Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Matthew J. Bown, Gregory T. Jones, Seamus C. Harrison, Benjamin J. Wright, Suzannah Bumpstead, Annette F. Baas, Solveig Gretarsdottir, Stephen A. Badger, Declan T. Bradley, Kevin Burnand, Anne H. Child, Rachel E. Clough, Gillian Cockerill, Hany Hafez, D. Julian A Scott, Simon Futers, Anne Johnson, Soroush Sohrabi, Alberto Smith, Matthew M. ThompsonFrank M. van Bockxmeer, Matthew Waltham, Stefan E. Matthiasson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Jan D. Blankensteijn, Joep A W Teijink, Cisca Wijmenga, Jacqueline de Graaf, Lambertus A. Kiemeney, Themistocles L. Assimes, Ruth McPherson, Lasse Folkersen, Anders Franco-Cereceda, Jutta Palmen, Andrew J. Smith, Nicolas Sylvius, John B. Wild, Mette Refstrup, Sarah Edkins, Rhian Gwilliam, Sarah E. Hunt, Simon Potter, Jes S. Lindholt, Ruth Frikke-Schmidt, Anne Tybjærg-Hansen, Anne E. Hughes, Jonathan Golledge, Paul E. Norman, Andre van Rij, Janet T. Powell, Per Eriksson, Kari Stefansson, John R. Thompson, Steve E. Humphries, Robert D. Sayers, Panos Deloukas, Nilesh J. Samani, Heribert Schunkert, Inke R. König, Sekar Kathiresan, Muredach P. Reilly, Themistocles L. Assimes, Hilma Holm, Michael Preuss, Alexandre F R Stewart, Maja Barbalic, Christian Gieger, Devin Absher, Zouhair Aherrahrou, Hooman Allayee, David Altshuler, Sonia S. Anand, Karl Andersen, Jeffrey L. Anderson, Diego Ardissino, Stephen G. Ball, Anthony J. Balmforth, Timothy A. Barnes, Diane M. Becker, Lewis C. Becker, Klaus Berger, Joshua C. Bis, S. Matthijs Boekholdt, Eric Boerwinkle, Peter S. Braund, Morris J. Brown, Mary Susan Burnett, Ian Buysschaert, John F. Carlquist, Li Chen, Sven Cichon, Veryan Codd, Robert W. Davies, George Dedoussis, Abbas Dehghan, Serkalem Demissie, Joseph M. Devaney, Patrick Diemert, Ron Do, Angela Doering, Sandra Eifert, Nour Eddine El Mokhtari, Stephen G. Ellis, Roberto Elosua, James C. Engert, Stephen E. Epstein, Ulf de Faire, Marcus Fischer, Aaron R. Folsom, Jennifer Freyer, Bruna Gigante, Domenico Girelli, Solveig Gretarsdottir, Vilmundur Gudnason, Jeffrey R. Gulcher, Eran Halperin, Naomi Hammond, Stanley L. Hazen, Albert Hofman, Benjamin D. Horne, Thomas Illig, Carlos Iribarren, Gregory T. Jones, J. Wouter Jukema, Michael A. Kaiser, Lee M. Kaplan, John J P Kastelein, Kay Tee Khaw, Joshua W. Knowles, Genovefa Kolovou, Augustine Kong, Reijo Laaksonen, Diether Lambrechts, Karin Leander, Guillaume Lettre, Mingyao Li, Wolfgang Lieb, Christina Loley, Andrew J. Lotery, Pier M. Mannucci, Seraya Maouche, Nicola Martinelli, Pascal P. McKeown, Christa Meisinger, Thomas Meitinger, Olle Melander, Pier Angelica Merlini, Vincent Mooser, Thomas Morgan, Thomas W. Mühleisen, Joseph B. Muhlestein, Thomas Münzel, Kiran Musunuru, Janja Nahrstaedt, Christopher P. Nelson, Markus M. Nöthen, Oliviero Olivieri, Riyaz S. Patel, Chris C. Patterson, Annette Peters, Flora Peyvandi, Liming Qu, Arshed A. Quyyumi, Daniel J. Rader, Loukianos S. Rallidis, Catherine Rice, Frits R. Rosendaal, Diana Rubin, Veikko Salomaa, M. Lourdes Sampietro, Manj S. Sandhu, Eric Schadt, Arne Schäfer, Arne Schillert, Stefan Schreiber, Jürgen Schrezenmeir, Stephen M. Schwartz, David S. Siscovick, Mohan Sivananthan, Suthesh Sivapalaratnam, Albert Smith, Tamara B. Smith, Jaapjan D. Snoep, Nicole Soranzo, John A. Spertus, Klaus Stark, Kathy Stirrups, Monika Stoll, W. H. Wilson Tang, Stephanie