Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study

Stephen Zewinger; Marcus E Kleber; Vinicius Tragante; Raymond O McCubrey; Amand F Schmidt; Kenan Direk; Ulrich Laufs; Christian Werner; Wolfgang Koenig; Dietrich Rothenbacher; Ute Mons; Lutz P Breitling; Herrmann Brenner; Richard T Jennings; Ioannis Petrakis; Sarah Triem; Mira Klug; Alexandra Filips; Stefan Blankenberg; Christoph Waldeyer; Christoph Sinning; Renate B Schnabel; Karl J Lackner; Efthymia Vlachopoulou; Ottar Nygård; Gard Frodahl Tveitevåg Svingen; Eva Ringdal Pedersen; Grethe S Tell; Juha Sinisalo; Markku S Nieminen; Reijo Laaksonen; Stella Trompet; Roelof A J Smit; Naveed Sattar; J Wouter Jukema; Heinrich V Groesdonk; Graciela Delgado; Tatjana Stojakovic; Anna P Pilbrow; Vicky A Cameron; A Mark Richards; Robert N Doughty; Yan Gong; Rhonda Cooper-DeHoff; Julie Johnson; Markus Scholz; Frank Beutner; Joachim Thiery; J Gustav Smith; Ragnar O Vilmundarson; Ruth McPherson; Alexandre F R Stewart; Sharon Cresci; Petra A Lenzini; John A Spertus; Oliviero Olivieri; Domenico Girelli; Nicola I Martinelli; Andreas Leiherer; Christoph H Saely; Heinz Drexel; Axel Mündlein; Peter S Braund; Christopher P Nelson; Nilesh J Samani; Daniel Kofink; Imo E Hoefer; Gerard Pasterkamp; Arshed A Quyyumi; Yi-An Ko; Jaana A Hartiala; Hooman Allayee; W H Wilson Tang; Stanley L Hazen; Niclas Eriksson; Claes Held; Emil Hagström; Lars Wallentin; Axel Åkerblom; Agneta Siegbahn; Igor Karp; Christopher Labos; Louise Pilote; James C Engert; James M Brophy; George Thanassoulis; Peter Bogaty; Wojciech Szczeklik; Marcin Kaczor; Marek Sanak; Salim S Virani; Christie M Ballantyne; Vei-Vei Lee; Eric Boerwinkle; Michael V Holmes; Benjamin D Horne; Aroon Hingorani; Folkert W Asselbergs; Riyaz S Patel; GENIUS-CHD consortium; Bernhard K Krämer; Hubert Scharnagl; Danilo Fliser; Winfried März; Thimoteus Speer

doi:10.1016/S2213-8587(17)30096-7

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study

Lancet Diabetes Endocrinol. 2017 Jul;5(7):534-543. doi: 10.1016/S2213-8587(17)30096-7. Epub 2017 May 26.

Authors

Stephen Zewinger¹, Marcus E Kleber², Vinicius Tragante³, Raymond O McCubrey⁴, Amand F Schmidt⁵, Kenan Direk⁵, Ulrich Laufs⁶, Christian Werner⁶, Wolfgang Koenig⁷, Dietrich Rothenbacher⁸, Ute Mons⁹, Lutz P Breitling⁹, Herrmann Brenner¹⁰, Richard T Jennings¹, Ioannis Petrakis¹, Sarah Triem¹, Mira Klug¹, Alexandra Filips¹, Stefan Blankenberg¹¹, Christoph Waldeyer¹¹, Christoph Sinning¹¹, Renate B Schnabel¹¹, Karl J Lackner¹², Efthymia Vlachopoulou¹³, Ottar Nygård¹⁴, Gard Frodahl Tveitevåg Svingen¹⁵, Eva Ringdal Pedersen¹⁶, Grethe S Tell¹⁷, Juha Sinisalo¹⁸, Markku S Nieminen¹⁸, Reijo Laaksonen¹⁹, Stella Trompet²⁰, Roelof A J Smit²⁰, Naveed Sattar²¹, J Wouter Jukema²², Heinrich V Groesdonk²³, Graciela Delgado²⁴, Tatjana Stojakovic²⁵, Anna P Pilbrow²⁶, Vicky A Cameron²⁶, A Mark Richards²⁷, Robert N Doughty²⁸, Yan Gong²⁹, Rhonda Cooper-DeHoff²⁹, Julie Johnson²⁹, Markus Scholz³⁰, Frank Beutner³¹, Joachim Thiery³², J Gustav Smith³³, Ragnar O Vilmundarson³⁴, Ruth McPherson³⁴, Alexandre F R Stewart³⁴, Sharon Cresci³⁵, Petra A Lenzini³⁶, John A Spertus³⁷, Oliviero Olivieri³⁸, Domenico Girelli³⁸, Nicola I Martinelli³⁸, Andreas Leiherer³⁹, Christoph H Saely³⁹, Heinz Drexel⁴⁰, Axel Mündlein⁴¹, Peter S Braund⁴², Christopher P Nelson⁴², Nilesh J Samani⁴², Daniel Kofink³, Imo E Hoefer⁴³, Gerard Pasterkamp⁴³, Arshed A Quyyumi⁴⁴, Yi-An Ko⁴⁴, Jaana A Hartiala⁴⁵, Hooman Allayee⁴⁵, W H Wilson Tang⁴⁶, Stanley L Hazen⁴⁶, Niclas Eriksson⁴⁷, Claes Held⁴⁷, Emil Hagström⁴⁷, Lars Wallentin⁴⁷, Axel Åkerblom⁴⁷, Agneta Siegbahn⁴⁸, Igor Karp⁴⁹, Christopher Labos⁵⁰, Louise Pilote⁵¹, James C Engert⁵⁰, James M Brophy⁵⁰, George Thanassoulis⁵⁰, Peter Bogaty⁵², Wojciech Szczeklik⁵³, Marcin Kaczor⁵³, Marek Sanak⁵³, Salim S Virani⁵⁴, Christie M Ballantyne⁵⁵, Vei-Vei Lee⁵⁶, Eric Boerwinkle⁵⁷, Michael V Holmes⁵⁸, Benjamin D Horne⁴, Aroon Hingorani⁵, Folkert W Asselbergs⁵⁹, Riyaz S Patel⁵; GENIUS-CHD consortium; Bernhard K Krämer²⁴, Hubert Scharnagl²⁵, Danilo Fliser¹, Winfried März⁶⁰, Thimoteus Speer¹

