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 language | English (US) |
|---|---|
| Pages (from-to) | 619-627 |
| Number of pages | 9 |
| Journal | American Journal of Human Genetics |
| Volume | 89 |
| Issue number | 5 |
| DOIs | |
| State | Published - Nov 11 2011 |
| Externally published | Yes |
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Access to Document
Other files and links
Fingerprint
Dive into the research topics of 'Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1'. Together they form a unique fingerprint.Cite this
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
In: American Journal of Human Genetics, Vol. 89, No. 5, 11.11.2011, p. 619-627.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1
AU - Bown, Morris J.
AU - Jones, Gregory T.
AU - Harrison, Seamus C.
AU - Wright, Benjamin J.
AU - Bumpstead, Suzannah
AU - Baas, Annette F.
AU - Gretarsdottir, Solveig
AU - Badger, Stephen A.
AU - Bradley, Declan T.
AU - Burnand, Kevin
AU - Child, Anne H.
AU - Clough, Rachel E.
AU - Cockerill, Gillian
AU - Hafez, Hany
AU - Scott, D. Julian A.
AU - Futers, Simon
AU - Johnson, Anne
AU - Sohrabi, Soroush
AU - Smith, Alberto
AU - Thompson, Matthew M.
AU - van Bockxmeer, Frank M.
AU - Waltham, Matthew
AU - Matthiasson, Stefan E.
AU - Thorleifsson, Gudmar
AU - Thorsteinsdottir, Unnur
AU - Blankensteijn, Jan D.
AU - Teijink, Joep A.W.
AU - Wijmenga, Cisca
AU - de Graaf, Jacqueline
AU - Kiemeney, Lambertus A.
AU - Assimes, Themistocles L.
AU - McPherson, Ruth
AU - Folkersen, Lasse
AU - Franco-Cereceda, Anders
AU - Palmen, Jutta
AU - Smith, Andrew J.
AU - Sylvius, Nicolas
AU - Wild, John B.
AU - Refstrup, Mette
AU - Edkins, Sarah
AU - Gwilliam, Rhian
AU - Hunt, Sarah E.
AU - Potter, Simon
AU - Lindholt, Jes S.
AU - Frikke-Schmidt, Ruth
AU - Tybjærg-Hansen, Anne
AU - Hughes, Anne E.
AU - Golledge, Jonathan
AU - Norman, Paul E.
AU - van Rij, Andre
AU - Powell, Janet T.
AU - Eriksson, Per
AU - Stefansson, Kari
AU - Thompson, John R.
AU - Humphries, Steve E.
AU - Sayers, Robert D.
AU - Deloukas, Panos
AU - Samani, Nilesh J.
AU - Schunkert, Heribert
AU - König, Inke R.
AU - Kathiresan, Sekar
AU - Reilly, Muredach P.
AU - Holm, Hilma
AU - Preuss, Michael
AU - Stewart, Alexandre F.R.
AU - Barbalic, Maja
AU - Gieger, Christian
AU - Absher, Devin
AU - Aherrahrou, Zouhair
AU - Allayee, Hooman
AU - Altshuler, David
AU - Anand, Sonia S.
AU - Andersen, Karl
AU - Anderson, Jeffrey L.
AU - Ardissino, Diego
AU - Ball, Stephen G.
AU - Balmforth, Anthony J.
AU - Barnes, Timothy A.
AU - Becker, Diane M.
AU - Becker, Lewis C.
AU - Berger, Klaus
AU - Bis, Joshua C.
AU - Matthijs Boekholdt, S.
AU - Boerwinkle, Eric
AU - Braund, Peter S.
AU - Susan Burnett, Mary
AU - Buysschaert, Ian
AU - Carlquist, John F.
AU - Chen, Li
AU - Cichon, Sven
AU - Codd, Veryan
AU - Davies, Robert W.
AU - Dedoussis, George
AU - Dehghan, Abbas
AU - Demissie, Serkalem
AU - Devaney, Joseph M.
