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

Morris 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, Thomas Quertermous, Konstantinos Papadakis, 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 M. van Rij, Janet T. Powell, Per Eriksson, Kari Stefansson, Lachlan Coin, Steve E. Humphries, Robert D. Sayers, Panos Deloukas, Nilesh J. Samani, Heribert Schunkert, Inke R. König, Sekar Kathiresan, Muredach P. Reilly, Hilma Holm, Michael Preuss, Maja Barbalic, Maja Barbalic, Giovanni Tognoni, 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, Mary Susan Burnett, Ian Buysschaert, John F. Carlquist, Li Chen, Sven Cichon, Veryan Codd, Robert W. Davies, George Dedoussis, Joseph M. Devaney, Serkalem Demissie, Joseph M. Devaney, Patrick Diemert, Ron Do, Angela Döring, Sandra Eifert, Nour Eddine El Mokhtari, Stephen G. Ellis, Stephen E. Epstein, James C. Engert, Stephen E. Epstein, Ulf de Faire, Marcus Fischer, Aaron R. Folsom, Jennifer Freyer, Bruna Gigante, Domenico Girelli, Vilmundur Gudnason, Jeffrey R. Gulcher, Eran Halperin, Naomi Hammond, Stanley L. Hazen, Carlos Iribarren, J. Wouter Jukema, Thomas Illig, Carlos Iribarren, 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, Andrew J. Lotery, Man Li, Wolfgang Lieb, Christina Loley, Andrew J. Lotery, Pier M. Mannucci, Seraya Maouche, Nicola Martinelli, Pascal P. McKeown, Christa Meisinger, Richa Saxena, 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, Daniel J. Rader, Riyaz S. Patel, Chris C. Patterson, Annette Peters, Frits R. Rosendaal, 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, Jürgen Schrezenmeir, Arne Schäfer, Arne Schillert, Stefan Schreiber, Jürgen Schrezenmeir, Stephen M. Schwartz, Jaapjan D. Snoep, Mohan Sivananthan, Suthesh Sivapalaratnam, 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, H. Erich Wichmann, Andre G. Uitterlinden, Andre M. van Rij, Benjamin F. Voight, Nicholas J. Wareham, Tanja Zeller, H. Erich Wichmann, Philipp S. Wild, Christina Willenborg, L. Adrienne Cupples, 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, Robert Roberts, Christopher J. O'Donnell, Arshed A. Quyyumi, 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, Alexander Teumer, Feng Zhang, Martin Farrall, Johanna Kuusisto, Paul R. Burton, John C. Chambers, Peter Nilsson, Anna Dominiczak, Silvia Polidoro, Diederick E. Grobbee, N. Charlotte Onland-Moret, Jacques S. Beckmann, Louise V. Wain, Katherine S. Elliott, Alexander Teumer, Jian'an Luan, Gavin Lucas, Johanna Kuusisto, Paul R. Burton, David Hadley, Wendy L. McArdle, Alessandra Di Gregorio, Anna Dominiczak, Salvatore Panico, John Webster, Eleftheria Zeggini, Jacques S. Beckmann, 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, Robert N. Luben, Gabriel J. Crawford, Pekka Jousilahti, Markus Perola, Michael Boehnke, Lori L. Bonnycastle, Anne U. Jackson, Karen L. Mohlke, Heather M. Stringham, Timo T. Valle, Cristen J. Willer, Richard N. Bergman, Mario A. Morken, Angela Döring, Elin Org, Jaume Marrugat, Jaume Marrugat, Isaac Subirana, Nelson B. Freimer, Anna Liisa Hartikainen, Mark I. McCarthy, Paul F. O'Reilly, Leena Peltonen, Paul E. de Jong, 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, Georg Homuth, Georg Homuth, Roberto Lorbeer, Thorsten Reffelmann, Rainer Rettig, Uwe Völker, Pilar Galan, Ivo G. Gut, Serge Hercberg, G. Mark Lathrop, Diana Zelenika, Frances M. Williams, Guangju Zhai, Markku Laakso, Nita G. Forouhi, Henry Völzke, Cuno S. Uiterwaal, Yvonne T. van der Schouw, Mattijs E. Numans, Gerjan Navis, 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 P. Strachan, Maris Laan, Pierre Meneton, Manuela Uda, Marjo Riitta Jarvelin, Ruth J.F. Loos, Paul Elliott, Goncalo R. Abecasis, Mark Caulfield, Patricia B. Munroe, Valgerdur Steinthorsdottir, Andrew P. Morris, Christian Dina, Ryan P. Welch, Cornelia Huth, Yurii S. Aulchenko, Laura J. McCulloch, Teresa Ferreira, Harald Grallert, Josée Dupuis, Guanming Wu, Soumya Raychaudhuri, Steve A. McCarroll, Claudia Langenberg, Oliver M. Hofmann, Josée Dupuis, Cecilia M. Lindgren, Ayellet V. Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J. Bennett, Roza Blagieva, Kristina Bengtsson Boström, Bert Bravenboer, Noël P. Burtt, Guillaume Charpentier, Peter S. Chines, Marilyn Cornelis, David J. Couper, Gabe Crawford, Alex S.F. Doney, Amanda L. Elliott, Amanda L. Elliott, Michael R. Erdos, Caroline S. Fox, Christopher S. Franklin, Martha Ganser, Niels Grarup, Todd Green, Timon W. van Haeften, Christopher J. Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Paul R.V. Johnson, Torben Jørgensen, Wen H.L. Kao, Norman Klopp, Peter Kraft, Torsten Lauritzen, Aloysius Lieverse, Cecilia M. Lindgren, Valeriya Lyssenko, Andre Uitterlinden, Kristian Midthjell, Narisu Narisu, 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, Dilip K. Naik, Klaus Strassburger, 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, Stephane Cauchi, Anna L. Gloyn, Ulf Gyllensten, Torben Hansen, Winston A. Hide, Graham A. Hitman, David J. Hunter, Kristian Hveem, Andrew D. Morris, Colin N.A. Palmer, Peter P. Pramstaller, Igor Rudan, Jose C. Florez, Lincoln D. Stein, Andre Uitterlinden, Mark Walker, Richard M. Watanabe, Bernhard O. Boehm, Harry Campbell, Mark J. Daly, Andrew T. Hattersley, Frank B. Hu, James B. Meigs, James S. Pankow, Oluf Pedersen, Jose C. Florez, Timothy M. Frayling, Rob Sladek, James F. Wilson, Philippe Froguel, Ross D. Blair, 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

*Korrespondierende/r Autor/-in für diese Arbeit
121 Zitate (Scopus)

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.

OriginalspracheEnglisch
ZeitschriftAmerican Journal of Human Genetics
Jahrgang89
Ausgabenummer5
Seiten (von - bis)619-627
Seitenumfang9
ISSN0002-9297
DOIs
PublikationsstatusVeröffentlicht - 11.11.2011

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