JoVE Visualize What is visualize?
Stop Reading. Start Watching.
Advanced Search
Stop Reading. Start Watching.
Regular Search
Find video protocols related to scientific articles indexed in Pubmed.
HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.
Daniel I Swerdlow, David Preiss, Karoline B Kuchenbaecker, Michael V Holmes, Jorgen E L Engmann, Tina Shah, Reecha Sofat, Stefan Stender, Paul C D Johnson, Robert A Scott, Maarten Leusink, Niek Verweij, Stephen J Sharp, Yiran Guo, Claudia Giambartolomei, Christina Chung, Anne Peasey, Antoinette Amuzu, KaWah Li, Jutta Palmen, Philip Howard, Jackie A Cooper, Fotios Drenos, Yun R Li, Gordon Lowe, John Gallacher, Marlene C W Stewart, Ioanna Tzoulaki, Sarah G Buxbaum, Daphne L van der A, Nita G Forouhi, N Charlotte Onland-Moret, Yvonne T van der Schouw, Renate B Schnabel, Jaroslav A Hubacek, Růžena Kubinova, Miglė Bacevičienė, Abdonas Tamosiunas, Andrzej Pająk, Romanvan Topor-Madry, Urszula Stepaniak, Sofia Malyutina, Damiano Baldassarre, Bengt Sennblad, Elena Tremoli, Ulf de Faire, Fabrizio Veglia, Ian Ford, J Wouter Jukema, Rudi G J Westendorp, Gert Jan de Borst, Pim A de Jong, Ale Algra, Wilko Spiering, Anke H Maitland-van der Zee, Olaf H Klungel, Anthonius de Boer, Pieter A Doevendans, Charles B Eaton, Jennifer G Robinson, David Duggan, , John Kjekshus, John R Downs, Antonio M Gotto, Anthony C Keech, Roberto Marchioli, Gianni Tognoni, Peter S Sever, Neil R Poulter, David D Waters, Terje R Pedersen, Pierre Amarenco, Haruo Nakamura, John J V McMurray, James D Lewsey, Daniel I Chasman, Paul M Ridker, Aldo P Maggioni, Luigi Tavazzi, Kausik K Ray, Sreenivasa Rao Kondapally Seshasai, JoAnn E Manson, Jackie F Price, Peter H Whincup, Richard W Morris, Debbie A Lawlor, George Davey Smith, Yoav Ben-Shlomo, Pamela J Schreiner, Myriam Fornage, David S Siscovick, Mary Cushman, Meena Kumari, Nick J Wareham, W M Monique Verschuren, Susan Redline, Sanjay R Patel, John C Whittaker, Anders Hamsten, Joseph A Delaney, Caroline Dale, Tom R Gaunt, Andrew Wong, Diana Kuh, Rebecca Hardy, Sekar Kathiresan, Berta A Castillo, Pim van der Harst, Eric J Brunner, Anne Tybjaerg-Hansen, Michael G Marmot, Ronald M Krauss, Michael Tsai, Josef Coresh, Ronald C Hoogeveen, Bruce M Psaty, Leslie A Lange, Hakon Hakonarson, Frank Dudbridge, Steve E Humphries, Philippa J Talmud, Mika Kivimäki, Nicholas J Timpson, Claudia Langenberg, Folkert W Asselbergs, Mikhail Voevoda, Martin Bobak, Hynek Pikhart, James G Wilson, Alex P Reiner, Brendan J Keating, Aroon D Hingorani, Naveed Sattar.
Lancet
PUBLISHED: 09-29-2014
Show Abstract
Hide Abstract
Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.
Related JoVE Video
Defining the role of common variation in the genomic and biological architecture of adult human height.
Andrew R Wood, Tonu Esko, Jian Yang, Sailaja Vedantam, Tune H Pers, Stefan Gustafsson, Audrey Y Chu, Karol Estrada, Jian'an Luan, Zoltan Kutalik, Najaf Amin, Martin L Buchkovich, Damien C Croteau-Chonka, Felix R Day, Yanan Duan, Tove Fall, Rudolf Fehrmann, Teresa Ferreira, Anne U Jackson, Juha Karjalainen, Ken Sin Lo, Adam E Locke, Reedik Mägi, Evelin Mihailov, Eleonora Porcu, Joshua C Randall, André Scherag, Anna A E Vinkhuyzen, Harm-Jan Westra, Thomas W Winkler, Tsegaselassie Workalemahu, Jing Hua Zhao, Devin Absher, Eva Albrecht, Denise Anderson, Jeffrey Baron, Marian Beekman, Ayse Demirkan, Georg B Ehret, Bjarke Feenstra, Mary F Feitosa, Krista Fischer, Ross M Fraser, Anuj Goel, Jian Gong, Anne E Justice, Stavroula Kanoni, Marcus E Kleber, Kati Kristiansson, Unhee Lim, Vaneet Lotay, Julian C Lui, Massimo Mangino, Irene Mateo Leach, Carolina Medina-Gomez, Michael A Nalls, Dale R Nyholt, Cameron D Palmer, Dorota Pasko, Sonali Pechlivanis, Inga Prokopenko, Janina S Ried, Stephan Ripke, Dmitry Shungin, Alena Stančáková, Rona J Strawbridge, Yun Ju Sung, Toshiko Tanaka, Alexander Teumer, Stella Trompet, Sander W van der Laan, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Zhaoming Wang, Loïc Yengo, Weihua Zhang, Uzma Afzal, Johan Arnlöv, Gillian M Arscott, Stefania Bandinelli, Amy Barrett, Claire Bellis, Amanda J Bennett, Christian Berne, Matthias Blüher, Jennifer L Bolton, Yvonne Böttcher, Heather A Boyd, Marcel Bruinenberg, Brendan M Buckley, Steven Buyske, Ida H Caspersen, Peter S Chines, Robert Clarke, Simone Claudi-Boehm, Matthew Cooper, E Warwick Daw, Pim A de Jong, Joris Deelen, Graciela Delgado, Josh C Denny, Rosalie Dhonukshe-Rutten, Maria Dimitriou, Alex S F Doney, Marcus Dörr, Niina Eklund, Elodie Eury, Lasse Folkersen, Melissa E Garcia, Frank Geller, Vilmantas Giedraitis, Alan S Go, Harald Grallert, Tanja B Grammer, Jürgen Gräßler, Henrik Grönberg, Lisette C P G M de Groot, Christopher J Groves, Jeffrey Haessler, Per Hall, Toomas Haller, Göran Hallmans, Anke Hannemann, Catharina A Hartman, Maija Hassinen, Caroline Hayward, Nancy L Heard-Costa, Quinta Helmer, Gibran Hemani, Anjali K Henders, Hans L Hillege, Mark A Hlatky, Wolfgang Hoffmann, Per Hoffmann, Oddgeir Holmen, Jeanine J Houwing-Duistermaat, Thomas Illig, Aaron Isaacs, Alan L James, Janina Jeff, Berit Johansen, Asa Johansson, Jennifer Jolley, Thorhildur Juliusdottir, Juhani Junttila, Abel N Kho, Leena Kinnunen, Norman Klopp, Thomas Kocher, Wolfgang Kratzer, Peter Lichtner, Lars Lind, Jaana Lindström, Stéphane Lobbens, Mattias Lorentzon, Yingchang Lu, Valeriya Lyssenko, Patrik K E Magnusson, Anubha Mahajan, Marc Maillard, Wendy L McArdle, Colin A McKenzie, Stela McLachlan, Paul J McLaren, Cristina Menni, Sigrun Merger, Lili Milani, Alireza Moayyeri, Keri L Monda, Mario A Morken, Gabriele Müller, Martina Müller-Nurasyid, Arthur W Musk, Narisu Narisu, Matthias Nauck, Ilja M Nolte, Markus M Nöthen, Laticia Oozageer, Stefan Pilz, Nigel W Rayner, Frida Renstrom, Neil R Robertson, Lynda M Rose, Ronan Roussel, Serena Sanna, Hubert Scharnagl, Salome Scholtens, Fredrick R Schumacher, Heribert Schunkert, Robert A Scott, Joban Sehmi, Thomas Seufferlein, Jianxin Shi, Karri Silventoinen, Johannes H Smit, Albert Vernon Smith, Joanna Smolonska, Alice V Stanton, Kathleen Stirrups, David J Stott, Heather M Stringham, Johan Sundström, Morris A Swertz, Ann-Christine Syvänen, Bamidele O Tayo, Gudmar Thorleifsson, Jonathan P Tyrer, Suzanne van Dijk, Natasja M van Schoor, Nathalie van der Velde, Diana van Heemst, Floor V A van Oort, Sita H Vermeulen, Niek Verweij, Judith M Vonk, Lindsay L Waite, Melanie Waldenberger, Roman Wennauer, Lynne R Wilkens, Christina Willenborg, Tom Wilsgaard, Mary K Wojczynski, Andrew Wong, Alan F Wright, Qunyuan Zhang, Dominique Arveiler, Stephan J L Bakker, John Beilby, Richard N Bergman, Sven Bergmann, Reiner Biffar, John Blangero, Dorret I Boomsma, Stefan R Bornstein, Pascal Bovet, Paolo Brambilla, Morris J Brown, Harry Campbell, Mark J Caulfield, Aravinda Chakravarti, Rory Collins, Francis S Collins, Dana C Crawford, L Adrienne Cupples, John Danesh, Ulf de Faire, Hester M den Ruijter, Raimund Erbel, Jeanette Erdmann, Johan G Eriksson, Martin Farrall, Ele Ferrannini, Jean Ferrières, Ian Ford, Nita G Forouhi, Terrence Forrester, Ron T Gansevoort, Pablo V Gejman, Christian Gieger, Alain Golay, Omri Gottesman, Vilmundur Gudnason, Ulf Gyllensten, David W Haas, Alistair S Hall, Tamara B Harris, Andrew T Hattersley, Andrew C Heath, Christian Hengstenberg, Andrew A Hicks, Lucia A Hindorff, Aroon D Hingorani, Albert Hofman, G Kees Hovingh, Steve E Humphries, Steven C Hunt, Elina Hyppönen, Kevin B Jacobs, Marjo-Riitta Järvelin, Pekka Jousilahti, Antti M Jula, Jaakko Kaprio, John J P Kastelein, Manfred Kayser, Frank Kee, Sirkka M Keinanen-Kiukaanniemi, Lambertus A Kiemeney, Jaspal S Kooner, Charles Kooperberg, Seppo Koskinen, Peter Kovacs, Aldi T Kraja, Meena Kumari, Johanna Kuusisto, Timo A Lakka, Claudia Langenberg, Loic Le Marchand, Terho Lehtimäki, Sara Lupoli, Pamela A F Madden, Satu Mannisto, Paolo Manunta, André Marette, Tara C Matise, Barbara McKnight, Thomas Meitinger, Frans L Moll, Grant W Montgomery, Andrew D Morris, Andrew P Morris, Jeffrey C Murray, Mari Nelis, Claes Ohlsson, Albertine J Oldehinkel, Ken K Ong, Willem H Ouwehand, Gerard Pasterkamp, Annette Peters, Peter P Pramstaller, Jackie F Price, Lu Qi, Olli T Raitakari, Tuomo Rankinen, D C Rao, Treva K Rice, Marylyn Ritchie, Igor Rudan, Veikko Salomaa, Nilesh J Samani, Jouko Saramies, Mark A Sarzynski, Peter E H Schwarz, Sylvain Sebert, Peter Sever, Alan R Shuldiner, Juha Sinisalo, Valgerdur Steinthorsdottir, Ronald P Stolk, Jean-Claude Tardif, Anke Tönjes, Angelo Tremblay, Elena Tremoli, Jarmo Virtamo, Marie-Claude Vohl, , Philippe Amouyel, Folkert W Asselbergs, Themistocles L Assimes, Murielle Bochud, Bernhard O Boehm, Eric Boerwinkle, Erwin P Bottinger, Claude Bouchard, Stéphane Cauchi, John C Chambers, Stephen J Chanock, Richard S Cooper, Paul I W de Bakker, George Dedoussis, Luigi Ferrucci, Paul W Franks, Philippe Froguel, Leif C Groop, Christopher A Haiman, Anders Hamsten, M Geoffrey Hayes, Jennie Hui, David J Hunter, Kristian Hveem, J Wouter Jukema, Robert C Kaplan, Mika Kivimäki, Diana Kuh, Markku Laakso, Yongmei Liu, Nicholas G Martin, Winfried März, Mads Melbye, Susanne Moebus, Patricia B Munroe, Inger Njølstad, Ben A Oostra, Colin N A Palmer, Nancy L Pedersen, Markus Perola, Louis Pérusse, Ulrike Peters, Joseph E Powell, Chris Power, Thomas Quertermous, Rainer Rauramaa, Eva Reinmaa, Paul M Ridker, Fernando Rivadeneira, Jerome I Rotter, Timo E Saaristo, Danish Saleheen, David Schlessinger, P Eline Slagboom, Harold Snieder, Tim D Spector, Konstantin Strauch, Michael Stumvoll, Jaakko Tuomilehto, Matti Uusitupa, Pim van der Harst, Henry Völzke, Mark Walker, Nicholas J Wareham, Hugh Watkins, H-Erich Wichmann, James F Wilson, Pieter Zanen, Panos Deloukas, Iris M Heid, Cecilia M Lindgren, Karen L Mohlke, Elizabeth K Speliotes, Unnur Thorsteinsdottir, Inês Barroso, Caroline S Fox, Kari E North, David P Strachan, Jacques S Beckmann, Sonja I Berndt, Michael Boehnke, Ingrid B Borecki, Mark I McCarthy, Andres Metspalu, Kari Stefansson, André G Uitterlinden, Cornelia M van Duijn, Lude Franke, Cristen J Willer, Alkes L Price, Guillaume Lettre, Ruth J F Loos, Michael N Weedon, Erik Ingelsson, Jeffrey R O'Connell, Gonçalo R Abecasis, Daniel I Chasman, Michael E Goddard, Peter M Visscher, Joel N Hirschhorn, Timothy M Frayling.