AU - Diemert, Patrick
AU - Do, Ron
AU - Doering, Angela
AU - Eifert, Sandra
AU - El Mokhtari, Nour Eddine
AU - Ellis, Stephen G.
AU - Elosua, Roberto
AU - Engert, James C.
AU - Epstein, Stephen E.
AU - de Faire, Ulf
AU - Fischer, Marcus
AU - Folsom, Aaron R.
AU - Freyer, Jennifer
AU - Gigante, Bruna
AU - Girelli, Domenico
AU - Gudnason, Vilmundur
AU - Gulcher, Jeffrey R.
AU - Halperin, Eran
AU - Hammond, Naomi
AU - Hazen, Stanley L.
AU - Hofman, Albert
AU - Horne, Benjamin D.
AU - Illig, Thomas
AU - Iribarren, Carlos
AU - Wouter Jukema, J.
AU - Kaiser, Michael A.
AU - Kaplan, Lee M.
AU - Kastelein, John J.P.
AU - Khaw, Kay Tee
AU - Knowles, Joshua W.
AU - Kolovou, Genovefa
AU - Kong, Augustine
AU - Laaksonen, Reijo
AU - Lambrechts, Diether
AU - Leander, Karin
AU - Lettre, Guillaume
AU - Li, Man
AU - Lieb, Wolfgang
AU - Loley, Christina
AU - Lotery, Andrew J.
AU - Mannucci, Pier M.
AU - Maouche, Seraya
AU - Martinelli, Nicola
AU - McKeown, Pascal P.
AU - Meisinger, Christa
AU - Meitinger, Thomas
AU - Melander, Olle
AU - Angelica Merlini, Pier
AU - Mooser, Vincent
AU - Morgan, Thomas
AU - Mühleisen, Thomas W.
AU - Muhlestein, Joseph B.
AU - Münzel, Thomas
AU - Musunuru, Kiran
AU - Nahrstaedt, Janja
AU - Nelson, Christopher P.
AU - Nöthen, Markus M.
AU - Olivieri, Oliviero
AU - Patel, Riyaz S.
AU - Patterson, Chris C.
AU - Peters, Annette
AU - Peyvandi, Flora
AU - Qu, Liming
AU - Quyyumi, Arshed A.
AU - Rader, Daniel J.
AU - Rallidis, Loukianos S.
AU - Rice, Catherine
AU - Rosendaal, Frits R.
AU - Rubin, Diana
AU - Salomaa, Veikko
AU - Lourdes Sampietro, M.
AU - Sandhu, Manj S.
AU - Schadt, Eric
AU - Schäfer, Arne
AU - Schillert, Arne
AU - Schreiber, Stefan
AU - Schrezenmeir, Jürgen
AU - Schwartz, Stephen M.
AU - Siscovick, David S.
AU - Sivananthan, Mohan
AU - Sivapalaratnam, Suthesh
AU - Smith, Tamara B.
AU - Snoep, Jaapjan D.
AU - Soranzo, Nicole
AU - Spertus, John A.
AU - Stark, Klaus
AU - Stirrups, Kathy
AU - Stoll, Monika
AU - Wilson Tang, W. H.
AU - Tennstedt, Stephanie
AU - Thorgeirsson, Gudmundur
AU - Tomaszewski, Maciej
AU - van Rij, Andre M.
AU - Voight, Benjamin F.
AU - Wareham, Nicholas J.
AU - Wells, George A.
AU - Wichmann, H. Erich
AU - Wild, Philipp S.
AU - Willenborg, Christina
AU - Witteman, Jaqueline C.M.
AU - Ye, Shu
AU - Zeller, Tanja
AU - Ziegler, Andreas
AU - Cambien, Francois
AU - Goodall, Alison H.
AU - Adrienne Cupples, L.
