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Zeng L, Moser S, Mirza-Schreiber N, et al. Cis-epistasis at the LPA locus and risk of cardiovascular diseases. Cardiovasc Res. 2021;doi: 10.1093/cvr/cvab136.
Zeng, L., Moser, S., Mirza-Schreiber, N., Lamina, C., Coassin, S., Nelson, C. P., Annilo, T., Franzén, O., Kleber, M. E., Mack, S., Andlauer, T. F. M., Jiang, B., Stiller, B., Li, L., Willenborg, C., Munz, M., Kessler, T., Kastrati, A., Laugwitz, K. L., Erdmann, J., Moebus, S., NöThen, M. M., Peters, A., Strauch, K., MüLler-Nurasyid, M., Gieger, C., Meitinger, T., Steinhagen-Thiessen, E., MäRz, W., Metspalu, A., BjöRkegren, J. L. M., Samani, N. J., Kronenberg, F., MüLler-Myhsok, B., & Schunkert, H. (2021). Cis-epistasis at the LPA locus and risk of cardiovascular diseases. Cardiovascular research, . https://doi.org/10.1093/cvr/cvab136
Zeng, Lingyao, et al. "Cis-epistasis at the LPA locus and risk of cardiovascular diseases." Cardiovascular research vol. (2021). doi: https://doi.org/10.1093/cvr/cvab136
Zeng L, Moser S, Mirza-Schreiber N, Lamina C, Coassin S, Nelson CP, Annilo T, Franzén O, Kleber ME, Mack S, Andlauer TFM, Jiang B, Stiller B, Li L, Willenborg C, Munz M, Kessler T, Kastrati A, Laugwitz KL, Erdmann J, Moebus S, NöThen MM, Peters A, Strauch K, MüLler-Nurasyid M, Gieger C, Meitinger T, Steinhagen-Thiessen E, MäRz W, Metspalu A, BjöRkegren JLM, Samani NJ, Kronenberg F, MüLler-Myhsok B, Schunkert H. Cis-epistasis at the LPA locus and risk of cardiovascular diseases. Cardiovasc Res. 2021 Apr 20; doi: 10.1093/cvr/cvab136. Epub 2021 Apr 20. PMID: 33878186.
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Cardiovasc Res. 2021 Apr 20; doi: 10.1093/cvr/cvab136. Epub 2021 Apr 20.

Cis-epistasis at the LPA locus and risk of cardiovascular diseases.

Cardiovascular research

Lingyao Zeng, Sylvain Moser, Nazanin Mirza-Schreiber, Claudia Lamina, Stefan Coassin, Christopher P Nelson, Tarmo Annilo, Oscar Franzén, Marcus E Kleber, Salome Mack, Till F M Andlauer, Beibei Jiang, Barbara Stiller, Ling Li, Christina Willenborg, Matthias Munz, Thorsten Kessler, Adnan Kastrati, Karl-Ludwig Laugwitz, Jeanette Erdmann, Susanne Moebus, Markus M NöThen, Annette Peters, Konstantin Strauch, Martina MüLler-Nurasyid, Christian Gieger, Thomas Meitinger, Elisabeth Steinhagen-Thiessen, Winfried MäRz, Andres Metspalu, Johan L M BjöRkegren, Nilesh J Samani, Florian Kronenberg, Bertram MüLler-Myhsok, Heribert Schunkert