Nat. Genet.
PUBLISHED: 08-29-2014
Show Abstract
Hide Abstract
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ?2,000, ?3,700 and ?9,500 SNPs explained ?21%, ?24% and ?29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/?-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
Related JoVE Video
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
Show Abstract
Hide Abstract
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.
Related JoVE Video
Genetic determinants of circulating interleukin-1 receptor antagonist levels and their association with glycemic traits.
Diabetes
PUBLISHED: 06-26-2014
Show Abstract
Hide Abstract
The proinflammatory cytokine interleukin (IL)-1? is implicated in the development of insulin resistance and ?-cell dysfunction, whereas higher circulating levels of IL-1 receptor antagonist (IL-1RA), an endogenous inhibitor of IL-1?, has been suggested to improve glycemia and ?-cell function in patients with type 2 diabetes. To elucidate the protective role of IL-1RA, this study aimed to identify genetic determinants of circulating IL-1RA concentration and to investigate their associations with immunological and metabolic variables related to cardiometabolic risk. In the analysis of seven discovery and four replication cohort studies, two single nucleotide polymorphisms (SNPs) were independently associated with circulating IL-1RA concentration (rs4251961 at the IL1RN locus [n = 13,955, P = 2.76 × 10(-21)] and rs6759676, closest gene locus IL1F10 [n = 13,994, P = 1.73 × 10(-17)]). The proportion of the variance in IL-1RA explained by both SNPs combined was 2.0%. IL-1RA-raising alleles of both SNPs were associated with lower circulating C-reactive protein concentration. The IL-1RA-raising allele of rs6759676 was also associated with lower fasting insulin levels and lower HOMA insulin resistance. In conclusion, we show that circulating IL-1RA levels are predicted by two independent SNPs at the IL1RN and IL1F10 loci and that genetically raised IL-1RA may be protective against the development of insulin resistance.
Related JoVE Video
Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study.
Karani S Vimaleswaran, Alana Cavadino, Diane J Berry, , Rolf Jorde, Aida Karina Dieffenbach, Chen Lu, Alexessander Couto Alves, Hiddo J Lambers Heerspink, Emmi Tikkanen, Joel Eriksson, Andrew Wong, Massimo Mangino, Kathleen A Jablonski, Ilja M Nolte, Denise K Houston, Tarunveer Singh Ahluwalia, Peter J van der Most, Dorota Pasko, Lina Zgaga, Elisabeth Thiering, Veronique Vitart, Ross M Fraser, Jennifer E Huffman, Rudolf A de Boer, Ben Schöttker, Kai-Uwe Saum, Mark I McCarthy, Josée Dupuis, Karl-Heinz Herzig, Sylvain Sebert, Anneli Pouta, Jaana Laitinen, Marcus E Kleber, Gerjan Navis, Mattias Lorentzon, Karen Jameson, Nigel Arden, Jackie A Cooper, Jayshree Acharya, Rebecca Hardy, Olli Raitakari, Samuli Ripatti, Liana K Billings, Jari Lahti, Clive Osmond, Brenda W Penninx, Lars Rejnmark, Kurt K Lohman, Lavinia Paternoster, Ronald P Stolk, Dena G Hernandez, Liisa Byberg, Emil Hagström, Håkan Melhus, Erik Ingelsson, Dan Mellström, Osten Ljunggren, Ioanna Tzoulaki, Stela McLachlan, Evropi Theodoratou, Carla M T Tiesler, Antti Jula, Pau Navarro, Alan F Wright, Ozren Polašek, James F Wilson, Igor Rudan, Veikko Salomaa, Joachim Heinrich, Harry Campbell, Jacqueline F Price, Magnus Karlsson, Lars Lind, Karl Michaëlsson, Stefania Bandinelli, Timothy M Frayling, Catharina A Hartman, Thorkild I A Sørensen, Stephen B Kritchevsky, Bente Lomholt Langdahl, Johan G Eriksson, Jose C Florez, Tim D Spector, Terho Lehtimäki, Diana Kuh, Steve E Humphries, Cyrus Cooper, Claes Ohlsson, Winfried März, Martin H de Borst, Meena Kumari, Mika Kivimäki, Thomas J Wang, Chris Power, Hermann Brenner, Guri Grimnes, Pim van der Harst, Harold Snieder, Aroon D Hingorani, Stefan Pilz, John C Whittaker, Marjo-Riitta Järvelin, Elina Hyppönen.
Lancet Diabetes Endocrinol
PUBLISHED: 06-25-2014
Show Abstract
Hide Abstract
Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk.
Related JoVE Video
Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1·25 million people.
Lancet
PUBLISHED: 06-03-2014
Show Abstract
Hide Abstract
The associations of blood pressure with the different manifestations of incident cardiovascular disease in a contemporary population have not been compared. In this study, we aimed to analyse the associations of blood pressure with 12 different presentations of cardiovascular disease.
Related JoVE Video
Red blood cell transfusion and mortality in trauma patients: risk-stratified analysis of an observational study.
PLoS Med.
PUBLISHED: 06-01-2014
Show Abstract
Hide Abstract
Haemorrhage is a common cause of death in trauma patients. Although transfusions are extensively used in the care of bleeding trauma patients, there is uncertainty about the balance of risks and benefits and how this balance depends on the baseline risk of death. Our objective was to evaluate the association of red blood cell (RBC) transfusion with mortality according to the predicted risk of death.
Related JoVE Video
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
Show Abstract
Hide Abstract
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ?8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
Related JoVE Video
Bayesian test for colocalisation between pairs of genetic association studies using summary statistics.
PLoS Genet.
PUBLISHED: 05-01-2014
Show Abstract
Hide Abstract
Genetic association studies, in particular the genome-wide association study (GWAS) design, have provided a wealth of novel insights into the aetiology of a wide range of human diseases and traits, in particular cardiovascular diseases and lipid biomarkers. The next challenge consists of understanding the molecular basis of these associations. The integration of multiple association datasets, including gene expression datasets, can contribute to this goal. We have developed a novel statistical methodology to assess whether two association signals are consistent with a shared causal variant. An application is the integration of disease scans with expression quantitative trait locus (eQTL) studies, but any pair of GWAS datasets can be integrated in this framework. We demonstrate the value of the approach by re-analysing a gene expression dataset in 966 liver samples with a published meta-analysis of lipid traits including >100,000 individuals of European ancestry. Combining all lipid biomarkers, our re-analysis supported 26 out of 38 reported colocalisation results with eQTLs and identified 14 new colocalisation results, hence highlighting the value of a formal statistical test. In three cases of reported eQTL-lipid pairs (SYPL2, IFT172, TBKBP1) for which our analysis suggests that the eQTL pattern is not consistent with the lipid association, we identify alternative colocalisation results with SORT1, GCKR, and KPNB1, indicating that these genes are more likely to be causal in these genomic intervals. A key feature of the method is the ability to derive the output statistics from single SNP summary statistics, hence making it possible to perform systematic meta-analysis type comparisons across multiple GWAS datasets (implemented online at http://coloc.cs.ucl.ac.uk/coloc/). Our methodology provides information about candidate causal genes in associated intervals and has direct implications for the understanding of complex diseases as well as the design of drugs to target disease pathways.
Related JoVE Video
Association between periodontal disease and its treatment, flow-mediated dilatation and carotid intima-media thickness: a systematic review and meta-analysis.
Atherosclerosis
PUBLISHED: 04-06-2014
Show Abstract
Hide Abstract
This meta-analysis sought to investigate the association between carotid intima-media thickness (c-IMT), flow-mediated dilation (FMD) and periodontitis (PD) and to assess the effect of periodontal treatment on c-IMT and FMD.
Related JoVE Video
Novel genetic approach to investigate the role of plasma secretory phospholipase A2 (sPLA2)-V isoenzyme in coronary heart disease: modified Mendelian randomization analysis using PLA2G5 expression levels.
Circ Cardiovasc Genet
PUBLISHED: 02-21-2014
Show Abstract
Hide Abstract
Secretory phospholipase A2 (sPLA2) enzymes are considered to play a role in atherosclerosis. sPLA2 activity encompasses several sPLA2 isoenzymes, including sPLA2-V. Although observational studies show a strong association between elevated sPLA2 activity and CHD, no assay to measure sPLA2-V levels exists, and the only evidence linking the sPLA2-V isoform to atherosclerosis progression comes from animal studies. In the absence of an assay that directly quantifies sPLA2-V levels, we used PLA2G5 mRNA levels in a novel, modified Mendelian randomization approach to investigate the hypothesized causal role of sPLA2-V in coronary heart disease (CHD) pathogenesis.
Related JoVE Video
Mendelian randomization of blood lipids for coronary heart disease.
Eur. Heart J.
PUBLISHED: 01-30-2014
Show Abstract
Hide Abstract
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.
Related JoVE Video
Causal effects of body mass index on cardiometabolic traits and events: a Mendelian randomization analysis.
Am. J. Hum. Genet.
PUBLISHED: 01-23-2014
Show Abstract
Hide Abstract
Elevated body mass index (BMI) associates with cardiometabolic traits on observational analysis, yet the underlying causal relationships remain unclear. We conducted Mendelian randomization analyses by using a genetic score (GS) comprising 14 BMI-associated SNPs from a recent discovery analysis to investigate the causal role of BMI in cardiometabolic traits and events. We used eight population-based cohorts, including 34,538 European-descent individuals (4,407 type 2 diabetes (T2D), 6,073 coronary heart disease (CHD), and 3,813 stroke cases). A 1 kg/m(2) genetically elevated BMI increased fasting glucose (0.18 mmol/l; 95% confidence interval (CI) = 0.12-0.24), fasting insulin (8.5%; 95% CI = 5.9-11.1), interleukin-6 (7.0%; 95% CI = 4.0-10.1), and systolic blood pressure (0.70 mmHg; 95% CI = 0.24-1.16) and reduced high-density lipoprotein cholesterol (-0.02 mmol/l; 95% CI = -0.03 to -0.01) and low-density lipoprotein cholesterol (LDL-C; -0.04 mmol/l; 95% CI = -0.07 to -0.01). Observational and causal estimates were directionally concordant, except for LDL-C. A 1 kg/m(2) genetically elevated BMI increased the odds of T2D (odds ratio [OR] = 1.27; 95% CI = 1.18-1.36) but did not alter risk of CHD (OR 1.01; 95% CI = 0.94-1.08) or stroke (OR = 1.03; 95% CI = 0.95-1.12). A meta-analysis incorporating published studies reporting 27,465 CHD events in 219,423 individuals yielded a pooled OR of 1.04 (95% CI = 0.97-1.12) per 1 kg/m(2) increase in BMI. In conclusion, we identified causal effects of BMI on several cardiometabolic traits; however, whether BMI causally impacts CHD risk requires further evidence.