AU - Quertermous, Thomas
AU - März, Winfried
AU - Hengstenberg, Christian
AU - Blankenberg, Stefan
AU - Ouwehand, Willem H.
AU - Hall, Alistair S.
AU - Roberts, Robert
AU - O'Donnell, Christopher J.
AU - Erdmann, Jeanette
AU - Newton-Cheh, Christopher
AU - Johnson, Toby
AU - Gateva, Vesela
AU - Tobin, Martin D.
AU - Bochud, Murielle
AU - Coin, Lachlan
AU - Najjar, Samer S.
AU - Hua Zhao, Jing
AU - Heath, Simon C.
AU - Eyheramendy, Susana
AU - Papadakis, Konstantinos
AU - Scott, Laura J.
AU - Zhang, Feng
AU - Farrall, Martin
AU - Tanaka, Toshiko
AU - Wallace, Chris
AU - Chambers, John C.
AU - Nilsson, Peter
AU - van der Harst, Pim
AU - Polidoro, Silvia
AU - Grobbee, Diederick E.
AU - Onland-Moret, N. Charlotte
AU - Bots, Michiel L.
AU - Wain, Louise V.
AU - Elliott, Katherine S.
AU - Teumer, Alexander
AU - Luan, Jian'an
AU - Lucas, Gavin
AU - Kuusisto, Johanna
AU - Burton, Paul R.
AU - Hadley, David
AU - McArdle, Wendy L.
AU - Brown, Morris
AU - Dominiczak, Anna
AU - Newhouse, Stephen J.
AU - Webster, John
AU - Zeggini, Eleftheria
AU - Beckmann, Jacques S.
AU - Lim, Noha
AU - Song, Kijoung
AU - Vollenweider, Peter
AU - Waeber, Gerard
AU - Waterworth, Dawn M.
AU - Yuan, Xin
AU - Groop, Leif
AU - Orho-Melander, Marju
AU - Allione, Alessandra
AU - Di Gregorio, Alessandra
AU - Guarrera, Simonetta
AU - Panico, Salvatore
AU - Ricceri, Fulvio
AU - Romanazzi, Valeria
AU - Sacerdote, Carlotta
AU - Vineis, Paolo
AU - Barroso, Inês
AU - Luben, Robert N.
AU - Crawford, Gabriel J.
AU - Jousilahti, Pekka
AU - Perola, Markus
AU - Boehnke, Michael
AU - Bonnycastle, Lori L.
AU - Jackson, Anne U.
AU - Mohlke, Karen L.
AU - Stringham, Heather M.
AU - Valle, Timo T.
AU - Willer, Cristen J.
AU - Bergman, Richard N.
AU - Morken, Mario A.
AU - Döring, Angela
AU - Org, Elin
AU - Pfeufer, Arne
AU - Marrugat, Jaume
AU - Subirana, Isaac
AU - Freimer, Nelson B.
AU - Hartikainen, Anna Liisa
AU - McCarthy, Mark I.
AU - O'Reilly, Paul F.
AU - Peltonen, Leena
AU - Pouta, Anneli
AU - de Jong, Paul E.
AU - Snieder, Harold
AU - van Gilst, Wiek H.
AU - Clarke, Robert
AU - Goel, Anuj
AU - Hamsten, Anders
AU - Peden, John F.
AU - Seedorf, Udo
AU - Syvänen, Ann Christine
AU - Tognoni, Giovanni
AU - Lakatta, Edward G.
AU - Sanna, Serena
AU - Scheet, Paul
AU - Schlessinger, David
AU - Scuteri, Angelo
AU - Dörr, Marcus
AU - Ernst, Florian
AU - Felix, Stephan B.
AU - Homuth, Georg
AU - Lorbeer, Roberto
AU - Reffelmann, Thorsten
AU - Rettig, Rainer
AU - Völker, Uwe
AU - Galan, Pilar
AU - Gut, Ivo G.
AU - Hercberg, Serge
AU - Mark Lathrop, G.
