Hovingh, Jouke-Jan Hottenga, Albert Hofman, Andrew A Hicks, Christian Hengstenberg, Iris M Heid, Caroline Hayward, Aki S Havulinna, Nicholas D Hastie, Tamara B Harris, Talin Haritunians, Alistair S Hall, Ulf Gyllensten, Candace Guiducci, Leif C Groop, Elena González, Christian Gieger, Nelson B Freimer, Luigi Ferrucci, Jeanette Erdmann, Paul Elliott, Kenechi G Ejebe, Angela Döring, Anna F Dominiczak, Serkalem Demissie, Panagiotis Deloukas, Eco J C de Geus, Ulf de Faire, Gabriel Crawford, Francis S Collins, Yii-Der I Chen, Mark J Caulfield, Harry Campbell, Noel P Burtt, Lori L Bonnycastle, Dorret I Boomsma, S Matthijs Boekholdt, Richard N Bergman, Inês Barroso, Stefania Bandinelli, Christie M Ballantyne, Themistocles L Assimes, Thomas Quertermous, David Altshuler, Mark Seielstad, Tien Y Wong, E-Shyong Tai, Alan B Feranil, Christopher W Kuzawa, Linda S Adair, Herman A Taylor, Ingrid B Borecki, Stacey B Gabriel, James G Wilson, Hilma Holm, Unnur Thorsteinsdottir, Vilmundur Gudnason, Ronald M Krauss, Karen L Mohlke, José M Ordovás, Patricia B Munroe, Jaspal S Kooner, Alan R Tall, Robert A Hegele, John J P Kastelein, Eric E Schadt, Jerome I Rotter, Eric Boerwinkle, David P Strachan, Vincent Mooser, Kari Stefansson, Muredach P Reilly, Nilesh J Samani, Heribert Schunkert, L Adrienne Cupples, Manjinder S Sandhu, Paul M Ridker, Daniel J Rader, Cornelia M van Duijn, Leena Peltonen, Gonçalo R Abecasis, Michael Boehnke, Sekar Kathiresan.
Nature
PUBLISHED: 02-25-2010
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Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
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Genome-wide association studies of hypertension: light at the end of the tunnel.
Int J Hypertens
PUBLISHED: 01-28-2010
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Despite its significant genetic component, the study of hypertension by genome-wide association presents more challenges than other common complex diseases. Its high prevalence, heterogeneity, and somewhat unclear definition are the challenges that need to be overcome on one hand. On the other hand, there are issues of small effect sizes and pleiotropism that are not specific to hypertension alone but nonetheless magnify the problems of genetic dissection when coupled with phenotypic misclassification. We discuss issues of study design and summarise published genome-wide association studies (GWASs) of hypertension and blood pressure. With careful study design and analysis success is possible, as demonstrated by the recent large-scale studies. Following these, there is still further scope to advance the field through high fidelity phenotyping and deep sequencing.
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Reduced LDL-cholesterol levels in patients with coronary artery disease are paralleled by improved endothelial function: An observational study in patients from 2003 and 2007.
Atherosclerosis
PUBLISHED: 01-11-2010
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Recent guidelines recommend more aggressive lipid-lowering in secondary prevention protocols. We examined whether this resulted in improved endothelial function.
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Resting heart rate pattern during follow-up and mortality in hypertensive patients.
Hypertension
PUBLISHED: 12-28-2009
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There is a linear relationship between resting heart rate (HR) and mortality in normotensive and untreated hypertensive individuals. However, it is not clear whether HR is a marker of increased risk in hypertensive patients on treatment. We investigated the relationship between HR and mortality in patients with hypertension. We analyzed baseline HR, final HR, and HR change during follow-up in patients attending the Glasgow Blood Pressure Clinic. Using a threshold of 80 bpm, we classified patients into those who had a consistently high (high-high) or low (low-low) HR or patients whose HR increased (low-high) or decreased (high-low) over time. Survival analysis was carried out using Cox proportional hazards models adjusted for age, sex, body mass index, smoking, rate-limiting therapy, systolic blood pressure, and serum cholesterol. For each beat of HR change there was a 1% change in mortality risk. The highest risk of an all-cause event was associated with patients who had increased their HR by >or=5 bpm at the end of follow-up (1.51 [95% CI: 1.03 to 2.20]; P=0.035). Compared with low-low patients, high-high patients had a 78% increase in the risk of all-cause mortality (HR: 1.78 [95% CI: 1.31 to 2.41]; P<0.001). Cardiovascular mortality showed a similar pattern of results. Rate-limiting therapy did not have an independent effect on outcomes in this analysis. Change in HR achieved during follow-up of hypertensive patients is a better predictor of risk than baseline or final HR. After correction for rate-limiting therapy, HR remained a significant independent risk factor.
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Genetics of hypertension: from experimental animals to humans.