Affiliations

¹ Department of Internal Medicine IV, Saarland University Hospital, Homburg/Saar, Germany.
² Fifth Department of Medicine, University Heidelberg, Mannheim, Germany; Institute of Nutrition, Friedrich-Schiller University, Jena, Germany.
³ Department of Cardiology, Heart and Lungs Division, UMC Utrecht, Utrecht, Netherlands.
⁴ Intermountain Heart Institute, Intermountain Medical Center, University of Utah School of Medicine, Salt Lake City, UT, USA.
⁵ Institute of Cardiovascular Science Facultyof Population Health Science, University College London, London, UK.
⁶ Department of Internal Medicine III, Saarland University Hospital, Homburg/Saar, Germany.
⁷ Department of Internal Medicine II-Cardiology, University of Ulm Medical Centre, Ulm, Germany; Deutsches Herzzentrum München, Technische Universität München, Munich, Germany; German Centre of Cardiovascular Research (DZHK), Partner site Munich Heart Alliance, Munich, Germany.
⁸ Division of Clinical Epidemiology and Ageing Research, German Cancer Centre (DKFZ), Heidelberg, Germany; Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany.
⁹ Division of Clinical Epidemiology and Ageing Research, German Cancer Centre (DKFZ), Heidelberg, Germany.
¹⁰ Network Ageing Research, University Heidelberg, Mannheim, Germany; Division of Clinical Epidemiology and Ageing Research, German Cancer Centre (DKFZ), Heidelberg, Germany.
¹¹ University Heart Centre Hamburg, Clinic for General and Interventional Cardiology, Hamburg, Germany; German Centre for Cardiovascular Research (DZHK e.V.), partner site Hamburg/Kiel/Lübeck, Germany.
¹² Institute of Clinical Chemistry and Laboratory Medicine, University Medical Centre Mainz, Germany.
¹³ Transplantation Laboratory, Haartman Institute, University of Helsinki, Finland.
¹⁴ Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway.
¹⁵ Department of Heart Disease, Haukeland University Hospital, Bergen, Norway.
¹⁶ Department of Clinical Science, University of Bergen, Bergen, Norway.
¹⁷ Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
¹⁸ Heart and Lung Centre, Helsinki University Hospital, Helsinki, Finland.
¹⁹ Medical School, Tampere University, Tampere, Finland; Finnish Clinical Biobank Tampere, University Hospital of Tampere, Tampere, Finland.
²⁰ Department of Geriatics and Gerontology, Leiden University Medical Centre, Leiden, Netherlands; Department of Cardiology, Leiden University Medical Centre, Leiden, Netherlands.
²¹ Institute of Cardiovascular and Medical Science, BHF Glasgow, Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
²² Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, Netherlands.
²³ Department of Anesthesiology, Intensive Care Medicine, and Pain Medicine, Saarland University Hospital, Homburg/Saar, Germany.
²⁴ Fifth Department of Medicine, University Heidelberg, Mannheim, Germany.
²⁵ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz, Graz, Austria.
²⁶ Christchurch Heart Institute, University of Otago, Christchurch, New Zealand.
²⁷ Christchurch Heart Institute, University of Otago, Christchurch, New Zealand; Cardiovascular Research Institute, National University of Singapore, Singapore.
²⁸ Heart Health Research Group, University of Auckland, New Zealand.
²⁹ Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, Colleges of Pharmacy, University of Florida, Gainesville, FL, USA.
³⁰ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany; LIFE Research Centre for Civilisation Diseases, University of Leipzig, Leipzig, Germany.
³¹ Heart Centre Leipzig, Leipzig, Germany.
³² LIFE Research Centre for Civilisation Diseases, University of Leipzig, Leipzig, Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital, Leipzig, Germany.
³³ Department of Cardiology, Clinical Sciences, Lund University, Lund, Sweden; Skåne University Hospital, Lund, Sweden.
³⁴ Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada.
³⁵ Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA; Department of Genetics, Washington University School of Medicine, Saint Louis, MO, USA.
³⁶ Statistical Genomics Division, Department of Genetics, Washington University School of Medicine, Saint Louis, MO, USA.