AU - Zelenika, Diana
AU - Williams, Frances M.
AU - Zhai, Guangju
AU - Laakso, Markku
AU - Forouhi, Nita G.
AU - Völzke, Henry
AU - Uiterwaal, Cuno S.
AU - van der Schouw, Yvonne T.
AU - Numans, Mattijs E.
AU - Matullo, Giuseppe
AU - Navis, Gerjan
AU - Berglund, Göran
AU - Bingham, Sheila A.
AU - Kooner, Jaspal S.
AU - Connell, John M.
AU - Bandinelli, Stefania
AU - Ferrucci, Luigi
AU - Watkins, Hugh
AU - Spector, Tim D.
AU - Tuomilehto, Jaakko
AU - Strachan, David P.
AU - Laan, Maris
AU - Meneton, Pierre
AU - Uda, Manuela
AU - Jarvelin, Marjo Riitta
AU - Loos, Ruth J.F.
AU - Elliott, Paul
AU - Abecasis, Goncalo R.
AU - Caulfield, Mark
AU - Munroe, Patricia B.
AU - Steinthorsdottir, Valgerdur
AU - Morris, Andrew P.
AU - Dina, Christian
AU - Welch, Ryan P.
AU - Huth, Cornelia
AU - Aulchenko, Yurii S.
AU - McCulloch, Laura J.
AU - Ferreira, Teresa
AU - Grallert, Harald
AU - Amin, Najaf
AU - Wu, Guanming
AU - Raychaudhuri, Soumya
AU - McCarroll, Steve A.
AU - Langenberg, Claudia
AU - Hofmann, Oliver M.
AU - Dupuis, Josée
AU - Qi, Lu
AU - Segrè, Ayellet V.
AU - van Hoek, Mandy
AU - Navarro, Pau
AU - Ardlie, Kristin
AU - Balkau, Beverley
AU - Benediktsson, Rafn
AU - Bennett, Amanda J.
AU - Blagieva, Roza
AU - Bengtsson Boström, Kristina
AU - Bravenboer, Bert
AU - Burtt, Noël P.
AU - Charpentier, Guillaume
AU - Chines, Peter S.
AU - Cornelis, Marilyn
AU - Couper, David J.
AU - Crawford, Gabe
AU - Doney, Alex S.F.
AU - Elliott, Amanda L.
AU - Elliott, Amanda L.
AU - Erdos, Michael R.
AU - Fox, Caroline S.
AU - Franklin, Christopher S.
AU - Ganser, Martha
AU - Grarup, Niels
AU - Green, Todd
AU - Griffin, Simon
AU - Groves, Christopher J.
AU - Guiducci, Candace
AU - Hadjadj, Samy
AU - Hassanali, Neelam
AU - Herder, Christian
AU - Isomaa, Bo
AU - Johnson, Paul R.V.
AU - Jørgensen, Torben
AU - Kao, Wen H.L.
AU - Klopp, Norman
AU - Kraft, Peter
AU - Lauritzen, Torsten
AU - Lieverse, Aloysius
AU - Lindgren, Cecilia M.
AU - Lyssenko, Valeriya
AU - Marre, Michel
AU - Midthjell, Kristian
AU - Narisu, Narisu
AU - Owen, Katharine R.
AU - Payne, Felicity
AU - Perry, John R.B.
AU - Petersen, Ann Kristin
AU - Platou, Carl
AU - Proença, Christine
AU - Prokopenko, Inga
AU - Rathmann, Wolfgang
AU - William Rayner, N.
AU - Robertson, Neil R.
AU - Rocheleau, Ghislain
AU - Roden, Michael
AU - Sampson, Michael J.
AU - Saxena, Richa
AU - Shields, Beverley M.
AU - Shrader, Peter
AU - Sigurdsson, Gunnar
AU - Sparsø, Thomas
AU - Strassburger, Klaus
AU - Sun, Qi
AU - Swift, Amy J.
