Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

• Published in: Circulation research Vol. 120; no. 2; pp. 341 - 353
• Main Authors: Tromp, Gerard, Gretarsdottir, Solveig, Baas, Annette F, Giusti, Betti, Strauss, Ewa, van‘t Hof, Femke N.G, Webb, Thomas R, Erdman, Robert, Ritchie, Marylyn D, Elmore, James R, Verma, Anurag, Pendergrass, Sarah, Kullo, Iftikhar J, Peissig, Peggy L, Verma, Shefali S, Malinowski, Jennifer, Rasmussen-Torvik, Laura J, Borthwick, Kenneth M, Smelser, Diane T, Crosslin, David R, de Andrade, Mariza, Ryer, Evan J, McCarty, Catherine A, Böttinger, Erwin P, Pacheco, Jennifer A, Carrell, David S, Franklin, David P, Phillips, Victoria L, Williams, Michael J.A, Wei, Wenhua, Blair, Ross, Hill, Andrew A, Vasudevan, Thodor M, Lewis, David R, Thomson, Ian A, Krysa, Jo, Hill, Geraldine B, Roake, Justin, Merriman, Tony R, Oszkinis, Grzegorz, Galora, Silvia, Saracini, Claudia, Abbate, Rosanna, Pulli, Raffaele, Saratzis, Athanasios, Verissimo, Ana R, Bumpstead, Suzannah, Badger, Stephen A, Clough, Rachel E, Cockerill, Gillian, Hafez, Hany, Scott, D. Julian A, Futers, T Simon, Romaine, Simon P.R, Griffin, Kathryn J, Bailey, Marc A, Smith, Alberto, van Bockxmeer, Frank M, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Blankensteijn, Jan D, Teijink, Joep A.W, de Graaf, Jacqueline, Kiemeney, Lambertus A, Lindholt, Jes S, Hughes, Anne, Bradley, Declan T, Stirrups, Kathleen, Golledge, Jonathan, Norman, Paul E, Powell, Janet T, Humphries, Steve E, Goodall, Alison H, Nelson, Christopher P, Sakalihasan, Natzi, Courtois, Audrey, Ferrell, Robert E, Eriksson, Per, Folkersen, Lasse, Franco-Cereceda, Anders, Eicher, John D, Johnson, Andrew D, Betsholtz, Christer, Ruusalepp, Arno, Franzén, Oscar, Schadt, Eric E, Lipovich, Leonard, Verhoeven, Eric L, Zeebregts, Clark J, Geelkerken, Robert H, van Sambeek, Marc R, van Sterkenburg, Steven M, de Vries, Jean-Paul, Stefansson, Kari, de Bakker, Paul I.W, Deloukas, Panos, Harrison, Seamus C, van Rij, Andre M, Samani, Nilesh J, Bown, Matthew J
• Format: Journal Article Web Resource
• Language: English
• Published: United States American Heart Association, Inc 20.01.2017; Lippincott Williams & Wilkins Ovid Technologies; Lippincott Williams & Wilkins
• Subjects: abdominal; Aneurysms; aortic aneurysm; Aortic Aneurysm, Abdominal - diagnosis; Aortic Aneurysm, Abdominal - epidemiology; Aortic Aneurysm, Abdominal - genetics; Aortic aneurysms; Blood pressure; Cardiovascular disease; Cardiovascular diseases; Chirurgie; Chromosome 1; Chromosome 13; Clinical Track; computational biology; Coronary artery; Diabetes mellitus; Gelatinase B; Genetic Loci - genetics; Genetic Predisposition to Disease - epidemiology; Genetic Predisposition to Disease - genetics; Genetic Variation - genetics; genetics; Genome-wide association studies; genome-wide association study; Genome-Wide Association Study - methods; Genome-Wide Association Study - trends; Genomes; Heart diseases; Heritability; Human health sciences; Humans; Interleukin 6; Interleukin 6 receptors; Lipids; matrix metalloproteinases; Medicin och hälsovetenskap; Meta-analysis; Risk factors; Sciences de la santé humaine; Single-nucleotide polymorphism; Surgery; computational biology; meta-analysis; genetics; matrix metalloproteinases; aortic aneurysm, abdominal; genome-wide association study
• ISSN: 0009-7330; 1524-4571; 1524-4571
• DOI: 10.1161/CIRCRESAHA.116.308765

RATIONALE:Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. OBJECTIVE:To identify additional AAA risk loci using data from all available genome-wide association studies. METHODS AND RESULTS:Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. CONCLUSIONS:The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.