Related JoVE Video
Genetic variants at chromosome 9p21 and risk of first versus subsequent coronary heart disease events: a systematic review and meta-analysis.
J. Am. Coll. Cardiol.
PUBLISHED: 01-07-2014
Show Abstract
Hide Abstract
The purpose of this analysis was to compare the association between variants at the chromosome 9p21 locus (Ch9p21) and risk of first versus subsequent coronary heart disease (CHD) events through systematic review and meta-analysis.
Related JoVE Video
Prognostic models for stable coronary artery disease based on electronic health record cohort of 102 023 patients.
Eur. Heart J.
PUBLISHED: 12-17-2013
Show Abstract
Hide Abstract
The population with stable coronary artery disease (SCAD) is growing but validated models to guide their clinical management are lacking. We developed and validated prognostic models for all-cause mortality and non-fatal myocardial infarction (MI) or coronary death in SCAD.
Related JoVE Video
Associations of maternal 25-hydroxyvitamin D in pregnancy with offspring cardiovascular risk factors in childhood and adolescence: findings from the Avon Longitudinal Study of Parents and Children.
Heart
PUBLISHED: 10-14-2013
Show Abstract
Hide Abstract
Lower maternal vitamin D status in pregnancy may be associated with increased offspring cardiovascular risk in later life, but evidence for this is scant. We examined associations of maternal total 25-hydroxyvitamin D (25(OH)D) in pregnancy with offspring cardiovascular risk factors assessed in childhood and adolescence.
Related JoVE Video
Discovery and refinement of loci associated with lipid levels.
, Cristen J Willer, Ellen M Schmidt, Sebanti Sengupta, Gina M Peloso, Stefan Gustafsson, Stavroula Kanoni, Andrea Ganna, Jin Chen, Martin L Buchkovich, Samia Mora, Jacques S Beckmann, Jennifer L Bragg-Gresham, Hsing-Yi Chang, Ayse Demirkan, Heleen M den Hertog, Ron Do, Louise A Donnelly, Georg B Ehret, Tonu Esko, Mary F Feitosa, Teresa Ferreira, Krista Fischer, Pierre Fontanillas, Ross M Fraser, Daniel F Freitag, Deepti Gurdasani, Kauko Heikkilä, Elina Hyppönen, Aaron Isaacs, Anne U Jackson, Asa Johansson, Toby Johnson, Marika Kaakinen, Johannes Kettunen, Marcus E Kleber, Xiaohui Li, Jian'an Luan, Leo-Pekka Lyytikäinen, Patrik K E Magnusson, Massimo Mangino, Evelin Mihailov, May E Montasser, Martina Müller-Nurasyid, Ilja M Nolte, Jeffrey R O'Connell, Cameron D Palmer, Markus Perola, Ann-Kristin Petersen, Serena Sanna, Richa Saxena, Susan K Service, Sonia Shah, Dmitry Shungin, Carlo Sidore, Ci Song, Rona J Strawbridge, Ida Surakka, Toshiko Tanaka, Tanya M Teslovich, Gudmar Thorleifsson, Evita G van den Herik, Benjamin F Voight, Kelly A Volcik, Lindsay L Waite, Andrew Wong, Ying Wu, Weihua Zhang, Devin Absher, Gershim Asiki, Inês Barroso, Latonya F Been, Jennifer L Bolton, Lori L Bonnycastle, Paolo Brambilla, Mary S Burnett, Giancarlo Cesana, Maria Dimitriou, Alex S F Doney, Angela Döring, Paul Elliott, Stephen E Epstein, Gudmundur Ingi Eyjolfsson, Bruna Gigante, Mark O Goodarzi, Harald Grallert, Martha L Gravito, Christopher J Groves, Göran Hallmans, Anna-Liisa Hartikainen, Caroline Hayward, Dena Hernandez, Andrew A Hicks, Hilma Holm, Yi-Jen Hung, Thomas Illig, Michelle R Jones, Pontiano Kaleebu, John J P Kastelein, Kay-Tee Khaw, Eric Kim, Norman Klopp, Pirjo Komulainen, Meena Kumari, Claudia Langenberg, Terho Lehtimäki, Shih-Yi Lin, Jaana Lindström, Ruth J F Loos, François Mach, Wendy L McArdle, Christa Meisinger, Braxton D Mitchell, Gabrielle Müller, Ramaiah Nagaraja, Narisu Narisu, Tuomo V M Nieminen, Rebecca N Nsubuga, Isleifur Olafsson, Ken K Ong, Aarno Palotie, Theodore Papamarkou, Cristina Pomilla, Anneli Pouta, Daniel J Rader, Muredach P Reilly, Paul M Ridker, Fernando Rivadeneira, Igor Rudan, Aimo Ruokonen, Nilesh Samani, Hubert Scharnagl, Janet Seeley, Kaisa Silander, Alena Stančáková, Kathleen Stirrups, Amy J Swift, Laurence Tiret, André G Uitterlinden, L Joost van Pelt, Sailaja Vedantam, Nicholas Wainwright, Cisca Wijmenga, Sarah H Wild, Gonneke Willemsen, Tom Wilsgaard, James F Wilson, Elizabeth H Young, Jing Hua Zhao, Linda S Adair, Dominique Arveiler, Themistocles L Assimes, Stefania Bandinelli, Franklyn Bennett, Murielle Bochud, Bernhard O Boehm, Dorret I Boomsma, Ingrid B Borecki, Stefan R Bornstein, Pascal Bovet, Michel Burnier, Harry Campbell, Aravinda Chakravarti, John C Chambers, Yii-Der Ida Chen, Francis S Collins, Richard S Cooper, John Danesh, George Dedoussis, Ulf de Faire, Alan B Feranil, Jean Ferrières, Luigi Ferrucci, Nelson B Freimer, Christian Gieger, Leif C Groop, Vilmundur Gudnason, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Aroon Hingorani, Joel N Hirschhorn, Albert Hofman, G Kees Hovingh, Chao Agnes Hsiung, Steve E Humphries, Steven C Hunt, Kristian Hveem, Carlos Iribarren, Marjo-Riitta Järvelin, Antti Jula, Mika Kähönen, Jaakko Kaprio, Antero Kesäniemi, Mika Kivimäki, Jaspal S Kooner, Peter J Koudstaal, Ronald M Krauss, Diana Kuh, Johanna Kuusisto, Kirsten O Kyvik, Markku Laakso, Timo A Lakka, Lars Lind, Cecilia M Lindgren, Nicholas G Martin, Winfried März, Mark I McCarthy, Colin A McKenzie, Pierre Meneton, Andres Metspalu, Leena Moilanen, Andrew D Morris, Patricia B Munroe, Inger Njølstad, Nancy L Pedersen, Chris Power, Peter P Pramstaller, Jackie F Price, Bruce M Psaty, Thomas Quertermous, Rainer Rauramaa, Danish Saleheen, Veikko Salomaa, Dharambir K Sanghera, Jouko Saramies, Peter E H Schwarz, Wayne H-H Sheu, Alan R Shuldiner, Agneta Siegbahn, Tim D Spector, Kari Stefansson, David P Strachan, Bamidele O Tayo, Elena Tremoli, Jaakko Tuomilehto, Matti Uusitupa, Cornelia M van Duijn, Peter Vollenweider, Lars Wallentin, Nicholas J Wareham, John B Whitfield, Bruce H R Wolffenbuttel, José M Ordovás, Eric Boerwinkle, Colin N A Palmer, Unnur Thorsteinsdottir, Daniel I Chasman, Jerome I Rotter, Paul W Franks, Samuli Ripatti, L Adrienne Cupples, Manjinder S Sandhu, Stephen S Rich, Michael Boehnke, Panos Deloukas, Sekar Kathiresan, Karen L Mohlke, Erik Ingelsson, Gonçalo R Abecasis.
Nat. Genet.
PUBLISHED: 09-13-2013
Show Abstract
Hide Abstract
Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
Related JoVE Video
Genetic prediction of quantitative lipid traits: comparing shrinkage models to gene scores.
Genet. Epidemiol.
PUBLISHED: 06-06-2013
Show Abstract
Hide Abstract
Accurate genetic prediction of quantitative traits related to complex disease risk would have potential clinical impact, so investigation of statistical methodology to improve predictive performance is important. We compare a simple approach of polygenic scores using top ranking single nucleotide polymorphisms (SNPs) to a set of shrinkage models, namely Ridge Regression, Lasso and Hyper-Lasso. These penalised regression methods analyse all genotyped SNPs simultaneously, potentially including much larger sets of SNPs in the models, not only those with the smallest P values. We compare the accuracy of these models for predicting low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, two lipid traits of clinical relevance, in the Whitehall II and British Womens Health and Heart Study cohorts, using SNPs from the HumanCVD BeadChip. For gene scores, the most accurate predictions arise from multivariate weighted scores and include only a small number of SNPs, identified as top hits by the HumanCVD BeadChip. Furthermore, there was little benefit from including external results from published sets of SNPs. We found that shrinkage approaches rarely improved significantly on gene score results. Genetic predictive performance is trait specific, depending on the heritability and genetic architecture of the trait, and is limited by the training data sample size. Our results for lipid traits suggest no current benefit of more complex methods over existing gene score methods. Instead, the most important choice for the prediction model is the number of SNPs and selection of the most predictive SNPs to include. However further comparisons, in larger samples and for other phenotypes, would still be of interest.
Related JoVE Video
Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.