Biochim. Biophys. Acta
PUBLISHED: 12-03-2009
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Essential hypertension affects 20 to 30% of the population worldwide and contributes significantly to cardiovascular mortality and morbidity. Heridability of blood pressure is around 15 to 40% but there are also substantial environmental factors affecting blood pressure variability. It is assumed that blood pressure is under the control of a large number of genes each of which has only relatively mild effects. It has therefore been difficult to discover the genes that contribute to blood pressure variation using traditional approaches including candidate gene studies and linkage studies. Animal models of hypertension, particularly in the rat, have led to the discovery of quantitative trait loci harbouring one or several hypertension related genes, but translation of these findings into human essential hypertension remains challenging. Recent development of genotyping technology made large scale genome-wide association studies possible. This approach and the study of monogenic forms of hypertension has led to the discovery of novel and robust candidate genes for human essential hypertension, many of which require functional analysis in experimental models.
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Differences in the evolution of the ischemic penumbra in stroke-prone spontaneously hypertensive and Wistar-Kyoto rats.
Stroke
PUBLISHED: 09-24-2009
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Stroke-prone spontaneously hypertensive rats (SHRSP) are a highly pertinent stroke model with increased sensitivity to focal ischemia compared with the normotensive reference strain (Wistar-Kyoto rats; WKY). Study aims were to investigate temporal changes in the ischemic penumbra in SHRSP compared with WKY.
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Capillary electrophoresis-mass spectrometry as a powerful tool in biomarker discovery and clinical diagnosis: an update of recent developments.
Mass Spectrom Rev
PUBLISHED: 09-23-2009
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Proteome analysis has emerged as a powerful technology to decipher biological processes. One of the main goals is to discover biomarkers for diseases from tissues and body fluids. However, the complexity and wide dynamic range of protein expression present an enormous challenge to separation technologies and mass spectrometry (MS). In this review, we examine the limitations of proteomics, and aim towards the definition of the current key prerequisites. We focus on capillary electrophoresis coupled to mass spectrometry (CE-MS), because this technique continues to show great promise. We discuss CE-MS from an application point of view, and evaluate its merits and vices for biomarker discovery and clinical applications. Finally, we present several examples on the use of CE-MS to determine urinary biomarkers and implications for disease diagnosis, prognosis, and therapy evaluation.
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Obesity paradox in a cohort of 4880 consecutive patients undergoing percutaneous coronary intervention.
Eur. Heart J.
PUBLISHED: 08-17-2009
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We sought to investigate the impact of body mass index (BMI) on long-term all-cause mortality in patients following first-time elective percutaneous coronary intervention (PCI).
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Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.
Am. J. Hum. Genet.
PUBLISHED: 07-23-2009
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Blood lipids are important cardiovascular disease (CVD) risk factors with both genetic and environmental determinants. The Whitehall II study (n=5592) was genotyped with the gene-centric HumanCVD BeadChip (Illumina). We identified 195 SNPs in 16 genes/regions associated with 3 major lipid fractions and 2 apolipoprotein components at p<10(-5), with the associations being broadly concordant with prior genome-wide analysis. SNPs associated with LDL cholesterol and apolipoprotein B were located in LDLR, PCSK9, APOB, CELSR2, HMGCR, CETP, the TOMM40-APOE-C1-C2-C4 cluster, and the APOA5-A4-C3-A1 cluster; SNPs associated with HDL cholesterol and apolipoprotein AI were in CETP, LPL, LIPC, APOA5-A4-C3-A1, and ABCA1; and SNPs associated with triglycerides in GCKR, BAZ1B, MLXIPL, LPL, and APOA5-A4-C3-A1. For 48 SNPs in previously unreported loci that were significant at p<10(-4) in Whitehall II, in silico analysis including the British Womens Heart and Health Study, BRIGHT, ASCOT, and NORDIL studies (total n>12,500) revealed previously unreported associations of SH2B3 (p<2.2x10(-6)), BMPR2 (p<2.3x10(-7)), BCL3/PVRL2 (flanking APOE; p<4.4x10(-8)), and SMARCA4 (flanking LDLR; p<2.5x10(-7)) with LDL cholesterol. Common alleles in these genes explained 6.1%-14.7% of the variance in the five lipid-related traits, and individuals at opposite tails of the additive allele score exhibited substantial differences in trait levels (e.g., >1 mmol/L in LDL cholesterol [approximately 1 SD of the trait distribution]). These data suggest that multiple common alleles of small effect can make important contributions to individual differences in blood lipids potentially relevant to the assessment of CVD risk. These genes provide further insights into lipid metabolism and the likely effects of modifying the encoded targets therapeutically.
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Mitochondria-targeted antioxidant MitoQ10 improves endothelial function and attenuates cardiac hypertrophy.
Hypertension
PUBLISHED: 07-06-2009
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Mitochondria are a major site of reactive oxygen species production, which may contribute to the development of cardiovascular disease. Protecting mitochondria from oxidative damage should be an effective therapeutic strategy; however, conventional antioxidants are ineffective, because they cannot penetrate the mitochondria. This study investigated the role of mitochondrial oxidative stress during development of hypertension in the stroke-prone spontaneously hypertensive rat, using the mitochondria-targeted antioxidant, MitoQ(10). Eight-week-old male stroke-prone spontaneously hypertensive rats were treated with MitoQ(10) (500 mumol/L; n=16), control compound decyltriphenylphosphonium (decylTPP; 500 mumol/L; n=8), or vehicle (n=9) in drinking water for 8 weeks. Systolic blood pressure was significantly reduced by approximately 25 mm Hg over the 8-week MitoQ(10) treatment period compared with decylTPP (F=5.94; P=0.029) or untreated controls (F=65.6; P=0.0001). MitoQ(10) treatment significantly improved thoracic aorta NO bioavailability (1.16+/-0.03 g/g; P=0.002, area under the curve) compared with both untreated controls (0.68+/-0.02 g/g) and decylTPP-treated rats (0.60+/-0.06 g/g). Cardiac hypertrophy was significantly reduced by MitoQ(10) treatment compared with untreated control and decylTPP treatment (MitoQ(10): 4.01+/-0.05 mg/g; control: 4.42+/-0.11 mg/g; and decylTPP: 4.40+/-0.09 mg/g; ANOVA P=0.002). Total MitoQ(10) content was measured in liver, heart, carotid artery, and kidney harvested from MitoQ(10)-treated rats by liquid chromatography-tandem mass spectrometry. All of the organs analyzed demonstrated detectable levels of MitoQ(10), with comparable accumulation in vascular and cardiac tissues. Administration of the mitochondria-targeted antioxidant MitoQ(10) protects against the development of hypertension, improves endothelial function, and reduces cardiac hypertrophy in young stroke-prone spontaneously hypertensive rats. MitoQ(10) provides a novel approach to attenuate mitochondrial-specific oxidative damage with the potential to become a new therapeutic intervention in human cardiovascular disease.
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Renal and vascular glutathione S-transferase mu is not affected by pharmacological intervention to reduce systolic blood pressure.
J. Hypertens.
PUBLISHED: 06-18-2009
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Our previous studies demonstrated reduced rat glutathione S-transferase mu type 1 (Gstm1) expression in stroke-prone spontaneously hypertensive rats (SHRSPs), when compared with the normotensive Wistar-Kyoto rat.
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Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies.
PLoS ONE
PUBLISHED: 05-12-2009
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To identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS) including 3,558 subjects from the TwinsUK and BRIGHT cohorts in the UK and the DCCT/EDIC cohort from North America. Five loci were significantly associated with QT interval at P<1x10(-6). To validate these findings we performed an in silico comparison with data from two QT consortia: QTSCD (n = 15,842) and QTGEN (n = 13,685). Analysis confirmed the association between common variants near NOS1AP (P = 1.4x10(-83)) and the phospholamban (PLN) gene (P = 1.9x10(-29)). The most associated SNP near NOS1AP (rs12143842) explains 0.82% variance; the SNP near PLN (rs11153730) explains 0.74% variance of QT interval duration. We found no evidence for interaction between these two SNPs (P = 0.99). PLN is a key regulator of cardiac diastolic function and is involved in regulating intracellular calcium cycling, it has only recently been identified as a susceptibility locus for QT interval. These data offer further mechanistic insights into genetic influence on the QT interval which may predispose to life threatening arrhythmias and sudden cardiac death.
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Genome-wide scan identifies CDH13 as a novel susceptibility locus contributing to blood pressure determination in two European populations.
Hum. Mol. Genet.
PUBLISHED: 03-20-2009
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Hypertension is a complex disease that affects a large proportion of adult population. Although approximately half of the inter-individual variance in blood pressure (BP) level is heritable, identification of genes responsible for its regulation has remained challenging. Genome-wide association study (GWAS) is a novel approach to search for genetic variants contributing to complex diseases. We conducted GWAS for three BP traits [systolic and diastolic blood pressure (SBP and DBP); hypertension (HYP)] in the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) S3 cohort (n = 1644) recruited from general population in Southern Germany. GWAS with 395,912 single nucleotide polymorphisms (SNPs) identified an association between BP traits and a common variant rs11646213 (T/A) upstream of the CDH13 gene at 16q23.3. The initial associations with HYP and DBP were confirmed in two other European population-based cohorts: KORA S4 (Germans) and HYPEST (Estonians). The associations between rs11646213 and three BP traits were replicated in combined analyses (dominant model: DBP, P = 5.55 x 10(-5), effect -1.40 mmHg; SBP, P = 0.007, effect -1.56 mmHg; HYP, P = 5.30 x 10(-8), OR = 0.67). Carriers of the minor allele A had a decreased risk of hypertension. A non-significant trend for association was also detected with severe family based hypertension in the BRIGHT sample (British). The novel susceptibility locus, CDH13, encodes for an adhesion glycoprotein T-cadherin, a regulator of vascular wall remodeling and angiogenesis. Its function is compatible with the BP biology and may improve the understanding of the pathogenesis of hypertension.
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