Journal of Lipid Research (Sep 2017)
A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms[S]
- Salome Mack,
- Stefan Coassin,
- Rico Rueedi,
- Noha A. Yousri,
- Ilkka Seppälä,
- Christian Gieger,
- Sebastian Schönherr,
- Lukas Forer,
- Gertraud Erhart,
- Pedro Marques-Vidal,
- Janina S. Ried,
- Gerard Waeber,
- Sven Bergmann,
- Doreen Dähnhardt,
- Andrea Stöckl,
- Olli T. Raitakari,
- Mika Kähönen,
- Annette Peters,
- Thomas Meitinger,
- Konstantin Strauch,
- Ludmilla Kedenko,
- Bernhard Paulweber,
- Terho Lehtimäki,
- Steven C. Hunt,
- Peter Vollenweider,
- Claudia Lamina,
- Florian Kronenberg
Affiliations
- Salome Mack
- Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Stefan Coassin
- Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Rico Rueedi
- Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
- Noha A. Yousri
- Department of Physiology and Biophysics, Weill Cornell Medical College-Qatar, Doha, Qatar; Department of Computer and Systems Engineering, Alexandria University, 21526 Alexandria, Egypt
- Ilkka Seppälä
- Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, 33520 Tampere, Finland
- Christian Gieger
- Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany
- Sebastian Schönherr
- Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Lukas Forer
- Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Gertraud Erhart
- Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Pedro Marques-Vidal
- Department of Medicine, Internal Medicine, Lausanne University Hospital, 1015 Lausanne, Switzerland
- Janina S. Ried
- Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany
- Gerard Waeber
- Department of Medicine, Internal Medicine, Lausanne University Hospital, 1015 Lausanne, Switzerland
- Sven Bergmann
- Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
- Doreen Dähnhardt
- Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Andrea Stöckl
- Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Olli T. Raitakari
- Department of Clinical Physiology, Turku University Hospital, 20520 Turku, Finland; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, 20520 Turku, Finland
- Mika Kähönen
- Department of Clinical Physiology, Tampere University Hospital and University of Tampere, 33521 Tampere, Finland
- Annette Peters
- Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany; German Centre for Cardiovascular Research (DZHK), 80802 Munich, Germany; German Center for Diabetes Research (DZD e.V.), 85764 Neuherberg, Germany
- Thomas Meitinger
- Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany; Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany
- Konstantin Strauch
- Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Medical Informatics, Biometry, and Epidemiology, Ludwig-Maximilians-Universität, 81377 Munich, Germany
- Ludmilla Kedenko
- First Department of Internal Medicine, Paracelsus Private Medical University, 5020 Salzburg, Austria
- Bernhard Paulweber
- First Department of Internal Medicine, Paracelsus Private Medical University, 5020 Salzburg, Austria
- Terho Lehtimäki
- Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, 33520 Tampere, Finland
- Steven C. Hunt
- Cardiovascular Genetics Division, University of Utah School of Medicine, Salt Lake City, UT 84108; Department of Genetic Medicine, Weill Cornell Medicine, Doha, Qatar
- Peter Vollenweider
- Department of Medicine, Internal Medicine, Lausanne University Hospital, 1015 Lausanne, Switzerland
- Claudia Lamina
- To whom correspondence should be addressed. e-mail:; Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, 6020 Innsbruck, Austria; To whom correspondence should be addressed. e-mail:
- Florian Kronenberg
- To whom correspondence should be addressed. e-mail:; Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, 6020 Innsbruck, Austria; To whom correspondence should be addressed. e-mail:
- Journal volume & issue
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Vol. 58,
no. 9
pp. 1834 – 1844
Abstract
High lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. Concentrations are strongly influenced by apo(a) kringle IV repeat isoforms. We aimed to identify genetic loci associated with Lp(a) concentrations using data from five genome-wide association studies (n = 13,781). We identified 48 independent SNPs in the LPA and 1 SNP in the APOE gene region to be significantly associated with Lp(a) concentrations. We also adjusted for apo(a) isoforms to identify loci affecting Lp(a) levels independently from them, which resulted in 31 SNPs (30 in the LPA, 1 in the APOE gene region). Seven SNPs showed a genome-wide significant association with coronary artery disease (CAD) risk. A rare SNP (rs186696265; MAF ∼1%) showed the highest effect on Lp(a) and was also associated with increased risk of CAD (odds ratio = 1.73, P = 3.35 × 10−30). Median Lp(a) values increased from 2.1 to 91.1 mg/dl with increasing number of Lp(a)-increasing alleles. We found the APOE2-determining allele of rs7412 to be significantly associated with Lp(a) concentrations (P = 3.47 × 10−10). Each APOE2 allele decreased Lp(a) by 3.34 mg/dl corresponding to ∼15% of the populationʼns mean values. Performing a gene-based test of association, including suspected Lp(a) receptors and regulators, resulted in one significant association of the TLR2 gene with Lp(a) (P = 3.4 × 10−4). In summary, we identified a large number of independent SNPs in the LPA gene region, as well as the APOE2 allele, to be significantly associated with Lp(a) concentrations.