Joshua C Randall, Thomas W Winkler, Zoltan Kutalik, Sonja I Berndt, Anne U Jackson, Keri L Monda, Tuomas O Kilpeläinen, Tonu Esko, Reedik Mägi, Shengxu Li, Tsegaselassie Workalemahu, Mary F Feitosa, Damien C Croteau-Chonka, Felix R Day, Tove Fall, Teresa Ferreira, Stefan Gustafsson, Adam E Locke, Iain Mathieson, André Scherag, Sailaja Vedantam, Andrew R Wood, Liming Liang, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Emmanouil T Dermitzakis, Antigone S Dimas, Fredrik Karpe, Josine L Min, George Nicholson, Deborah J Clegg, Thomas Person, Jon P Krohn, Sabrina Bauer, Christa Buechler, Kristina Eisinger, , Amélie Bonnefond, Philippe Froguel, Jouke-Jan Hottenga, Inga Prokopenko, Lindsay L Waite, Tamara B Harris, Albert Vernon Smith, Alan R Shuldiner, Wendy L McArdle, Mark J Caulfield, Patricia B Munroe, Henrik Grönberg, Yii-Der Ida Chen, Guo Li, Jacques S Beckmann, Toby Johnson, Unnur Thorsteinsdottir, Maris Teder-Laving, Kay-Tee Khaw, Nicholas J Wareham, Jing Hua Zhao, Najaf Amin, Ben A Oostra, Aldi T Kraja, Michael A Province, L Adrienne Cupples, Nancy L Heard-Costa, Jaakko Kaprio, Samuli Ripatti, Ida Surakka, Francis S Collins, Jouko Saramies, Jaakko Tuomilehto, Antti Jula, Veikko Salomaa, Jeanette Erdmann, Christian Hengstenberg, Christina Loley, Heribert Schunkert, Claudia Lamina, H Erich Wichmann, Eva Albrecht, Christian Gieger, Andrew A Hicks, Asa Johansson, Peter P Pramstaller, Sekar Kathiresan, Elizabeth K Speliotes, Brenda Penninx, Anna-Liisa Hartikainen, Marjo-Riitta Järvelin, Ulf Gyllensten, Dorret I Boomsma, Harry Campbell, James F Wilson, Stephen J Chanock, Martin Farrall, Anuj Goel, Carolina Medina-Gomez, Fernando Rivadeneira, Karol Estrada, André G Uitterlinden, Albert Hofman, M Carola Zillikens, Martin den Heijer, Lambertus A Kiemeney, Andrea Maschio, Per Hall, Jonathan Tyrer, Alexander Teumer, Henry Völzke, Peter Kovacs, Anke Tönjes, Massimo Mangino, Tim D Spector, Caroline Hayward, Igor Rudan, Alistair S Hall, Nilesh J Samani, Antony Paul Attwood, Jennifer G Sambrook, Joseph Hung, Lyle J Palmer, Marja-Liisa Lokki, Juha Sinisalo, Gabrielle Boucher, Heikki Huikuri, Mattias Lorentzon, Claes Ohlsson, Niina Eklund, Johan G Eriksson, Cristina Barlassina, Carlo Rivolta, Ilja M Nolte, Harold Snieder, Melanie M van der Klauw, Jana V van Vliet-Ostaptchouk, Pablo V Gejman, Jianxin Shi, Kevin B Jacobs, Zhaoming Wang, Stephan J L Bakker, Irene Mateo Leach, Gerjan Navis, Pim van der Harst, Nicholas G Martin, Sarah E Medland, Grant W Montgomery, Jian Yang, Daniel I Chasman, Paul M Ridker, Lynda M Rose, Terho Lehtimäki, Olli Raitakari, Devin Absher, Carlos Iribarren, Hanneke Basart, Kees G Hovingh, Elina Hyppönen, Chris Power, Denise Anderson, John P Beilby, Jennie Hui, Jennifer Jolley, Hendrik Sager, Stefan R Bornstein, Peter E H Schwarz, Kati Kristiansson, Markus Perola, Jaana Lindström, Amy J Swift, Matti Uusitupa, Mustafa Atalay, Timo A Lakka, Rainer Rauramaa, Jennifer L Bolton, Gerry Fowkes, Ross M Fraser, Jackie F Price, Krista Fischer, Kaarel Krjutå Kov, Andres Metspalu, Evelin Mihailov, Claudia Langenberg, Jian'an Luan, Ken K Ong, Peter S Chines, Sirkka M Keinanen-Kiukaanniemi, Timo E Saaristo, Sarah Edkins, Paul W Franks, Göran Hallmans, Dmitry Shungin, Andrew David Morris, Colin N A Palmer, Raimund Erbel, Susanne Moebus, Markus M Nöthen, Sonali Pechlivanis, Kristian Hveem, Narisu Narisu, Anders Hamsten, Steve E Humphries, Rona J Strawbridge, Elena Tremoli, Harald Grallert, Barbara Thorand, Thomas Illig, Wolfgang Koenig, Martina Müller-Nurasyid, Annette Peters, Bernhard O Boehm, Marcus E Kleber, Winfried März, Bernhard R Winkelmann, Johanna Kuusisto, Markku Laakso, Dominique Arveiler, Giancarlo Cesana, Kari Kuulasmaa, Jarmo Virtamo, John W G Yarnell, Diana Kuh, Andrew Wong, Lars Lind, Ulf de Faire, Bruna Gigante, Patrik K E Magnusson, Nancy L Pedersen, George Dedoussis, Maria Dimitriou, Genovefa Kolovou, Stavroula Kanoni, Kathleen Stirrups, Lori L Bonnycastle, Inger Njølstad, Tom Wilsgaard, Andrea Ganna, Emil Rehnberg, Aroon Hingorani, Mika Kivimäki, Meena Kumari, Themistocles L Assimes, Inês Barroso, Michael Boehnke, Ingrid B Borecki, Panos Deloukas, Caroline S Fox, Timothy Frayling, Leif C Groop, Talin Haritunians, David Hunter, Erik Ingelsson, Robert Kaplan, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Gonçalo R Abecasis, Mark I McCarthy, Joel N Hirschhorn, Lu Qi, Ruth J F Loos, Cecilia M Lindgren, Kari E North, Iris M Heid.
PLoS Genet.
PUBLISHED: 06-01-2013
Show Abstract
Hide Abstract
Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
Related JoVE Video
Secretory Phospholipase A2-IIA and Cardiovascular Disease: A Mendelian Randomization Study.
Michael V Holmes, Tabassome Simon, Holly J Exeter, Lasse Folkersen, Folkert W Asselbergs, Montse Guardiola, Jackie A Cooper, Jutta Palmen, Jaroslav A Hubacek, Kathryn F Carruthers, Benjamin D Horne, Kimberly D Brunisholz, Jessica L Mega, Erik P A van Iperen, Mingyao Li, Maarten Leusink, Stella Trompet, Jeffrey J W Verschuren, G Kees Hovingh, Abbas Dehghan, Christopher P Nelson, Salma Kotti, Nicolas Danchin, Markus Scholz, Christiane L Haase, Dietrich Rothenbacher, Daniel I Swerdlow, Karoline B Kuchenbaecker, Eleonora Staines-Urias, Anuj Goel, Ferdinand van 't Hooft, Karl Gertow, Ulf de Faire, Andrie G Panayiotou, Elena Tremoli, Damiano Baldassarre, Fabrizio Veglia, Lesca M Holdt, Frank Beutner, Ron T Gansevoort, Gerjan J Navis, Irene Mateo Leach, Lutz P Breitling, Hermann Brenner, Joachim Thiery, Dhayana Dallmeier, Anders Franco-Cereceda, Jolanda M A Boer, Jeffrey W Stephens, Marten H Hofker, Alain Tedgui, Albert Hofman, André G Uitterlinden, Vera Adamkova, Jan Piťha, N Charlotte Onland-Moret, Maarten J Cramer, Hendrik M Nathoe, Wilko Spiering, Olaf H Klungel, Meena Kumari, Peter H Whincup, David A Morrow, Peter S Braund, Alistair S Hall, Anders G Olsson, Pieter A Doevendans, Mieke D Trip, Martin D Tobin, Anders Hamsten, Hugh Watkins, Wolfgang Koenig, Andrew N Nicolaides, Daniel Teupser, Ian N M Day, John F Carlquist, Tom R Gaunt, Ian Ford, Naveed Sattar, Sotirios Tsimikas, Gregory G Schwartz, Debbie A Lawlor, Richard W Morris, Manjinder S Sandhu, Rudolf Poledne, Anke H Maitland-van der Zee, Kay-Tee Khaw, Brendan J Keating, Pim van der Harst, Jackie F Price, Shamir R Mehta, Salim Yusuf, Jaqueline C M Witteman, Oscar H Franco, J Wouter Jukema, Peter de Knijff, Anne Tybjaerg-Hansen, Daniel J Rader, Martin Farrall, Nilesh J Samani, Mika Kivimäki, Keith A A Fox, Steve E Humphries, Jeffrey L Anderson, S Matthijs Boekholdt, Tom M Palmer, Per Eriksson, Guillaume Paré, Aroon D Hingorani, Marc S Sabatine, Ziad Mallat, Juan P Casas, Philippa J Talmud.
J. Am. Coll. Cardiol.
PUBLISHED: 04-24-2013
Show Abstract
Hide Abstract
This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease.
Related JoVE Video
Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke: systematic review and meta-analysis of 14,015 stroke cases and pooled analysis of primary biomarker data from up to 60,883 individuals.
Int J Epidemiol
PUBLISHED: 04-10-2013
Show Abstract
Hide Abstract
At the APOE gene, encoding apolipoprotein E, genotypes of the ?2/?3/?4 alleles associated with higher LDL-cholesterol (LDL-C) levels are also associated with higher coronary risk. However, the association of APOE genotype with other cardiovascular biomarkers and risk of ischaemic stroke is less clear. We evaluated the association of APOE genotype with risk of ischaemic stroke and assessed whether the observed effect was consistent with the effects of APOE genotype on LDL-C or other lipids and biomarkers of cardiovascular risk.
Related JoVE Video
Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.
Marcel den Hoed, Mark Eijgelsheim, Tonu Esko, Bianca J J M Brundel, David S Peal, David M Evans, Ilja M Nolte, Ayellet V Segrè, Hilma Holm, Robert E Handsaker, Harm-Jan Westra, Toby Johnson, Aaron Isaacs, Jian Yang, Alicia Lundby, Jing Hua Zhao, Young Jin Kim, Min Jin Go, Peter Almgren, Murielle Bochud, Gabrielle Boucher, Marilyn C Cornelis, Daniel Gudbjartsson, David Hadley, Pim van der Harst, Caroline Hayward, Martin den Heijer, Wilmar Igl, Anne U Jackson, Zoltan Kutalik, Jian'an Luan, John P Kemp, Kati Kristiansson, Claes Ladenvall, Mattias Lorentzon, May E Montasser, Omer T Njajou, Paul F O'Reilly, Sandosh Padmanabhan, Beate St Pourcain, Tuomo Rankinen, Perttu Salo, Toshiko Tanaka, Nicholas J Timpson, Veronique Vitart, Lindsay Waite, William Wheeler, Weihua Zhang, Harmen H M Draisma, Mary F Feitosa, Kathleen F Kerr, Penelope A Lind, Evelin Mihailov, N Charlotte Onland-Moret, Ci Song, Michael N Weedon, Weijia Xie, Loïc Yengo, Devin Absher, Christine M Albert, Alvaro Alonso, Dan E Arking, Paul I W de Bakker, Beverley Balkau, Cristina Barlassina, Paola Benaglio, Joshua C Bis, Nabila Bouatia-Naji, Søren Brage, Stephen J Chanock, Peter S Chines, Mina Chung, Dawood Darbar, Christian Dina, Marcus Dörr, Paul Elliott, Stephan B Felix, Krista Fischer, Christian Fuchsberger, Eco J C de Geus, Philippe Goyette, Vilmundur Gudnason, Tamara B Harris, Anna-Liisa Hartikainen, Aki S Havulinna, Susan R Heckbert, Andrew A Hicks, Albert Hofman, Suzanne Holewijn, Femke Hoogstra-Berends, Jouke-Jan Hottenga, Majken K Jensen, Asa Johansson, Juhani Junttila, Stefan Kääb, Bart Kanon, Shamika Ketkar, Kay-Tee Khaw, Joshua W Knowles, Angrad S Kooner, Jan A Kors, Meena Kumari, Lili Milani, Päivi Laiho, Edward G Lakatta, Claudia Langenberg, Maarten Leusink, Yongmei Liu, Robert N Luben, Kathryn L Lunetta, Stacey N Lynch, Marcello R P Markus, Pedro Marques-Vidal, Irene Mateo Leach, Wendy L McArdle, Steven A McCarroll, Sarah E Medland, Kathryn A Miller, Grant W Montgomery, Alanna C Morrison, Martina Müller-Nurasyid, Pau Navarro, Mari Nelis, Jeffrey R O'Connell, Christopher J O'Donnell, Ken K Ong, Anne B Newman, Annette Peters, Ozren Polašek, Anneli Pouta, Peter P Pramstaller, Bruce M Psaty, Dabeeru C Rao, Susan M Ring, Elizabeth J Rossin, Diana Rudan, Serena Sanna, Robert A Scott, Jaban S Sehmi, Stephen Sharp, Jordan T Shin, Andrew B Singleton, Albert V Smith, Nicole Soranzo, Tim D Spector, Chip Stewart, Heather M Stringham, Kirill V Tarasov, André G Uitterlinden, Liesbeth Vandenput, Shih-Jen Hwang, John B Whitfield, Cisca Wijmenga, Sarah H Wild, Gonneke Willemsen, James F Wilson, Jacqueline C M Witteman, Andrew Wong, Quenna Wong, Yalda Jamshidi, Paavo Zitting, Jolanda M A Boer, Dorret I Boomsma, Ingrid B Borecki, Cornelia M van Duijn, Ulf Ekelund, Nita G Forouhi, Philippe Froguel, Aroon Hingorani, Erik Ingelsson, Mika Kivimäki, Richard A Kronmal, Diana Kuh, Lars Lind, Nicholas G Martin, Ben A Oostra, Nancy L Pedersen, Thomas Quertermous, Jerome I Rotter, Yvonne T van der Schouw, W M Monique Verschuren, Mark Walker, Demetrius Albanes, David O Arnar, Themistocles L Assimes, Stefania Bandinelli, Michael Boehnke, Rudolf A de Boer, Claude Bouchard, W L Mark Caulfield, John C Chambers, Gary Curhan, Daniele Cusi, Johan Eriksson, Luigi Ferrucci, Wiek H van Gilst, Nicola Glorioso, Jacqueline de Graaf, Leif Groop, Ulf Gyllensten, Wen-Chi Hsueh, Frank B Hu, Heikki V Huikuri, David J Hunter, Carlos Iribarren, Bo Isomaa, Marjo-Riitta Järvelin, Antti Jula, Mika Kähönen, Lambertus A Kiemeney, Melanie M van der Klauw, Jaspal S Kooner, Peter Kraft, Licia Iacoviello, Terho Lehtimäki, Marja-Liisa L Lokki, Braxton D Mitchell, Gerjan Navis, Markku S Nieminen, Claes Ohlsson, Neil R Poulter, Lu Qi, Olli T Raitakari, Eric B Rimm, John D Rioux, Federica Rizzi, Igor Rudan, Veikko Salomaa, Peter S Sever, Denis C Shields, Alan R Shuldiner, Juha Sinisalo, Alice V Stanton, Ronald P Stolk, David P Strachan, Jean-Claude Tardif, Unnur Thorsteinsdottir, Jaako Tuomilehto, Dirk J van Veldhuisen, Jarmo Virtamo, Jorma Viikari, Peter Vollenweider, Gérard Waeber, Elisabeth Widén, Yoon Shin Cho, Jesper V Olsen, Peter M Visscher, Cristen Willer, Lude Franke, , Jeanette Erdmann, John R Thompson, Arne Pfeufer, Nona Sotoodehnia, Christopher Newton-Cheh, Patrick T Ellinor, Bruno H Ch Stricker, Andres Metspalu, Markus Perola, Jacques S Beckmann, George Davey Smith, Kari Stefansson, Nicholas J Wareham, Patricia B Munroe, Ody C M Sibon, David J Milan, Harold Snieder, Nilesh J Samani, Ruth J F Loos.
