Apolipoprotein(a) Genetic Sequence Variants Associated With Systemic Atherosclerosis and Coronary Atherosclerotic Burden But Not With Venous Thromboembolism

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

卷:60

Article

Helgadottir, Anna^1,2,3  Gretarsdottir, Solveig¹  Thorleifsson, Gudmar¹  Holm, Hilma¹  Patel, Riyaz S.^4,5  Gudnason, Thorarinn^6,7  Jones, Gregory T.⁸  van Rij, Andre M.⁸  Eapen, Danny J.⁴  Baas, Annette F.⁹  Tregouet, David-Alexandre^10,11  Morange, Pierre-Emmanuel^12,13  Emmerich, Joseph¹⁴  Lindblad, Bengt¹⁵  Gottsater, Anders¹⁵  Kiemeny, Lambertus A.¹⁶  Lindholt, Jes S.¹⁷  Sakalihasan, Natzi¹⁸  Ferrell, Robert E.¹⁹  Elmore, James R.²⁰  Tsao, Philip S.²¹  Grarup, Niels²²  Jorgensen, Torben²³  Witte, Daniel R.²⁴  Hansen, Torben^22,25  Pedersen, Oluf^22,26,27,28  Pola, Roberto^29,30  Gaetani, Eleonora²⁹  Magnadottir, Hulda B.³¹  Wijmenga, Cisca³²  Ronkainen, Antti³³  Ruigrok, Ynte M.³⁴  Blankensteijn, Jan D.^35,36  Mueller, Thomas³⁷  Wells, Philip S.³⁸  Corral, Javier³⁹  Manuel Soria, Jose⁴⁰  Carlos Souto, Juan⁴¹  Peden, John F.⁴²  Jalilzadeh, Shapour⁴²  Mayosi, Bongani M.⁴³  Keavney, Bernard⁴⁴  Strawbridge, Rona J.⁴⁵  Sabater-Lleal, Maria⁴⁵  Gertow, Karl⁴⁵  Baldassarre, Damiano⁴⁶  Nyyssonen, Kristiina⁴⁷  Rauramaa, Rainer⁴⁸  Smit, Andries J.⁴⁹  Mannarino, Elmo⁵⁰  Giral, Philippe⁶⁶  Tremoli, Elena⁴⁶  de Faire, Ulf⁵¹  Humphries, Steve E.⁵²  Hamsten, Anders⁴⁵  Magnusson, Magnus K.³  Samani, Nilesh J.^53,54  Levey, Allan I.⁴  Markus, Hugh S.⁵⁵  Kostulas, Konstantinos⁵⁶  Dichgans, Martin⁵⁷  Berger, Klaus⁵⁸  Kuhlenbaeumer, Gregor⁵⁹  Ringelstein, E. Bernd⁶⁰  Stoll, Monika⁶¹  Seedorf, Udo⁶¹  Rothwell, Peter M.⁶²  Powell, Janet T.⁶³  Onundarson, Pall T.³  Valdimarsson, Einar⁶⁴  Matthiasson, Stefan E.⁶⁵  Gudbjartsson, Daniel F.¹  Thorgeirsson, Guomundur^3,6,7  Quyyumi, Arshed A.⁴  Watkins, Hugh⁴²  Farrall, Martin⁴²  Thorsteinsdottir, Unnur^1,3  Stefansson, Kari^1,3 

[1] DeCODE Genet, Populat Genom, IS-101 Reykjavik, Iceland

[2] Univ Iceland, Inst Human Genet, Reykjavik, Iceland

[3] Univ Iceland, Fac Med, Reykjavik, Iceland

[4] Emory Univ, Sch Med, Atlanta, GA USA

[5] Cardiff Univ, Cardiff, S Glam, Wales

[6] Landspitali Univ Hosp, Dept Cardiol, Reykjavik, Iceland

[7] Landspitali Univ Hosp, Cardiovasc Res Inst, Reykjavik, Iceland

[8] Univ Otago, Dunedin Sch Med, Dept Surg, Otago, New Zealand

[9] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands

[10] Univ Paris 06, Paris, France

[11] ICAN Inst, INSERM UMRS 937, Paris, France

[12] Aix Marseille Univ, Marseille, France

[13] INSERM UMRS 1062, Marseille, France

[14] Univ Paris 05, Hop Europeen Georges Pompidou, INSERM UMRS 765, Med Vasc HTA, Paris, France

[15] Lund Univ, Dept Vasc Dis, Skane Univ Hosp, Malmo, Sweden

[16] Radboud Univ Nijmegen, Dept Epidemiol Biostat & HTA, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[17] Viborg Hosp, Vasc Res Unit, Viborg, Denmark

[18] Univ Hosp Liege, Liege, Belgium

[19] Univ Pittsburgh, Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15260 USA

[20] Weis Ctr Res, Geisinger Clin, Dept Vasc Surg, Danville, PA 17822 USA

[21] Stanford Univ, Div Cardiovasc Med, Sch Med, Stanford, CA 94305 USA

[22] Univ Copenhagen, Fac Hlth Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark

[23] Glostrup Cty Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark

[24] Steno Diabet Ctr, DK-2820 Gentofte, Denmark

[25] Univ So Denmark, Odense, Denmark

[26] Hagedorn Res Inst, Gentofte, Denmark

[27] Univ Copenhagen, Inst Biomed Sci, Fac Hlth Sci, Copenhagen, Denmark

[28] Univ Aarhus, Fac Hlth Sci, Aarhus, Denmark

[29] Catholic Univ, Lab Vasc Biol & Genet, Dept Med, A Gemelli Univ Hosp,Sch Med, Rome, Italy

[30] Tufts Univ, Sch Med, Dept Med, Div Cardiovasc Res,Caritas St Elizabeths Med Ctr, Boston, MA 02111 USA

[31] Upper Valley Neurol Neurosurg, Lebanon, NH USA

[32] Univ Groningen, Dept Genet, Univ Med Ctr Groningen, Groningen, Netherlands

[33] Kuopio Univ Hosp, Dept Neurosurg, SF-70210 Kuopio, Finland

[34] Univ Med Ctr Utrecht, Utrecht Stroke Ctr, Dept Neurol & Neurosurg, Rudolf Magnus Inst Neurosci, Utrecht, Netherlands

[35] Vrije Univ Amsterdam Med Ctr, Div Surg, Amsterdam, Netherlands

[36] Radboud Univ Nijmegen, Dept Vasc Surg, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[37] Konventhosp Barmherzige Brueder, Dept Lab Med, Linz, Austria

[38] Univ Ottawa, Div Hematol, Ottawa Hosp, Dept Med,Res Inst, Ottawa, ON, Canada

[39] Univ Murcia, Dept Med, Ctr Reg Hemodonac, Murcia, Spain

[40] Hosp Santa Creu i St Pau, Unit Genom Complex Dis, Res Inst, Barcelona, Spain

[41] Hosp Santa Creu i St Pau, Haemostasis & Thrombosis Unit, Dept Haematol, Barcelona, Spain

[42] Univ Oxford, Dept Cardiovasc Med, Wellcome Trust Ctr Human Genet, Oxford, England

[43] Univ Cape Town, Fac Hlth Sci, ZA-7925 Cape Town, South Africa

[44] Newcastle Univ, Inst Genet Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[45] Karolinska Inst, Atherosclerosis Res Unit, Dept Med Solna, Stockholm, Sweden

[46] Univ Milan, Dipartimento Sci Farmacol & Biomol, Ctr Cardiol Monzino, IRCCS, Milan, Italy

[47] Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland

[48] Fdn Res Hlth Exercise & Nutr, Kuopio Res Inst Exercise Med, Kuopio, Finland

[49] Univ Med Ctr Groningen, Dept Med, NL-9713 AV Groningen, Netherlands

[50] Univ Perugia, Dept Clin & Expt Med, I-06100 Perugia, Italy

[51] Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, S-10401 Stockholm, Sweden

[52] UCL, Ctr Cardiovasc Genet, BHF Labs, Inst Cardiovasc Sci, London, England

[53] Univ Leicester, Dept Cardiovasc Sci, Glenfield Hosp, Clin Sci Wing, Leicester, Leics, England

[54] St Georges Univ London, Leicester NIHR Biomed Res Unit Cardiovasc Dis, London, England

[55] St Georges Univ London, Stroke & Dementia Res Ctr, London, England

[56] Karolinska Univ Hosp, Karolinska Inst, Dept Neurol, Huddinge, Sweden

[57] Univ Munich, Klinikum Univ Munchen, Inst Stroke & Dementia Res, Munich, Germany

[58] Univ Munster, Inst Epidemiol & Social Med, Munster, Germany

[59] Univ Kiel, Inst Expt Med, Kiel, Germany

[60] Univ Munster, Dept Neurol, D-4400 Munster, Germany

[61] Univ Munster, Leibniz Inst Arteriosclerosis Res, Munster, Germany

[62] John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Oxford OX3 9DU, England

[63] Imperial Coll Charing Cross, Vasc Surg Res Grp, London, England

[64] Landspitali Univ Hosp, Dept Neurol, Reykjavik, Iceland

[65] Laekning, Med Clin, Reykjavik, Iceland

[66] Grp Hop Pitie Salpetriere, AP HP, Serv Endocrinol Metab, Unites Prevent Cardiovasc, Paris, France

关键词: association;    atherosclerosis;    genetic;    lipoprotein(a);    thrombosis;   

DOI  :  10.1016/j.jacc.2012.01.078

来源: Elsevier

【 摘 要 】

Objectives 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. Background 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. Methods 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 (ne = 4,572); venous thromboembolism (ne = 4,607); intracranial aneurysm (ne = 1,328); CAD (n(e) = 12,716), carotid intima-media thickness (n = 3,714), and angiographic CAD severity (n = 5,588). Results LPA score was associated with ischemic stroke subtype large artery atherosclerosis (odds ratio [OR]: 1.27; p = 6.7 X 10(-4)), peripheral artery disease (OR: 1.47; p = 2.9 x 10(-14)), and abdominal aortic aneurysm (OR: 1.23; p = 6.0 x 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 x 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 x 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). Conclusions LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes. (J Am Coll Cardiol 2012; 60: 722-9) (C) 2012 by the American College of Cardiology Foundation

【 授权许可】

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