Affiliations

  1. Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Technische Universität München, 80636, Munich, Germany.
  2. Statistical Genetics, Max Planck Institute of Psychiatry, 80804, Munich, Germany.
  3. International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Munich, 80804, Germany.
  4. Institute of Neurogenomics, Helmholtz Zentrum München, 85764, Neuherberg, Germany.
  5. Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, 6020, Austria.
  6. Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Groby Rd, Leicester, LE3 9QP, United Kingdom.
  7. NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, United Kingdom.
  8. Estonian Genome Center, Institute of Genomics, University of Tartu, 51010, Tartu, Estonia.
  9. Department of Genetics and Genomic Sciences and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
  10. Integrated Cardio Metabolic Centre, Karolinska Institutet, Huddinge, 14186, Stockholm, Sweden.
  11. Medizinische Klinik V (Nephrologie, Hypertensiologie, Rheumatologie, Endokrinologie, Diabetologie), Medizinische Fakultät Mannheim der Universität Heidelberg, 69120, Heidelberg, Germany.
  12. Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675, Munich, Germany.
  13. Institute for Cardiogenetics and University Heart Center Luebeck, University of Lübeck, 23562, Lübeck, Germany.
  14. Deutsches Zentrum für Herz- und Kreislauf-Forschung (DZHK), partner site Hamburg/Lübeck/Kiel, 23562, Lübeck, Germany.
  15. Charité - University Medicine Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute for Dental and Craniofacial Sciences, Department of Periodontology and Synoptic Dentistry, 14197, Berlin, Germany.
  16. Deutsches Zentrum für Herz- und Kreislauf-Forschung (DZHK), partner site Munich Heart Alliance, 80636, Munich, Germany.
  17. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 81675, Munich, Germany.
  18. Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, 45147, Essen, Germany.
  19. Centre for Urbane Epidemiology, University Hospital Essen, 45147, Essen, Germany.
  20. Institute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn, 53012, Bonn, Germany.
  21. Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764, Neuherberg, Germany.
  22. Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, 81377, Munich, Germany.
  23. Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University, 55101, Mainz, Germany.
  24. Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University (LMU) Munich, 81377, Munich, Germany.
  25. Institute of Epidemiology II, Helmholtz Zentrum München, 85764, Neuherberg, Germany.
  26. Institute of Human Genetics, Helmholtz Zentrum München, 85764, Neuherberg, Germany.
  27. Center for Internal Medicine with Gastroenterology and Nephrology, Lipid Clinic, Charité, 13353, Berlin, Germany.
  28. Synlab Akademie, Synlab Holding Deutschland GmbH, Mannheim und Augsburg, 86156, Augsburg, Germany.
  29. Institute of Molecular and Cell Biology, University of Tartu, 51010, Tartu, Estonia.
  30. Munich Cluster of Systems Biology, SyNergy, 81377, Munich, Germany.
  31. Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3BX, United Kingdom.

PMID: 33878186 DOI: 10.1093/cvr/cvab136

Abstract

AIMS: Coronary artery disease (CAD) has a strong genetic predisposition. However, despite substantial discoveries made by genome-wide association studies (GWAS), a large proportion of heritability awaits identification. Non-additive genetic-effects might be responsible for part of the unaccounted genetic variance. Here we attempted a proof-of-concept study to identify non-additive genetic effects, namely epistatic interactions, associated with CAD.

METHODS AND RESULTS: We tested for epistatic interactions in ten CAD case-control studies and UK Biobank with focus on 8,068 SNPs at 56 loci with known associations with CAD risk. We identified a SNP pair located in cis at the LPA locus, rs1800769 and rs9458001, to be jointly associated with risk for CAD (odds ratio [OR]=1.37, p = 1.07 × 10-11), peripheral arterial disease (OR = 1.22, p = 2.32 × 10-4), aortic stenosis (OR = 1.47, p = 6.95 × 10-7), hepatic lipoprotein(a) (Lp(a)) transcript levels (beta = 0.39, p = 1.41 × 10-8), and Lp(a) serum levels (beta = 0.58, p = 8.7 × 10-32), while individual SNPs displayed no association. Further exploration of the LPA locus revealed a strong dependency of these associations on a rare variant, rs140570886, that was previously associated with Lp(a) levels. We confirmed increased CAD risk for heterozygous (relative OR = 1.46, p = 9.97 × 10-32) and individuals homozygous for the minor allele (relative OR = 1.77, p = 0.09) of rs140570886. Using forward model selection, we also show that epistatic interactions between rs140570886, rs9458001, and rs1800769 modulate the effects of the rs140570886 risk allele.

CONCLUSIONS: These results demonstrate the feasibility of a large-scale knowledge-based epistasis scan and provide rare evidence of an epistatic interaction in a complex human disease. We were directed to a variant (rs140570886) influencing risk through additive genetic as well as epistatic effects. In summary, this study provides deeper insights into the genetic architecture of a locus important for cardiovascular diseases.

TRANSLATIONAL PERSPECTIVE: Genetic variants identified by GWAS studies explain about a quarter of the heritability of coronary artery disease by additive genetic effects. Our study demonstrates that non-additive effects contribute to the genetic architecture of the disease as well and identifies complex interaction patterns at the LPA locus, which affect LPA expression, Lp(a) plasma levels and risk of atherosclerosis. This proof-of-concept study encourages systematic searches for epistatic interactions in further studies to shed new light on the aetiology of the disease.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

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