Journal
CIRCULATION RESEARCH
Volume 120, Issue 2, Pages 341-+Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.116.308765
Keywords
aortic aneurysm, abdominal; computational biology; genetics; genome-wide association study; matrix metalloproteinases; meta-analysis
Funding
- Wellcome Trust [076113, 085475]
- Health Research Council of New Zealand [08-75, 14-155]
- National Heart, Lung, and Blood Institute, National Institutes of Health [HL064310, HL044682]
- Pennsylvania Commonwealth Universal Research Enhancement program
- Geisinger Clinical Research Fund
- American Heart Association
- Ben Franklin Technology Development Fund of Pennsylvania
- National Institute for Health Research
- National Institute of General Medical Sciences [U01HG004438, U01HG004424, U01HG004610, U01HG006375, U01HG004608, U01HG006389, U01HG04599, U01HG006379, U01HG004609, U01HG006388, U01HG04603, U01HG006378, U01HG006385, U01HG006382, U01HG006380]
- Netherlands Organization of Scientific Research (NWO) Investments [175.010.2005.011, 911-03-012]
- Research Institute for Diseases in the Elderly [014-93-015, RIDE2]
- Netherlands Genomics Initiative/NWO [050-060-810]
- Ente Cassa di Risparmio di Firenze to Fiorgen Foundation, Florence, Italy
- Italian Ministry of Health
- National Science Centre in Poland [6P05A03921, NN403250440]
- Marriot Award for Individualized Medicine
- Mayo Center of Individualized Medicine
- National Center for Research Resources [UL1 RR024975-01]
- National Center for Advancing Translational Sciences [UL1 TR000445-06]
- Swedish Research Council
- Swedish Heart-Lung Foundation
- Leducq Foundation (MIBAVA)
- British Heart Foundation [PG08/008]
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- European Union 6th Framework Programme [LSHM-CT-2006-037593]
- BHF clinical training fellowship [FS/11/16/28696]
- Astra-Zeneca Translational Science Centre-Karolinska Institutet
- University of Tartu (SP1GVARENG)
- Estonian Research Council [ETF 8853]
- Torsten and Ragnar Soderberg Foundation
- Knut and Alice Wallenberg Foundation
- American Heart Association [A14SFRN20840000]
- National Institute of Health [R01HL71207]
- Academy of Medical Sciences (AMS) [AMS-SGCL9-Clough] Funding Source: researchfish
- British Heart Foundation [RG/14/5/30893, FS/11/16/28696] Funding Source: researchfish
- National Institute for Health Research [ACF-2015-02-009(1), ACF-2016-02-008, NF-SI-0611-10170, CL-2014-11-001] Funding Source: researchfish
- Public Health Agency [EAT/3976/08] Funding Source: researchfish
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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 loci: 1q32.3 (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.
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