Tennstedt, Gudmundur Thorgeirsson, Gudmar Thorleifsson, Maciej Tomaszewski, Andre G. Uitterlinden, Andre M. van Rij, Benjamin F. Voight, Nick J. Wareham, George A. Wells, H. Erich Wichmann, Philipp S. Wild, Christina Willenborg, Jaqueline C M Witteman, Benjamin J. Wright, Shu Ye, Tanja Zeller, Andreas Ziegler, Francois Cambien, Alison H. Goodall, L. Adrienne Cupples, Thomas Quertermous, Winfried März, Christian Hengstenberg, Stefan Blankenberg, Willem H. Ouwehand, Alistair S. Hall, Panos Deloukas, John R. Thompson, Kari Stefansson, Robert Roberts, Unnur Thorsteinsdottir, Christopher J. O'Donnell, Ruth McPherson, Jeanette Erdmann, Nilesh J. Samani, Christopher Newton-Cheh, Toby Johnson, Vesela Gateva, Martin D. Tobin, Murielle Bochud, Lachlan Coin, Samer S. Najjar, Jing Hua Zhao, Simon C. Heath, Susana Eyheramendy, Konstantinos Papadakis, Benjamin F. Voight, Laura J. Scott, Feng Zhang, Martin Farrall, Toshiko Tanaka, Chris Wallace, John C. Chambers, Kay Tee Khaw, Peter Nilsson, Pim van der Harst, Silvia Polidoro, Diederick E. Grobbee, N. Charlotte Onland-Moret, Michiel L. Bots, Louise V. Wain, Katherine S. Elliott, Alexander Teumer, Jian'an Luan, Gavin Lucas, Johanna Kuusisto, Paul R. Burton, David Hadley, Wendy L. McArdle, Morris Brown, Anna Dominiczak, Stephen J. Newhouse, Nilesh J. Samani, John Webster, Eleftheria Zeggini, Jacques S. Beckmann, Sven Bergmann, Noha Lim, Kijoung Song, Peter Vollenweider, Gerard Waeber, Dawn M. Waterworth, Xin Yuan, Leif Groop, Marju Orho-Melander, Alessandra Allione, Alessandra Di Gregorio, Simonetta Guarrera, Salvatore Panico, Fulvio Ricceri, Valeria Romanazzi, Carlotta Sacerdote, Paolo Vineis, Inês Barroso, Manjinder S. Sandhu, Robert N. Luben, Gabriel J. Crawford, Pekka Jousilahti, Markus Perola, Michael Boehnke, Lori L. Bonnycastle, Francis S. Collins, Anne U. Jackson, Karen L. Mohlke, Heather M. Stringham, Timo T. Valle, Cristen J. Willer, Richard N. Bergman, Mario A. Morken, Angela Döring, Christian Gieger, Thomas Illig, Thomas Meitinger, Elin Org, Arne Pfeufer, H. Erich Wichmann, Sekar Kathiresan, Jaume Marrugat, Christopher J. O'Donnell, Stephen M. Schwartz, David S. Siscovick, Isaac Subirana, Nelson B. Freimer, Anna Liisa Hartikainen, Mark I. McCarthy, Paul F. O'Reilly, Leena Peltonen, Anneli Pouta, Paul E. de Jong, Harold Snieder, Wiek H. van Gilst, Robert Clarke, Anuj Goel, Anders Hamsten, John F. Peden, Udo Seedorf, Ann Christine Syvänen, Giovanni Tognoni, Edward G. Lakatta, Serena Sanna, Paul Scheet, David Schlessinger, Angelo Scuteri, Marcus Dörr, Florian Ernst, Stephan B. Felix, Georg Homuth, Roberto Lorbeer, Thorsten Reffelmann, Rainer Rettig, Uwe Völker, Pilar Galan, Ivo G. Gut, Serge Hercberg, G. Mark Lathrop, Diana Zelenika, Panos Deloukas, Nicole Soranzo, Frances M. Williams, Guangju Zhai, Veikko Salomaa, Markku Laakso, Roberto Elosua, Nita G. Forouhi, Henry Völzke, Cuno S. Uiterwaal, Yvonne T. van der Schouw, Mattijs E. Numans, Giuseppe Matullo, Gerjan Navis, Göran Berglund, Sheila A. Bingham, Jaspal S. Kooner, John M. Connell, Stefania Bandinelli, Luigi Ferrucci, Hugh Watkins, Tim D. Spector, Jaakko Tuomilehto, David Altshuler, David P. Strachan, Maris Laan, Pierre Meneton, Nicholas J. Wareham, Manuela Uda, Marjo Riitta Jarvelin, Vincent Mooser, Olle Melander, Ruth J F Loos, Paul Elliott, Gonçalo R. Abecasis, Mark Caulfield, Patricia B. Munroe, Benjamin F. Voight, Laura J. Scott, Valgerdur Steinthorsdottir, Andrew P. Morris, Christian Dina, Ryan P. Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S. Aulchenko, Gudmar Thorleifsson, Laura J. McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J. Willer, Soumya Raychaudhuri, Steve A. McCarroll, Claudia Langenberg, Oliver M. Hofmann, Josée Dupuis, Lu Qi, Ayellet V. Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J. Bennett, Roza Blagieva, Eric Boerwinkle, Lori L. Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noël P. Burtt, Guillaume Charpentier, Peter S. Chines, Marilyn Cornelis, David J. Couper, Gabe Crawford, Alex S F Doney, Katherine S. Elliott, Amanda L. Elliott, Michael R. Erdos, Caroline S. Fox, Christopher S. Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J. Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U. Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Norman Klopp, Augustine Kong, Peter Kraft, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M. Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A. Morken, Narisu Narisu, Peter Nilsson, Katharine R. Owen, Felicity Payne, John R B Perry, Ann Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N. William Rayner, Neil R. Robertson, Ghislain Rocheleau, Michael Roden, Michael J. Sampson, Richa Saxena, Beverley M. Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Strassburger, Heather M. Stringham, Qi Sun, Amy J. Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M. van Dam, Timon W. van Haeften, Thijs van Herpt, Jana V. van Vliet-Ostaptchouk, G. Bragi Walters, Michael N. Weedon, Cisca Wijmenga, Richard N. Bergman, Stephane Cauchi, Francis S. Collins, Anna L. Gloyn, Ulf Gyllensten, Torben Hansen, Winston A. Hide, Graham A. Hitman, Albert Hofman, David J. Hunter, Kristian Hveem, Markku Laakso, Karen L. Mohlke, Andrew D. Morris, Colin N A Palmer, Peter P. Pramstaller, Igor Rudan, Eric Sijbrands, Lincoln D. Stein, Jaakko Tuomilehto, Andre Uitterlinden, Mark Walker, Nicholas J. Wareham, Richard M. Watanabe, Goncalo R. Abecasis, Bernhard O. Boehm, Harry Campbell, Mark J. Daly, Andrew T. Hattersley, Frank B. Hu, James B. Meigs, James S. Pankow, Oluf Pedersen, H. Erich Wichmann, Inês Barroso, Jose C. Florez, Timothy M. Frayling, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F. Wilson, Thomas Illig, Philippe Froguel, Cornelia M. van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I. McCarthy, Ross D. Blair, Andrew A. Hill, B. Gerry Hill, David R. Lewis, Les A. McNoe, Tony R. Merriman, Dilip K. Naik, L. Vicky Phillips, Ian A. Thomson, Ruth Topless, Thodur M. Vasudevan, Grace Yu

Research output: Contribution to journalArticle

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Abstract

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.

Original languageEnglish (US)
Pages (from-to)619-627
Number of pages9
JournalAmerican journal of human genetics
Volume89
Issue number5
DOIs
StatePublished - Nov 11 2011

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Bown, M. J., Jones, G. T., Harrison, S. C., Wright, B. J., Bumpstead, S., Baas, A. F., Gretarsdottir, S., Badger, S. A., Bradley, D. T., Burnand, K., Child, A. H., Clough, R. E., Cockerill, G., Hafez, H., Scott, D. J. A., Futers, S., Johnson, A., Sohrabi, S., Smith, A., ... Yu, G. (2011). Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1. American journal of human genetics, 89(5), 619-627. https://doi.org/10.1016/j.ajhg.2011.10.002