AU - Thorand, Barbara
AU - Tichet, Jean
AU - Tuomi, Tiinamaija
AU - van Dam, Rob M.
AU - van Haeften, Timon W.
AU - van Herpt, Thijs
AU - van Vliet-Ostaptchouk, Jana V.
AU - Bragi Walters, G.
AU - Weedon, Michael N.
AU - Cauchi, Stephane
AU - Gloyn, Anna L.
AU - Gyllensten, Ulf
AU - Hansen, Torben
AU - Hide, Winston A.
AU - Hitman, Graham A.
AU - Hunter, David J.
AU - Hveem, Kristian
AU - Morris, Andrew D.
AU - Palmer, Colin N.A.
AU - Pramstaller, Peter P.
AU - Rudan, Igor
AU - Sijbrands, Eric
AU - Stein, Lincoln D.
AU - Uitterlinden, Andre
AU - Walker, Mark
AU - Watanabe, Richard M.
AU - Boehm, Bernhard O.
AU - Campbell, Harry
AU - Daly, Mark J.
AU - Hattersley, Andrew T.
AU - Hu, Frank B.
AU - Meigs, James B.
AU - Pankow, James S.
AU - Pedersen, Oluf
AU - Florez, Jose C.
AU - Frayling, Timothy M.
AU - Sladek, Rob
AU - Wilson, James F.
AU - Froguel, Philippe
AU - van Duijn, Cornelia M.
AU - Blair, Ross D.
AU - Hill, Andrew A.
AU - Gerry Hill, B.
AU - Lewis, David R.
AU - McNoe, Les A.
AU - Merriman, Tony R.
AU - Naik, Dilip K.
AU - Vicky Phillips, L.
AU - Thomson, Ian A.
AU - Topless, Ruth
AU - Vasudevan, Thodur M.
AU - Yu, Grace
N1 - Funding Information: This study was funded by the Wellcome Trust (number 084695). This study makes use of data generated by the WTCCC. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk . Funding for the WTCCC project was provided by the Wellcome Trust under award 076113 and 085475. Further funding was provided by the Higher Education Funding Council for England (M.J.B.), Health Research Council of New Zealand (08/075) (Vascular Research Consortium of New Zealand), National Health Medical Research Council (NHMRC) and the Office of Health and Medical Research (J.G.); Swedish Research Council, Swedish Heart-Lung foundation, the European Commission (FAD, Health-F2-2008-200647), a donation by Fredrik Lundberg (for the expression study); National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' National Health Service (NHS) Foundation Trust (R.C.), NHMRC (Australia), The Dunhill Medical Trust (Leicester), and the Garfield Weston Trust for Medical Research into Heart Surgery (Leeds) (provided additional funding for source cohorts); the European Community's Seventh Framework Programme (FP7/2007-2013); Fighting Aneurysmal Disease Project grant agreement HEALTH-F2-2008-200647 (provided replication data sets from Iceland and Netherlands); St George's Hospital NHS Trust Special Trustees and the Peter and Sonia Field Charitable Trust (A.H.C.); British Heart Foundation Clinical Training Fellowship (FS/11/16/28696) (S.E.H.); British Heart Foundation (RG2008/08) (S.E.H., A.J.S., J.P.); Netherlands Heart Foundation (2009T001) (A.F.B.); British Heart Foundation chairs (S.E.H and N.J.S.); and Leicester NIHR Biomedical Research Unit in Cardiovascular Disease (M.J.B., R.D.S. and N.J.S.). deCODE genetics is a biotechnology company, and authors employed by deCODE own stock or stock options in the company.
PY - 2011/11/11
Y1 - 2011/11/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84945173643&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84945173643&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2011.10.002
DO - 10.1016/j.ajhg.2011.10.002
M3 - Article
C2 - 22055160
AN - SCOPUS:84945173643
SN - 0002-9297
VL - 89
SP - 619
EP - 627
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -