Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism

Anna Helgadottir*, Solveig Gretarsdottir, Gudmar Thorleifsson, Hilma Holm, Riyaz S. Patel, Thorarinn Gudnason, Gregory T. Jones, Andre M. Van Rij, Danny J. Eapen, Annette F. Baas, David Alexandre Tregouet, Pierre Emmanuel Morange, Joseph Emmerich, Bengt Lindblad, Anders Gottster, Lambertus A. Kiemeny, Jes S. Lindholt, Natzi Sakalihasan, Robert E. Ferrell, David J. CareyJames R. Elmore, Philip S. Tsao, Niels Grarup, Torben Jørgensen, Daniel R. Witte, Torben Hansen, Oluf Pedersen, Roberto Pola, Eleonora Gaetani, Hulda B. Magnadottir, Cisca Wijmenga, Gerard Tromp, Antti Ronkainen, Ynte M. Ruigrok, Jan D. Blankensteijn, Thomas Mueller, Philip S. Wells, Javier Corral, Jose Manuel Soria, Juan Carlos Souto, John F. Peden, Shapour Jalilzadeh, Bongani M. Mayosi, Bernard Keavney, Rona J. Strawbridge, Maria Sabater-Lleal, Karl Gertow, Damiano Baldassarre, Kristiina Nyyssnen, Rainer Rauramaa, Andries J. Smit, Elmo Mannarino, Philippe Giral, Elena Tremoli, Ulf De Faire, Steve E. Humphries, Anders Hamsten, Vilhelmina Haraldsdottir, Isleifur Olafsson, Magnus K. Magnusson, Nilesh J. Samani, Allan I. Levey, Hugh S. Markus, Konstantinos Kostulas, Martin Dichgans, Klaus Berger, Gregor Kuhlenbumer, E. Bernd Ringelstein, Monika Stoll, Udo Seedorf, Peter M. Rothwell, Janet T. Powell, Helena Kuivaniemi, Pall T. Onundarson, Einar Valdimarsson, Stefan E. Matthiasson, Daniel F. Gudbjartsson, Gumundur Thorgeirsson, Arshed A. Quyyumi, Hugh Watkins, Martin Farrall, Unnur Thorsteinsdottir, Kari Stefansson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

118 Citations (Scopus)


The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene (LPA) on vascular diseases with different atherosclerotic and thrombotic components. It is unclear whether the LPA variants rs10455872 and rs3798220, which correlate with lipoprotein(a) levels and coronary artery disease (CAD), confer susceptibility predominantly via atherosclerosis or thrombosis. The 2 LPA variants were combined and examined as LPA scores for the association with ischemic stroke (and TOAST [Trial of Org 10172 in Acute Stroke Treatment] subtypes) (effective sample size [n e] = 9,396); peripheral arterial disease (n e = 5,215); abdominal aortic aneurysm (n e = 4,572); venous thromboembolism (n e = 4,607); intracranial aneurysm (n e = 1,328); CAD (n e = 12,716), carotid intima-media thickness (n = 3,714), and angiographic CAD severity (n = 5,588). LPA score was associated with ischemic stroke subtype large artery atherosclerosis (odds ratio [OR]: 1.27; p = 6.7 × 10 4), peripheral artery disease (OR: 1.47; p = 2.9 × 10 14), and abdominal aortic aneurysm (OR: 1.23; p = 6.0 × 10 5), but not with the ischemic stroke subtypes cardioembolism (OR: 1.03; p = 0.69) or small vessel disease (OR: 1.06; p = 0.52). Although the LPA variants were not associated with carotid intima-media thickness, they were associated with the number of obstructed coronary vessels (p = 4.8 × 10 12). Furthermore, CAD cases carrying LPA risk variants had increased susceptibility to atherosclerotic manifestations outside of the coronary tree (OR: 1.26; p = 0.0010) and had earlier onset of CAD (1.58 years/allele; p = 8.2 × 10 8) than CAD cases not carrying the risk variants. There was no association of LPA score with venous thromboembolism (OR: 0.97; p = 0.63) or intracranial aneurysm (OR: 0.85; p = 0.15). LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes.

Original languageEnglish
Pages (from-to)722-729
Number of pages8
JournalJournal of the American College of Cardiology
Issue number8
Publication statusPublished - 21 Aug 2012

Bibliographical note

Funding Information:
Work performed at deCODE was funded in part through grants from the U.S. National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health ( R01HL089650-02 ) and the European Community's Seventh Framework Programme FAD ( Fighting Aneurysmal Diseases ) project grant agreement HEALTH-F2-2008-200647 and ENGAGE ( European Network for Genetic and Genomic Epidemiology ) project, grant agreement HEALTH-F4-2007- 201413 . Funding for the New Zealand sample recruitment was provided by the Health Research Council of New Zealand. The MARTHA (MARseille THrombosis Association study) project was supported by a grant from the Program Hospitalier de Recherche Clinique and the FARIVE (Facteurs de Risque et de Récidives de la Maladie Thromboembolique Veineuse) study by grants from the Fondation pour la Recherche Médicale , the Program Hospitalier de recherche Clinique (PHRC 20002; PHRC2009 RENOVA-TV [REcherche de NOuveaux VAriants de susceptibilité à la Thrombose Veineuse]), the Fondation de France, and the Leducq Foundation. The Spanish VTE study was funded by RECAVA (Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares)-RD06/0039. The recruitment of patients with abdominal aortic aneurysm and controls from Belgium, Canada, and Pittsburgh, Pennsylvania, was funded in part by grants from the NHLBI ( HL064310 to H.K. and HL044682 to R.E.F). The sample collection at Geisinger Clinic was funded by a grant from the Pennsylvania Commonwealth Universal Research Enhancement program (to D.J.C.), a grant from the Geisinger Clinical Research Fund (to J.R.E.), and a Grant-In-Aid from the American Heart Association (to D.J.C.). The Geisinger MyCode Project was funded in part by a grant from the Ben Franklin Technology Development Fund of PA . AAA-STOP (Simple Treatment Or Prevention) was supported by a grant from the NIH-NHLBI ( 1P50HL08300 and 1R01HL101388 ). The Danish study was in part supported by The Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care (LuCamp). Collection of data from the Finnish sample with intracranial aneurysm was funded in part by the NINDS (National Institute of Neurological Disease and Stroke) ( NS034395 to G.T.), the American Heart Association, Michigan Affiliate (to G.T.), and the University of Kuopio (to A.R.). The PROCARDIS (PRecOcious Coronary ARtery DISease) study was supported by the European Community Sixth Framework Program ( LSHM-CT-2007-037273 ). Drs. Helgadottir, Watkins, and Farrall acknowledge support from the BHF (British Heart Foundation), Centre of Research Excellence, RE/08/004, as does SEH (BHF PG2008/08 ). Dr. Samani is supported by BHF and is also an NIHR (National Institute for Health Research) Senior Investigator. Dr. Keavney is supported by a BHF Personal Chair. Drs. Watkins and Farrall acknowledge support from the Wellcome Trust core award to the Wellcome Trust Centre for Human Genetics ( 090532/Z/09/Z ). Dr. Baas was supported by the Dr. E. Dekker program of the Netherlands Heart Foundation (2009T001). Dr. Ruigrok was supported by the NWO (Netherlands Organization for Scientific Research) VENI ( Innovational Research Incentives Scheme )) grant 916.10.016 . Dr. Soria was supported by “Programa d'Estabilització d'Investigadors de la Direcció d'Estrategia i Coordinació del Departament de Salut” (Generalitat de Catalunya). The GAIT (Genetic Analysis of Idiopathic Thrombophilia) project was supported by PI-08/0420 , PI-08/0756 , SAF2008/01859 , RECAVA-RD06/0014 and SGR 01068 from Agència de Gestió d'ajuts Universitaris i de Recerca. The IMPROVE (Carotid Intima Media Thickness (IMT) and IMT-PRogression as Predictors of Vascular Events in a High Risk European Population) study was supported by the European Commission (Contract number: QLG1-CT-2002- 00896 ), the Swedish Heart-Lung Foundation, the Swedish Research Council (projects 8691 and 0593), the Knut and Alice Wallenberg Foundation, the Stockholm County Council (project 562183), Academy of Finland (grant # 110413 ), and the British Heart Foundation ( RG2008/014 ). Drs. Helgadottir, Gretarsdottir, Gudbjartsson, Holm, Thorsteindottir, and Thorleifsson are employees of deCODE genetics, a biotechnology company. deCODE genetics intends to incorporate the variants described in this paper into its genetic testing services. Dr. Thorsteindottir reports that she receives stock options from deCODE genetics. Dr. Witte is an employee of Steno Diabetes Center A/S, owned by Novo Nordisk A/S, and reports that he owns shares in Novo Nordisk A/S. Dr. Wells is a member of the advisory boards of Boehringer-Ingelheim, Pfizer, and Bayer. Dr. Ringelstein is a consultant to Boehringer Ingelheim, Sygnis, Neurobiological Technologies, Novartis, Non Nordisk A/S, Sanofi-Aventis, Bayer Vital, Ma Science, Servier, UCB, and Tromminsdorff, and has received travel expenses and honoraria. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Other keywords

  • association
  • atherosclerosis
  • genetic
  • lipoprotein(a)
  • thrombosis


Dive into the research topics of 'Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism'. Together they form a unique fingerprint.

Cite this