Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1 |
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| Authors: | Bown Matthew J Jones Gregory T Harrison Seamus C Wright Benjamin J Bumpstead Suzannah Baas Annette F Gretarsdottir Solveig Badger Stephen A Bradley Declan T Burnand Kevin Child Anne H Clough Rachel E Cockerill Gillian Hafez Hany Scott D Julian A Futers Simon Johnson Anne Sohrabi Soroush Smith Alberto Thompson Matthew M van Bockxmeer Frank M Waltham Matthew Matthiasson Stefan E Thorleifsson Gudmar Thorsteinsdottir Unnur Blankensteijn Jan D Teijink Joep A W Wijmenga Cisca de Graaf Jacqueline Kiemeney Lambertus A Assimes Themistocles L |
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| Institution: | 1Department of Cardiovascular Sciences, University of Leicester, Leicester LE2 7LX, UK;2Department of Anatomy, University of Otago, Dunedin 9054, New Zealand;3Cardiovascular Medicine, University College London, London WC1E 6JF, UK;4Genetics of Complex Traits in Humans Group, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK;5Medical Genetics Research Section, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands;6deCODE Genetics and University of Iceland Faculty of Medicine, IS-101 Reykjavik, Iceland;7School of Medicine, Queens University, Belfast BT7 1NN, UK;8Department of Vascular Surgery, King's College London, London WC2R 2LS, UK;9Department of Vascular Surgery, St George's University of London, London SW17 0RE, UK;10Department of Vascular Surgery, St Richard's Hospital, Chichester PO19 6SE, UK;11Leeds Institute of Genetics, Health and Technology, University of Leeds, Leeds LS2 9JT, UK;12Department of Surgery, University of Western Australia, Crawley WA6009, Australia;13Laekning Medical Clinics, IS-108 Reykjavik, Iceland;14Department of Vascular Surgery Vrije Universiteit Medical Center, 1007 MB Amsterdam, The Netherlands;15Department of Vascular Surgery, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands;16Department of Genetics, University Medical Centre Groningen, 9700 RB Groningen, The Netherlands;17Department of Internal Medicine, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands;18Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305-5101, USA;19Division of Cardiology, University of Ottawa Heart Institute, Ottawa K1Y 4W7, Canada;20Cardiovascular Medicine, Karolinska Institute, SE-171 77 Stockholm, Sweden;21Department of Clinical Biochemistry, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark;22Department of Vascular Surgery, Viborg Hospital, 8800 Viborg, Denmark;23Vascular Biology Unit, James Cook University, Townsville QLD 4811, Australia;24Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK;25Department of Health Sciences, University of Leicester, Leicester LE2 7LX, UK |
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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. |
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