Nat. Genet.
PUBLISHED: 03-21-2013
Show Abstract
Hide Abstract
Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
Related JoVE Video
Gene-centric analysis identifies variants associated with interleukin-6 levels and shared pathways with other inflammation markers.
Circ Cardiovasc Genet
PUBLISHED: 03-16-2013
Show Abstract
Hide Abstract
BACKGROUND- Inflammatory cytokine interleukin-6 (IL-6), a possible risk factor for coronary heart disease, has an estimated heritability of >60%, but to date few genetic variants influencing IL-6 levels are known. METHODS AND RESULTS- We used the ITMAT-Broad-Care (IBC) HumanCVD disease BeadChip in the Whitehall II study (N=4911) and British Womens Heart and Health Study (N=3445) to identify single-nucleotide polymorphisms associated with circulating IL-6 levels. Twenty-two single-nucleotide polymorphisms from 7 loci (IL6R/TDRD10, HLA-DRB1, BUD13, SEZ6L, IL1RN, TRIB3, and ABO) were associated with IL-6 (P<10(-5)), although none were associated with the IL6 gene itself. With the exception of TRIB3, all loci have been previously reported in genome-wide association studies for autoimmune and cardiovascular diseases. Fourteen single-nucleotide polymorphisms in the IL6R region in high-linkage disequilibrium (r(2)>0.9) with a nonsynonymous variant, rs2228145, were also associated with IL-6 and C-reactive protein concentration (P<10(-5)). An IL-6-specific weighted allele score explained 2% of the variance of log IL-6 levels (P=2.4410(-22)) in Whitehall II and 1% (P=1.910(-8)) in British Womens Heart and Health Studies. CONCLUSIONS- Multiple common genetic variants of modest effect influence IL-6 concentration. Several loci contain single-nucleotide polymorphisms, exhibiting overlapping associations with autoimmune and cardiovascular disorders and other circulating biomarkers. Genetic variants associated with IL-6 provide important tools for probing the causal relevance of IL-6 signaling in a range of cardiometabolic diseases.
Related JoVE Video
Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.
Sonja I Berndt, Stefan Gustafsson, Reedik Mägi, Andrea Ganna, Eleanor Wheeler, Mary F Feitosa, Anne E Justice, Keri L Monda, Damien C Croteau-Chonka, Felix R Day, Tonu Esko, Tove Fall, Teresa Ferreira, Davide Gentilini, Anne U Jackson, Jian'an Luan, Joshua C Randall, Sailaja Vedantam, Cristen J Willer, Thomas W Winkler, Andrew R Wood, Tsegaselassie Workalemahu, Yi-Juan Hu, Sang Hong Lee, Liming Liang, Dan-Yu Lin, Josine L Min, Benjamin M Neale, Gudmar Thorleifsson, Jian Yang, Eva Albrecht, Najaf Amin, Jennifer L Bragg-Gresham, Gemma Cadby, Martin den Heijer, Niina Eklund, Krista Fischer, Anuj Goel, Jouke-Jan Hottenga, Jennifer E Huffman, Ivonne Jarick, Asa Johansson, Toby Johnson, Stavroula Kanoni, Marcus E Kleber, Inke R König, Kati Kristiansson, Zoltan Kutalik, Claudia Lamina, Cécile Lecoeur, Guo Li, Massimo Mangino, Wendy L McArdle, Carolina Medina-Gomez, Martina Müller-Nurasyid, Julius S Ngwa, Ilja M Nolte, Lavinia Paternoster, Sonali Pechlivanis, Markus Perola, Marjolein J Peters, Michael Preuss, Lynda M Rose, Jianxin Shi, Dmitry Shungin, Albert Vernon Smith, Rona J Strawbridge, Ida Surakka, Alexander Teumer, Mieke D Trip, Jonathan Tyrer, Jana V van Vliet-Ostaptchouk, Liesbeth Vandenput, Lindsay L Waite, Jing Hua Zhao, Devin Absher, Folkert W Asselbergs, Mustafa Atalay, Antony P Attwood, Anthony J Balmforth, Hanneke Basart, John Beilby, Lori L Bonnycastle, Paolo Brambilla, Marcel Bruinenberg, Harry Campbell, Daniel I Chasman, Peter S Chines, Francis S Collins, John M Connell, William O Cookson, Ulf de Faire, Femmie de Vegt, Mariano Dei, Maria Dimitriou, Sarah Edkins, Karol Estrada, David M Evans, Martin Farrall, Marco M Ferrario, Jean Ferrières, Lude Franke, Francesca Frau, Pablo V Gejman, Harald Grallert, Henrik Grönberg, Vilmundur Gudnason, Alistair S Hall, Per Hall, Anna-Liisa Hartikainen, Caroline Hayward, Nancy L Heard-Costa, Andrew C Heath, Johannes Hebebrand, Georg Homuth, Frank B Hu, Sarah E Hunt, Elina Hyppönen, Carlos Iribarren, Kevin B Jacobs, John-Olov Jansson, Antti Jula, Mika Kähönen, Sekar Kathiresan, Frank Kee, Kay-Tee Khaw, Mika Kivimäki, Wolfgang Koenig, Aldi T Kraja, Meena Kumari, Kari Kuulasmaa, Johanna Kuusisto, Jaana H Laitinen, Timo A Lakka, Claudia Langenberg, Lenore J Launer, Lars Lind, Jaana Lindström, Jianjun Liu, Antonio Liuzzi, Marja-Liisa Lokki, Mattias Lorentzon, Pamela A Madden, Patrik K Magnusson, Paolo Manunta, Diana Marek, Winfried März, Irene Mateo Leach, Barbara McKnight, Sarah E Medland, Evelin Mihailov, Lili Milani, Grant W Montgomery, Vincent Mooser, Thomas W Mühleisen, Patricia B Munroe, Arthur W Musk, Narisu Narisu, Gerjan Navis, George Nicholson, Ellen A Nohr, Ken K Ong, Ben A Oostra, Colin N A Palmer, Aarno Palotie, John F Peden, Nancy Pedersen, Annette Peters, Ozren Polašek, Anneli Pouta, Peter P Pramstaller, Inga Prokopenko, Carolin Pütter, Aparna Radhakrishnan, Olli Raitakari, Augusto Rendon, Fernando Rivadeneira, Igor Rudan, Timo E Saaristo, Jennifer G Sambrook, Alan R Sanders, Serena Sanna, Jouko Saramies, Sabine Schipf, Stefan Schreiber, Heribert Schunkert, So-Youn Shin, Stefano Signorini, Juha Sinisalo, Boris Skrobek, Nicole Soranzo, Alena Stančáková, Klaus Stark, Jonathan C Stephens, Kathleen Stirrups, Ronald P Stolk, Michael Stumvoll, Amy J Swift, Eirini V Theodoraki, Barbara Thorand, David-Alexandre Trégouët, Elena Tremoli, Melanie M van der Klauw, Joyce B J van Meurs, Sita H Vermeulen, Jorma Viikari, Jarmo Virtamo, Veronique Vitart, Gérard Waeber, Zhaoming Wang, Elisabeth Widén, Sarah H Wild, Gonneke Willemsen, Bernhard R Winkelmann, Jacqueline C M Witteman, Bruce H R Wolffenbuttel, Andrew Wong, Alan F Wright, M Carola Zillikens, Philippe Amouyel, Bernhard O Boehm, Eric Boerwinkle, Dorret I Boomsma, Mark J Caulfield, Stephen J Chanock, L Adrienne Cupples, Daniele Cusi, George V Dedoussis, Jeanette Erdmann, Johan G Eriksson, Paul W Franks, Philippe Froguel, Christian Gieger, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Christian Hengstenberg, Andrew A Hicks, Aroon Hingorani, Anke Hinney, Albert Hofman, Kees G Hovingh, Kristian Hveem, Thomas Illig, Marjo-Riitta Järvelin, Karl-Heinz Jöckel, Sirkka M Keinanen-Kiukaanniemi, Lambertus A Kiemeney, Diana Kuh, Markku Laakso, Terho Lehtimäki, Douglas F Levinson, Nicholas G Martin, Andres Metspalu, Andrew D Morris, Markku S Nieminen, Inger Njølstad, Claes Ohlsson, Albertine J Oldehinkel, Willem H Ouwehand, Lyle J Palmer, Brenda Penninx, Chris Power, Michael A Province, Bruce M Psaty, Lu Qi, Rainer Rauramaa, Paul M Ridker, Samuli Ripatti, Veikko Salomaa, Nilesh J Samani, Harold Snieder, Thorkild I A Sørensen, Timothy D Spector, Kari Stefansson, Anke Tönjes, Jaakko Tuomilehto, André G Uitterlinden, Matti Uusitupa, Pim van der Harst, Peter Vollenweider, Henri Wallaschofski, Nicholas J Wareham, Hugh Watkins, H-Erich Wichmann, James F Wilson, Gonçalo R Abecasis, Themistocles L Assimes, Inês Barroso, Michael Boehnke, Ingrid B Borecki, Panos Deloukas, Caroline S Fox, Timothy Frayling, Leif C Groop, Talin Haritunian, Iris M Heid, David Hunter, Robert C Kaplan, Fredrik Karpe, Miriam F Moffatt, Karen L Mohlke, Jeffrey R O'Connell, Yudi Pawitan, Eric E Schadt, David Schlessinger, Valgerdur Steinthorsdottir, David P Strachan, Unnur Thorsteinsdottir, Cornelia M van Duijn, Peter M Visscher, Anna Maria Di Blasio, Joel N Hirschhorn, Cecilia M Lindgren, Andrew P Morris, David Meyre, André Scherag, Mark I McCarthy, Elizabeth K Speliotes, Kari E North, Ruth J F Loos, Erik Ingelsson.
Nat. Genet.
PUBLISHED: 03-14-2013
Show Abstract
Hide Abstract
Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
Related JoVE Video
Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study.
Lancet
PUBLISHED: 02-22-2013
Show Abstract
Hide Abstract
Familial hypercholesterolaemia is a common autosomal-dominant disorder caused by mutations in three known genes. DNA-based cascade testing is recommended by UK guidelines to identify affected relatives; however, about 60% of patients are mutation-negative. We assessed the hypothesis that familial hypercholesterolaemia can also be caused by an accumulation of common small-effect LDL-C-raising alleles.
Related JoVE Video
Common variants associated with plasma triglycerides and risk for coronary artery disease.
Ron Do, Cristen J Willer, Ellen M Schmidt, Sebanti Sengupta, Chi Gao, Gina M Peloso, Stefan Gustafsson, Stavroula Kanoni, Andrea Ganna, Jin Chen, Martin L Buchkovich, Samia Mora, Jacques S Beckmann, Jennifer L Bragg-Gresham, Hsing-Yi Chang, Ayse Demirkan, Heleen M den Hertog, Louise A Donnelly, Georg B Ehret, Tonu Esko, Mary F Feitosa, Teresa Ferreira, Krista Fischer, Pierre Fontanillas, Ross M Fraser, Daniel F Freitag, Deepti Gurdasani, Kauko Heikkilä, Elina Hyppönen, Aaron Isaacs, Anne U Jackson, Asa Johansson, Toby Johnson, Marika Kaakinen, Johannes Kettunen, Marcus E Kleber, Xiaohui Li, Jian'an Luan, Leo-Pekka Lyytikäinen, Patrik K E Magnusson, Massimo Mangino, Evelin Mihailov, May E Montasser, Martina Müller-Nurasyid, Ilja M Nolte, Jeffrey R O'Connell, Cameron D Palmer, Markus Perola, Ann-Kristin Petersen, Serena Sanna, Richa Saxena, Susan K Service, Sonia Shah, Dmitry Shungin, Carlo Sidore, Ci Song, Rona J Strawbridge, Ida Surakka, Toshiko Tanaka, Tanya M Teslovich, Gudmar Thorleifsson, Evita G van den Herik, Benjamin F Voight, Kelly A Volcik, Lindsay L Waite, Andrew Wong, Ying Wu, Weihua Zhang, Devin Absher, Gershim Asiki, Inês Barroso, Latonya F Been, Jennifer L Bolton, Lori L Bonnycastle, Paolo Brambilla, Mary S Burnett, Giancarlo Cesana, Maria Dimitriou, Alex S F Doney, Angela Döring, Paul Elliott, Stephen E Epstein, Gudmundur Ingi Eyjolfsson, Bruna Gigante, Mark O Goodarzi, Harald Grallert, Martha L Gravito, Christopher J Groves, Göran Hallmans, Anna-Liisa Hartikainen, Caroline Hayward, Dena Hernandez, Andrew A Hicks, Hilma Holm, Yi-Jen Hung, Thomas Illig, Michelle R Jones, Pontiano Kaleebu, John J P Kastelein, Kay-Tee Khaw, Eric Kim, Norman Klopp, Pirjo Komulainen, Meena Kumari, Claudia Langenberg, Terho Lehtimäki, Shih-Yi Lin, Jaana Lindström, Ruth J F Loos, François Mach, Wendy L McArdle, Christa Meisinger, Braxton D Mitchell, Gabrielle Müller, Ramaiah Nagaraja, Narisu Narisu, Tuomo V M Nieminen, Rebecca N Nsubuga, Isleifur Olafsson, Ken K Ong, Aarno Palotie, Theodore Papamarkou, Cristina Pomilla, Anneli Pouta, Daniel J Rader, Muredach P Reilly, Paul M Ridker, Fernando Rivadeneira, Igor Rudan, Aimo Ruokonen, Nilesh Samani, Hubert Scharnagl, Janet Seeley, Kaisa Silander, Alena Stančáková, Kathleen Stirrups, Amy J Swift, Laurence Tiret, André G Uitterlinden, L Joost van Pelt, Sailaja Vedantam, Nicholas Wainwright, Cisca Wijmenga, Sarah H Wild, Gonneke Willemsen, Tom Wilsgaard, James F Wilson, Elizabeth H Young, Jing Hua Zhao, Linda S Adair, Dominique Arveiler, Themistocles L Assimes, Stefania Bandinelli, Franklyn Bennett, Murielle Bochud, Bernhard O Boehm, Dorret I Boomsma, Ingrid B Borecki, Stefan R Bornstein, Pascal Bovet, Michel Burnier, Harry Campbell, Aravinda Chakravarti, John C Chambers, Yii-Der Ida Chen, Francis S Collins, Richard S Cooper, John Danesh, George Dedoussis, Ulf de Faire, Alan B Feranil, Jean Ferrières, Luigi Ferrucci, Nelson B Freimer, Christian Gieger, Leif C Groop, Vilmundur Gudnason, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Aroon Hingorani, Joel N Hirschhorn, Albert Hofman, G Kees Hovingh, Chao Agnes Hsiung, Steve E Humphries, Steven C Hunt, Kristian Hveem, Carlos Iribarren, Marjo-Riitta Järvelin, Antti Jula, Mika Kähönen, Jaakko Kaprio, Antero Kesäniemi, Mika Kivimäki, Jaspal S Kooner, Peter J Koudstaal, Ronald M Krauss, Diana Kuh, Johanna Kuusisto, Kirsten O Kyvik, Markku Laakso, Timo A Lakka, Lars Lind, Cecilia M Lindgren, Nicholas G Martin, Winfried März, Mark I McCarthy, Colin A McKenzie, Pierre Meneton, Andres Metspalu, Leena Moilanen, Andrew D Morris, Patricia B Munroe, Inger Njølstad, Nancy L Pedersen, Chris Power, Peter P Pramstaller, Jackie F Price, Bruce M Psaty, Thomas Quertermous, Rainer Rauramaa, Danish Saleheen, Veikko Salomaa, Dharambir K Sanghera, Jouko Saramies, Peter E H Schwarz, Wayne H-H Sheu, Alan R Shuldiner, Agneta Siegbahn, Tim D Spector, Kari Stefansson, David P Strachan, Bamidele O Tayo, Elena Tremoli, Jaakko Tuomilehto, Matti Uusitupa, Cornelia M van Duijn, Peter Vollenweider, Lars Wallentin, Nicholas J Wareham, John B Whitfield, Bruce H R Wolffenbuttel, David Altshuler, José M Ordovás, Eric Boerwinkle, Colin N A Palmer, Unnur Thorsteinsdottir, Daniel I Chasman, Jerome I Rotter, Paul W Franks, Samuli Ripatti, L Adrienne Cupples, Manjinder S Sandhu, Stephen S Rich, Michael Boehnke, Panos Deloukas, Karen L Mohlke, Erik Ingelsson, Gonçalo R Abecasis, Mark J Daly, Benjamin M Neale, Sekar Kathiresan.
Nat. Genet.
PUBLISHED: 02-20-2013
Show Abstract
Hide Abstract
Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphisms effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
Related JoVE Video
Related JoVE Video
The benefits of using genetic information to design prevention trials.
Am. J. Hum. Genet.
PUBLISHED: 02-01-2013
Show Abstract
Hide Abstract
Clinical trials for preventative therapies are complex and costly endeavors focused on individuals likely to develop disease in a short time frame, randomizing them to treatment groups, and following them over time. In such trials, statistical power is governed by the rate of disease events in each group and cost is determined by randomization, treatment, and follow-up. Strategies that increase the rate of disease events by enrolling individuals with high risk of disease can significantly reduce study size, duration, and cost. Comprehensive study of common, complex diseases has resulted in a growing list of robustly associated genetic markers. Here, we evaluate the utility--in terms of trial size, duration, and cost--of enriching prevention trial samples by combining clinical information with genetic risk scores to identify individuals at greater risk of disease. We also describe a framework for utilizing genetic risk scores in these trials and evaluating the associated cost and time savings. With type 1 diabetes (T1D), type 2 diabetes (T2D), myocardial infarction (MI), and advanced age-related macular degeneration (AMD) as examples, we illustrate the potential and limitations of using genetic data for prevention trial design. We illustrate settings where incorporating genetic information could reduce trial cost or duration considerably, as well as settings where potential savings are negligible. Results are strongly dependent on the genetic architecture of the disease, but we also show that these benefits should increase as the list of robustly associated markers for each disease grows and as large samples of genotyped individuals become available.
Related JoVE Video
Distribution and determinants of circulating complement factor H concentration determined by a high-throughput immunonephelometric assay.
J. Immunol. Methods
PUBLISHED: 01-22-2013
Show Abstract
Hide Abstract
Research on complement factor H (fH) in human disease is hampered by lack of an assay suitable for use in large-scale epidemiological studies. We describe the development and validation of a high throughput nephelometric assay for fH.
Related JoVE Video
Comparative efficacy and tolerability of anti-epileptic drugs for refractory focal epilepsy: systematic review and network meta-analysis reveals the need for long term comparator trials.
Br J Clin Pharmacol
PUBLISHED: 01-22-2013
Show Abstract
Hide Abstract
To evaluate the comparative efficacy (50% reduction in seizure frequency) and tolerability (premature withdrawal due to adverse events) of anti-epileptic drugs (AEDs) for refractory epilepsy.
Related JoVE Video
CYP2D6 genotype and tamoxifen response for breast cancer: a systematic review and meta-analysis.
PLoS ONE
PUBLISHED: 01-01-2013
Show Abstract
Hide Abstract
To evaluate evidence on the association between CYP2D6 genotype and tamoxifen response through.
Related JoVE Video
Population genomics of cardiometabolic traits: design of the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium.
PLoS ONE
PUBLISHED: 01-01-2013
Show Abstract
Hide Abstract
Substantial advances have been made in identifying common genetic variants influencing cardiometabolic traits and disease outcomes through genome wide association studies. Nevertheless, gaps in knowledge remain and new questions have arisen regarding the population relevance, mechanisms, and applications for healthcare. Using a new high-resolution custom single nucleotide polymorphism (SNP) array (Metabochip) incorporating dense coverage of genomic regions linked to cardiometabolic disease, the University College-London School-Edinburgh-Bristol (UCLEB) consortium of highly-phenotyped population-based prospective studies, aims to: (1) fine map functionally relevant SNPs; (2) precisely estimate individual absolute and population attributable risks based on individual SNPs and their combination; (3) investigate mechanisms leading to altered risk factor profiles and CVD events; and (4) use Mendelian randomisation to undertake studies of the causal role in CVD of a range of cardiovascular biomarkers to inform public health policy and help develop new preventative therapies.
Related JoVE Video
CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis.
JAMA
PUBLISHED: 12-29-2011
Show Abstract
Hide Abstract
The US Food and Drug Administration recently recommended that CYP2C19 genotyping be considered prior to prescribing clopidogrel, but the American Heart Association and American College of Cardiologists have argued evidence is insufficient to support CYP2C19 genotype testing.
Related JoVE Video
Cardiovascular biomarkers and vascular function during childhood in the offspring of mothers with hypertensive disorders of pregnancy: findings from the Avon Longitudinal Study of Parents and Children.
Eur. Heart J.
PUBLISHED: 08-22-2011
Show Abstract
Hide Abstract
It is uncertain if the higher blood pressure (BP) observed in the offspring of hypertensive pregnancies is an isolated abnormality or one that is accompanied by impaired vascular function and alterations in lipid and inflammation markers that would be indicative of a more general cardiometabolic disturbance of the type observed in the mother during pre-eclampsia.
Related JoVE Video
Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials.
Lancet
PUBLISHED: 07-29-2011
Show Abstract
Hide Abstract
The MTHFR 677C?T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke. A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and small-study bias was difficult. A meta-analysis of randomised trials of homocysteine-lowering interventions showed no reduction in coronary heart disease events or stroke, but the trials were generally set in populations with high folate consumption. We aimed to reduce the effect of small-study bias and investigate whether folate status modifies the association between MTHFR 677C?T and stroke in a genetic analysis and meta-analysis of randomised controlled trials.
Related JoVE Video
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
Show Abstract
Hide Abstract
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.
Related JoVE Video
Evaluation of C-reactive protein prior to and on-treatment as a predictor of benefit from atorvastatin: observations from the Anglo-Scandinavian Cardiac Outcomes Trial.
Eur. Heart J.
PUBLISHED: 07-28-2011
Show Abstract
Hide Abstract
We tested whether on-statin C-reactive protein is associated with cardiovascular (CV) outcome in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).
Related JoVE Video
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
Show Abstract
Hide Abstract
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.
Related JoVE Video
A gene-centric association scan for Coagulation Factor VII levels in European and African Americans: the Candidate Gene Association Resource (CARe) Consortium.
Hum. Mol. Genet.
PUBLISHED: 06-15-2011
Show Abstract
Hide Abstract
Polymorphisms in several distinct genomic regions, including the F7 gene, were recently associated with factor VII (FVII) levels in European Americans (EAs). The genetic determinants of FVII in African Americans (AAs) are unknown. We used a 50,000 single nucleotide polymorphism (SNP) gene-centric array having dense coverage of over 2,000 candidate genes for cardiovascular disease (CVD) pathways in a community-based sample of 16,324 EA and 3898 AA participants from the Candidate Gene Association Resource (CARe) consortium. Our aim was the discovery of new genomic loci and more detailed characterization of existing loci associated with FVII levels. In EAs, we identified three new loci associated with FVII, of which APOA5 on chromosome 11q23 and HNF4A on chromosome 20q12-13 were replicated in a sample of 4289 participants from the Whitehall II study. We confirmed four previously reported FVII-associated loci (GCKR, MS4A6A, F7 and PROCR) in CARe EA samples. In AAs, the F7 and PROCR regions were significantly associated with FVII. Several of the FVII-associated regions are known to be associated with lipids and other cardiovascular-related traits. At the F7 locus, there was evidence of at least five independently associated SNPs in EAs and three independent signals in AAs. Though the variance in FVII explained by the existing loci is substantial (20% in EA and 10% in AA), larger sample sizes and investigation of lower frequency variants may be required to identify additional FVII-associated loci in EAs and AAs and further clarify the relationship between FVII and other CVD risk factors.
Related JoVE Video
Genetic variation at CHRNA5-CHRNA3-CHRNB4 interacts with smoking status to influence body mass index.
Int J Epidemiol
PUBLISHED: 05-18-2011
Show Abstract
Hide Abstract
Cigarette smoking is associated with lower body mass index (BMI), and a commonly cited reason for unwillingness to quit smoking is a concern about weight gain. Common variation in the CHRNA5-CHRNA3-CHRNB4 gene region (chromosome 15q25) is robustly associated with smoking quantity in smokers, but its association with BMI is unknown. We hypothesized that genotype would accurately reflect smoking exposure and that, if smoking were causally related to weight, it would be associated with BMI in smokers, but not in never smokers.
Related JoVE Video
Genetic variants associated with Von Willebrand factor levels in healthy men and women identified using the HumanCVD BeadChip.
Ann. Hum. Genet.
PUBLISHED: 04-28-2011
Show Abstract
Hide Abstract
We have used the gene-centric Illumina HumanCVD BeadChip to identify common genetic determinants of Von Willebrand factor (vWF) levels in healthy men and women. The Whitehall II (WHII) study (n= 5592) and the British Womens Heart and Health Study (BWHHS) (n= 3445) were genotyped using the HumanCVD BeadChip. Replication was conducted in the British Regional Heart Study (n= 3897) and 1958 Birth Cohort (n= 5048). We identified 48 single nucleotide polymorphisms (SNPs) in four genes/regions associated with vWF at P < 10(-4) . These included 19 SNPs at the ABO blood group locus with the lead variant being rs657152 (P= 9.7 × 10(-233) ). The lead variant in the 24 VWF SNPs was rs1063856 (P= 2.3 × 10(-20) ). SNPs at ESR1 (rs6909023) and NRG1(rs1685103) showed modest associations with vWF, but these were not confirmed in a meta-analysis. Using variable selection, five SNPs at the locus for ABO and two for VWF were found to have independent associations with vWF levels. After adjustment for age and gender, the selected ABO SNPs explained 15% and the VWF SNPs an additional 2% of the variance in vWF levels. Individuals at opposite tails of the additive seven SNP allele score exhibited substantial differences in vWF levels. These data demonstrate that multiple common alleles with small effects make, in combination, important contributions to individual differences in vWF levels.
Related JoVE Video
Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.
María Soler Artigas, Daan W Loth, Louise V Wain, Sina A Gharib, Ma'en Obeidat, Wenbo Tang, Guangju Zhai, Jing Hua Zhao, Albert Vernon Smith, Jennifer E Huffman, Eva Albrecht, Catherine M Jackson, David M Evans, Gemma Cadby, Myriam Fornage, Ani Manichaikul, Lorna M Lopez, Toby Johnson, Melinda C Aldrich, Thor Aspelund, Inês Barroso, Harry Campbell, Patricia A Cassano, David J Couper, Gudny Eiriksdottir, Nora Franceschini, Melissa Garcia, Christian Gieger, Gauti Kjartan Gislason, Ivica Grković, Christopher J Hammond, Dana B Hancock, Tamara B Harris, Adaikalavan Ramasamy, Susan R Heckbert, Markku Heliövaara, Georg Homuth, Pirro G Hysi, Alan L James, Stipan Janković, Bonnie R Joubert, Stefan Karrasch, Norman Klopp, Beate Koch, Stephen B Kritchevsky, Lenore J Launer, Yongmei Liu, Laura R Loehr, Kurt Lohman, Ruth J F Loos, Thomas Lumley, Khalid A Al Balushi, Wei Q Ang, R Graham Barr, John Beilby, John D Blakey, Mladen Boban, Vesna Boraska, Jonas Brisman, John R Britton, Guy G Brusselle, Cyrus Cooper, Ivan Curjuric, Santosh Dahgam, Ian J Deary, Shah Ebrahim, Mark Eijgelsheim, Clyde Francks, Darya Gaysina, Raquel Granell, Xiangjun Gu, John L Hankinson, Rebecca Hardy, Sarah E Harris, John Henderson, Amanda Henry, Aroon D Hingorani, Albert Hofman, Patrick G Holt, Jennie Hui, Michael L Hunter, Medea Imboden, Karen A Jameson, Shona M Kerr, Ivana Kolčić, Florian Kronenberg, Jason Z Liu, Jonathan Marchini, Tricia McKeever, Andrew D Morris, Anna-Carin Olin, David J Porteous, Dirkje S Postma, Stephen S Rich, Susan M Ring, Fernando Rivadeneira, Thierry Rochat, Avan Aihie Sayer, Ian Sayers, Peter D Sly, George Davey Smith, Akshay Sood, John M Starr, André G Uitterlinden, Judith M Vonk, S Goya Wannamethee, Peter H Whincup, Cisca Wijmenga, O Dale Williams, Andrew Wong, Massimo Mangino, Kristin D Marciante, Wendy L McArdle, Bernd Meibohm, Alanna C Morrison, Kari E North, Ernst Omenaas, Lyle J Palmer, Kirsi H Pietiläinen, Isabelle Pin, Ozren Pola Sbreve Ek, Anneli Pouta, Bruce M Psaty, Anna-Liisa Hartikainen, Taina Rantanen, Samuli Ripatti, Jerome I Rotter, Igor Rudan, Alicja R Rudnicka, Holger Schulz, So-Youn Shin, Tim D Spector, Ida Surakka, Veronique Vitart, Henry Völzke, Nicholas J Wareham, Nicole M Warrington, H-Erich Wichmann, Sarah H Wild, Jemma B Wilk, Matthias Wjst, Alan F Wright, Lina Zgaga, Tatijana Zemunik, Craig E Pennell, Fredrik Nyberg, Diana Kuh, John W Holloway, H Marike Boezen, Debbie A Lawlor, Richard W Morris, Nicole Probst-Hensch, , Jaakko Kaprio, James F Wilson, Caroline Hayward, Mika Kähönen, Joachim Heinrich, Arthur W Musk, Deborah L Jarvis, Sven Gläser, Marjo-Riitta Järvelin, Bruno H Ch Stricker, Paul Elliott, George T O'Connor, David P Strachan, Stephanie J London, Ian P Hall, Vilmundur Gudnason, Martin D Tobin.
Nat. Genet.
PUBLISHED: 04-20-2011
Show Abstract
Hide Abstract
Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
Related JoVE Video
Threshold haemoglobin levels and the prognosis of stable coronary disease: two new cohorts and a systematic review and meta-analysis.
PLoS Med.
PUBLISHED: 04-19-2011
Show Abstract
Hide Abstract
Low haemoglobin concentration has been associated with adverse prognosis in patients with angina and myocardial infarction (MI), but the strength and shape of the association and the presence of any threshold has not been precisely evaluated.
Related JoVE Video
Variations in apolipoprotein E frequency with age in a pooled analysis of a large group of older people.
Am. J. Epidemiol.
PUBLISHED: 04-15-2011
Show Abstract
Hide Abstract
Variation in the apolipoprotein E gene (APOE) has been reported to be associated with longevity in humans. The authors assessed the allelic distribution of APOE isoforms ?2, ?3, and ?4 among 10,623 participants from 15 case-control and cohort studies of age-related macular degeneration (AMD) in populations of European ancestry (study dates ranged from 1990 to 2009). The authors included only the 10,623 control subjects from these studies who were classified as having no evidence of AMD, since variation within the APOE gene has previously been associated with AMD. In an analysis stratified by study center, gender, and smoking status, there was a decreasing frequency of the APOE ?4 isoform with increasing age (?(2) for trend = 14.9 (1 df); P = 0.0001), with a concomitant increase in the ?3 isoform (?(2) for trend = 11.3 (1 df); P = 0.001). The association with age was strongest in ?4 homozygotes; the frequency of ?4 homozygosity decreased from 2.7% for participants aged 60 years or less to 0.8% for those over age 85 years, while the proportion of participants with the ?3/?4 genotype decreased from 26.8% to 17.5% across the same age range. Gender had no significant effect on the isoform frequencies. This study provides strong support for an association of the APOE gene with human longevity.
Related JoVE Video
Meta analysis of candidate gene variants outside the LPA locus with Lp(a) plasma levels in 14,500 participants of six White European cohorts.
Atherosclerosis
PUBLISHED: 04-13-2011
Show Abstract
Hide Abstract
Both genome-wide association studies and candidate gene studies have reported that the major determinant of plasma levels of the Lipoprotein (a) [Lp(a)] reside within the LPA locus on chromosome 6. We have used data from the HumanCVD BeadChip to explore the contribution of other candidate genes determining Lp(a) levels.
Related JoVE Video
Evidence of association of APOE with age-related macular degeneration: a pooled analysis of 15 studies.
Hum. Mutat.
PUBLISHED: 03-25-2011
Show Abstract
Hide Abstract
Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status has been reported. We present a pooled analysis (n = 21,160) demonstrating associations between late AMD and APO?4 (odds ratio [OR] = 0.72 per haplotype; confidence interval [CI]: 0.65-0.74; P = 4.41×10(-11) ) and APO?2 (OR = 1.83 for homozygote carriers; CI: 1.04-3.23; P = 0.04), following adjustment for age group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR = 1.54; CI: 1.38-1.72; P = 2.8×10(-15) ) and atrophic (OR = 1.38; CI: 1.18-1.61; P = 3.37×10(-5) ) AMD but not early AMD (OR = 0.94; CI: 0.86-1.03; P = 0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyond ?2 and ?4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology.
Related JoVE Video
Associations of common genetic variants with age-related changes in fasting and postload glucose: evidence from 18 years of follow-up of the Whitehall II cohort.
Diabetes
PUBLISHED: 03-25-2011
Show Abstract
Hide Abstract
In the general, nondiabetic population, fasting glucose increases only slightly over time, whereas 2-h postload glucose shows a much steeper age-related rise. The reasons underlying these different age trajectories are unknown. We investigated whether common genetic variants associated with fasting and 2-h glucose contribute to age-related changes of these traits.
Related JoVE Video
Utility of genetic determinants of lipids and cardiovascular events in assessing risk.
Nat Rev Cardiol
PUBLISHED: 02-15-2011
Show Abstract
Hide Abstract
The prevention of coronary heart disease (CHD) is a major public-health goal, but disease architecture is such that a larger proportion of clinical events occur among the average majority than among the high-risk minority--the prevention paradox. Genetic findings over the past few years have resulted in the reopening of the old debate on whether an individualized or a population-based approach to prevention is preferable. Genetic testing is an attractive tool for CHD risk prediction because it is a low-cost, high-fidelity technology with multiplex capability. Moreover, by contrast with nongenetic markers, genotype is invariant and determined from conception, which eliminates biological variability and makes prediction from early life possible. Mindful of the prevention paradox, this Review examines the potential applications and challenges of using genetic information for predicting CHD, focusing on lipid risk factors and drawing on experience in the evaluation of nongenetic risk factors as screening tests for CHD. Many of the issues we discuss hold true for any late-onset common disease with modifiable risk factors and proven preventative strategies.
Related JoVE Video
Examining overweight and obesity as risk factors for common mental disorders using fat mass and obesity-associated (FTO) genotype-instrumented analysis: The Whitehall II Study, 1985-2004.
Am. J. Epidemiol.
PUBLISHED: 01-19-2011
Show Abstract
Hide Abstract
The Mendelian randomization approach exploits genetic variants to improve causal inference when using observational data. The authors examined the relation between long-term obesity and common mental disorders (CMD) by utilizing the known relation between fat mass and obesity-associated (FTO) genotype and body mass index (BMI; weight (kg)/height (m)(2)). Data collection in 2,981 men and 1,164 women (mean age at baseline = 44 years) from the Whitehall II Study (London, United Kingdom) included 4 repeated examinations of BMI and CMD over a 19-year follow-up period (1985-2004), plus an assessment of FTO polymorphism rs1421085. In men, there was an association of FTO genotype with all measures of adiposity (mean BMI, number of times obese, and, in nonobese persons, number of times overweight). FTO was also associated with CMD in men. This was independent of adiposity, thus potentially violating the exclusion restriction assumption. According to both conventional and FTO-instrumented regression analysis, measurement of obesity was associated with an increased occurrence of CMD. In the FTO-instrumented analysis only, higher BMI and overweight were also associated with CMD. In women, there was no link between FTO and adiposity. Mendelian randomization analyses supported the status of long-term obesity as a risk factor for CMD in men-a finding that should be interpreted cautiously because the function of the FTO gene is unknown.
Related JoVE Video
IQ, educational attainment, memory and plasma lipids: associations with apolipoprotein E genotype in 5995 children.
Biol. Psychiatry
PUBLISHED: 01-07-2011
Show Abstract
Hide Abstract
Apolipoprotein E (APOE) genotype (?2/?3/?4: rs429358 ?4 allele; rs7412 ?2 allele) is strongly associated with both lipid levels and Alzheimers disease. Although there is also evidence of milder cognitive impairment in later life in carriers of the APOE ?4 allele, there have been few studies investigating the impact of APOE genotype on cognitive function in children.
Related JoVE Video
Adiposity and cardiovascular risk factors in a large contemporary population of pre-pubertal children.
Eur. Heart J.
PUBLISHED: 10-23-2010
Show Abstract
Hide Abstract
to examine the associations of several markers of adiposity and a wide range of cardiovascular risk factors and biomarkers in pre-pubertal children.
Related JoVE Video
Invasive dental treatment and risk for vascular events: a self-controlled case series.
Ann. Intern. Med.
PUBLISHED: 10-20-2010
Show Abstract
Hide Abstract
Treatment of periodontal disease may reduce cardiovascular risk in the longer term, but studies have suggested a link among dental procedures, acute inflammation, and endothelial dysfunction. However, whether such acute inflammatory effects translate into a short-lived increased risk for vascular events is not known.
Related JoVE Video
Endothelial, sympathetic, and cardiac function in inherited (6R)-L-erythro-5,6,7,8-tetrahydro-L-biopterin deficiency.
Circ Cardiovasc Genet
PUBLISHED: 10-11-2010
Show Abstract
Hide Abstract
(6R)-5,6,7,8-Tetrahydro-l-biopterin (BH4) is a cofactor for enzymes involved in catecholamine and nitric oxide generation whose synthesis is initiated by GTP cyclohydrolase I (GTPCH-1), encoded by GCH1. In the absence of a potent, specific GTPCH-1 inhibitor, natural BH4 deficiency caused by mutations in GCH1 in the rare movement disorder, DOPA-responsive dystonia (OMIM DYT5), offers the opportunity to study the role of endogenous BH4 in humans.
Related JoVE Video
Ancestry as a determinant of mean population C-reactive protein values: implications for cardiovascular risk prediction.
Circ Cardiovasc Genet
PUBLISHED: 09-28-2010
Show Abstract
Hide Abstract
Eligibility for rosuvastatin treatment for cardiovascular disease prevention includes a C-reactive protein (CRP) concentration >2 mg/L. Most observational studies of CRP and cardiovascular disease have been in Europeans. We evaluated the influence of ancestry on population CRP concentration to assess the implications for statin targeting in non-Europeans.
Related JoVE Video
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
Show Abstract
Hide Abstract
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.
Related JoVE Video
Is periodontal inflammation associated with raised blood pressure? Evidence from a National US survey.
J. Hypertens.
PUBLISHED: 08-14-2010
Show Abstract
Hide Abstract
There is incomplete and inconclusive evidence for the association between periodontal disease markers and arterial blood pressure, particularly from large national epidemiological studies. This study assessed the relationship between different markers of periodontal inflammation and disease with arterial blood pressure in people aged 17 years and over in USA. We analysed data from the Third National Health and Nutrition Examination Survey on 6617 men and 7377 women who received a periodontal examination. Blood pressure was analysed in both a continuous format and a binary variable for case definition of hypertension. Periodontal disease markers (extent of gingival bleeding, pocket depth, and loss of attachment, and a case definition of periodontitis) were associated on the arterial blood pressure outcomes through a series of regression models, incrementally adjusting for confounders (demographic, inflammation markers, chronic conditions, smoking, BMI, socio-economic status). All periodontal measures had significant crude associations with SBP and hypertension. Gingival bleeding, a marker of current periodontal inflammation, was the only measure consistently and significantly associated with raised SBP and an increased odds of hypertension in the US adult population throughout the adjustment process. For a 10% greater extent of gingival bleeding, the average SBP was higher by 0.5 (0.3, 0.6) mmHg in the fully adjusted model. By referring to the general population and the whole distribution of blood pressure, not only to those at higher risk for hypertension, this association might have some important implications for clinical practice and public health strategies.
Related JoVE Video
Prospective study of placental angiogenic factors and maternal vascular function before and after preeclampsia and gestational hypertension.
Circulation
PUBLISHED: 07-19-2010
Show Abstract
Hide Abstract
Preeclampsia is a life-threatening pregnancy syndrome of uncertain origin. To elucidate the pathogenesis, we evaluated the temporal relationships between changes in vascular function and circulating biomarkers of angiogenic activity before and after the onset of preeclampsia and gestational hypertension.
Related JoVE Video
Related JoVE Video
Frequency of eNOS polymorphisms in the Colombian general population.
BMC Genet.
PUBLISHED: 06-20-2010
Show Abstract
Hide Abstract
Nitric oxide (NO) synthesized by endothelial cells is known to be a potent vasodilator. It has been suggested that polymorphisms in endothelial nitric oxide synthase (eNOS) can affect the response of the vascular endothelium to increased oxidative stress. The objective of the present study was to determine the presence of G894T (rs1799983), intron-4 (27-bp TR) and -T786C (rs2070744) polymorphisms in the eNOS gene among the Colombian general population.
Related JoVE Video
Association of maternal weight gain in pregnancy with offspring obesity and metabolic and vascular traits in childhood.
Circulation
PUBLISHED: 06-01-2010
Show Abstract
Hide Abstract
We sought to examine the association of gestational weight gain (GWG) and prepregnancy weight with offspring adiposity and cardiovascular risk factors.
Related JoVE Video
Adiponectin and its association with bone mass accrual in childhood.
J. Bone Miner. Res.
PUBLISHED: 05-26-2010
Show Abstract
Hide Abstract
Circulating adiponectin levels are inversely related to bone mineral density (BMD) in humans and animal models. Previous studies in humans have been confined largely to adult populations, and whether adiponectin influences bone mass accrual in childhood is unclear. We examined this question using the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort by investigating relationships between circulating adiponectin levels at a mean age of 9.9 years, indices of bone mass as measured by total-body dual-energy X-ray absorptiometry (DXA) at ages 9.9 and 15.5 years, and cortical bone parameters as measured by peripheral quantitative computed tomography (pQCT) of the midtibia at age 15.5 years. A total of 4927 children were included at age 9.9 years, of whom 97% and 90% of boys and girls, respectively, were in prepuberty or early puberty, as defined by Tanner stage 1-2. A total of 2754 children were included at age 15.5 years, of whom 95% and 97% of boys and girls, respectively, were in late puberty, as defined by Tanner stage 4-5. Circulating adiponectin was found to be related to fat mass, lean mass, and, to a lesser extent, height, so analyses were adjusted for these three variables to identify possible independent effects of adiponectin on bone development. Adiponectin was inversely related to total-body-less-head bone mineral content (BMC; -3.0%), bone area (BA; -1.8%), BMC divided by BA (BMD; -4.8%), and BMC adjusted for BA by linear regression (aBMC; -5.6%), as measured at age 9.9 years (coefficients show change per doubling in adiponectin concentration, p?
Related JoVE Video
PLA2G7 genotype, lipoprotein-associated phospholipase A2 activity, and coronary heart disease risk in 10 494 cases and 15 624 controls of European Ancestry.
Circulation
PUBLISHED: 05-17-2010
Show Abstract
Hide Abstract
Higher lipoprotein-associated phospholipase A(2)(Lp-PLA2) activity is associated with increased risk of coronary heart disease (CHD), making Lp-PLA2 a potential therapeutic target. PLA2G7 variants associated with Lp-PLA2 activity could evaluate whether this relationship is causal.
Related JoVE Video
Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies.
Lancet
PUBLISHED: 05-11-2010
Show Abstract
Hide Abstract
Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality.
Related JoVE Video
Short-term vascular risk: time to take notice?
Nat Rev Cardiol
PUBLISHED: 05-04-2010
Show Abstract
Hide Abstract
Current guidance around the prevention of cardiovascular events is based on long-term risk, typically calculated over 10 years. A growing body of evidence, however, suggests that vascular risk fluctuates greatly over much shorter time periods. We suggest a new paradigm for cardiovascular risk management that is based on targeting interventions during periods of enhanced risk. During such high-risk time windows, prophylactic therapy could have a disproportionately large absolute benefit, altering the risk-benefit balance and cost-effectiveness of available treatments. Major surgery is an example of an exposure known to lead to a transient increase in vascular risk. Emerging evidence supports the usefulness of short-term preventative interventions in the perioperative period. Influenza infection is another exposure known to increase the risk of vascular events, and cardiovascular mortality and morbidity are likely to be major features associated with pandemic influenza. Important questions remain, however, before preventative interventions can be offered as a routine part of influenza management.
Related JoVE Video

What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.