³⁷ Saint Luke's Mid America Heart Institute, Kansas City, MO, USA; Department of Biomedical and Health Informatics, University of Missouri-Kansas City, Kansas City, MO, USA.
³⁸ Department of Medicine, University of Verona, Verona, Italy.
³⁹ Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria; Private University of the Principality of Liechtenstein, Triesen, Liechtenstein.
⁴⁰ Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria; Private University of the Principality of Liechtenstein, Triesen, Liechtenstein; Department of Medicine and Cardiology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria; Drexel University College of Medicine, Philadelphia, PA, USA.
⁴¹ Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria.
⁴² Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Leicester, UK; Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, UK.
⁴³ Laboratory of Experimental Cardiology, UMC Utrecht, Utrecht, Netherlands.
⁴⁴ Emory Clinical Cardiovascular Research Institute, Emory University School of Medicine, Atlanta, GA, USA.
⁴⁵ University of Southern California, Los Angeles, CA, USA.
⁴⁶ Cleveland Clinic, Cleveland, OH, USA.
⁴⁷ Uppsala Clinical Research Centre, Uppsala University, Uppsala, Sweden; Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden.
⁴⁸ Uppsala Clinical Research Centre, Uppsala University, Uppsala, Sweden; Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden.
⁴⁹ University of Montreal Hospital Research Centre (CRCHUM), University of Montreal, Montreal, QC, Canada; Department of Social and Preventive Medicine, University of Montreal, Montreal, QC, Canada; Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
⁵⁰ Department of Medicine, McGill University, Montreal, QC, Canada.
⁵¹ Department of Medicine, McGill University, Montreal, QC, Canada; Division of General Internal Medicine, McGill University Health Centre, Montreal, QC, Canada; Division of Clinical Epidemiology, McGill University Health Centre, Montreal, QC, Canada.
⁵² Department of Medicine, Université Laval, QC, Canada.
⁵³ Jagielonian University Medical College, Kraków, Poland.
⁵⁴ Section of Cardiology, Michael E DeBakey Veterans Affairs Medical Center, Baylor College of Medicine, Houston, TX, USA.
⁵⁵ Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
⁵⁶ Department of Biostatistics 7, Epidemiology, Texas Heart Institute, Houston, TX, USA.
⁵⁷ School of Public Health, University of Texas, Houston, TX, USA.
⁵⁸ Medical Research Council Population Health Research Unit at the University of Oxford, University of Oxford, Oxford, UK; Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, UK.
⁵⁹ Department of Cardiology, Heart and Lungs Division, UMC Utrecht, Utrecht, Netherlands; Institute of Cardiovascular Science Facultyof Population Health Science, University College London, London, UK; Durrer Centre of Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, Netherlands.
⁶⁰ Fifth Department of Medicine, University Heidelberg, Mannheim, Germany; Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz, Graz, Austria; Synlab Academy, Synlab Holding, Mannheim, Germany. Electronic address: winfried.maerz@medma.uni-heidelberg.de.

Abstract

Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear.

Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts.

Findings: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14-1·83) and the presence of either LPA SNP (1·88, 1·40-2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81-1·11 and either LPA SNP 1·10, 0·92-1·31) or cardiovascular mortality (0·99, 0·81-1·2 and 1·13, 0·90-1·40, respectively) or in the validation studies.

Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established.

Funding: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers / blood*
Cohort Studies
Coronary Disease / blood
Coronary Disease / epidemiology
Coronary Disease / genetics
Coronary Disease / mortality*
Europe / epidemiology
Female
Genetic Association Studies*
Humans
Lipoprotein(a) / blood*
Lipoprotein(a) / genetics*
Male
Middle Aged
Polymorphism, Single Nucleotide*
Prognosis
Risk Factors
Survival Rate

Substances

Biomarkers
Lipoprotein(a)

Abstract

Publication types

MeSH terms

Substances

Grants and funding