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Genetic Susceptibility Loci for Cardiovascular Disease and Their Impact on Atherosclerotic Plaques
BACKGROUND: Atherosclerosis is a chronic inflammatory disease in part caused by lipid uptake in the vascular wall, but the exact underlying mechanisms leading to acute myocardial infarction and stroke remain poorly understood. Large consortia identified genetic susceptibility loci that associate wit...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664607/ https://www.ncbi.nlm.nih.gov/pubmed/30354329 http://dx.doi.org/10.1161/CIRCGEN.118.002115 |
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author | van der Laan, Sander W. Siemelink, Marten A. Haitjema, Saskia Foroughi Asl, Hassan Perisic, Ljubica Mokry, Michal van Setten, Jessica Malik, Rainer Dichgans, Martin Worrall, Bradford B Samani, Nilesh J Schunkert, Heribert Erdmann, Jeanette Hedin, Ulf Paulsson-Berne, Gabrielle Björkegrenn, Johan L.M de Borst, Gert J. Asselbergs, Folkert W den Ruijter, Folkert W de Bakker, Paul I.W Pasterkamp, Gerard |
author_facet | van der Laan, Sander W. Siemelink, Marten A. Haitjema, Saskia Foroughi Asl, Hassan Perisic, Ljubica Mokry, Michal van Setten, Jessica Malik, Rainer Dichgans, Martin Worrall, Bradford B Samani, Nilesh J Schunkert, Heribert Erdmann, Jeanette Hedin, Ulf Paulsson-Berne, Gabrielle Björkegrenn, Johan L.M de Borst, Gert J. Asselbergs, Folkert W den Ruijter, Folkert W de Bakker, Paul I.W Pasterkamp, Gerard |
author_sort | van der Laan, Sander W. |
collection | PubMed |
description | BACKGROUND: Atherosclerosis is a chronic inflammatory disease in part caused by lipid uptake in the vascular wall, but the exact underlying mechanisms leading to acute myocardial infarction and stroke remain poorly understood. Large consortia identified genetic susceptibility loci that associate with large artery ischemic stroke and coronary artery disease. However, deciphering their underlying mechanisms are challenging. Histological studies identified destabilizing characteristics in human atherosclerotic plaques that associate with clinical outcome. To what extent established susceptibility loci for large artery ischemic stroke and coronary artery disease relate to plaque characteristics is thus far unknown but may point to novel mechanisms. METHODS: We studied the associations of 61 established cardiovascular risk loci with 7 histological plaque characteristics assessed in 1443 carotid plaque specimens from the Athero-Express Biobank Study. We also assessed if the genotyped cardiovascular risk loci impact the tissue-specific gene expression in 2 independent biobanks, Biobank of Karolinska Endarterectomy and Stockholm Atherosclerosis Gene Expression. RESULTS: A total of 21 established risk variants (out of 61) nominally associated to a plaque characteristic. One variant (rs12539895, risk allele A) at 7q22 associated to a reduction of intraplaque fat, P=5.09×10(−6) after correction for multiple testing. We further characterized this 7q22 Locus and show tissue-specific effects of rs12539895 on HBP1 expression in plaques and COG5 expression in whole blood and provide data from public resources showing an association with decreased LDL (low-density lipoprotein) and increase HDL (high-density lipoprotein) in the blood. CONCLUSIONS: Our study supports the view that cardiovascular susceptibility loci may exert their effect by influencing the atherosclerotic plaque characteristics. |
format | Online Article Text |
id | pubmed-7664607 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-76646072020-11-16 Genetic Susceptibility Loci for Cardiovascular Disease and Their Impact on Atherosclerotic Plaques van der Laan, Sander W. Siemelink, Marten A. Haitjema, Saskia Foroughi Asl, Hassan Perisic, Ljubica Mokry, Michal van Setten, Jessica Malik, Rainer Dichgans, Martin Worrall, Bradford B Samani, Nilesh J Schunkert, Heribert Erdmann, Jeanette Hedin, Ulf Paulsson-Berne, Gabrielle Björkegrenn, Johan L.M de Borst, Gert J. Asselbergs, Folkert W den Ruijter, Folkert W de Bakker, Paul I.W Pasterkamp, Gerard Circ Cardiovasc Genet Original Articles BACKGROUND: Atherosclerosis is a chronic inflammatory disease in part caused by lipid uptake in the vascular wall, but the exact underlying mechanisms leading to acute myocardial infarction and stroke remain poorly understood. Large consortia identified genetic susceptibility loci that associate with large artery ischemic stroke and coronary artery disease. However, deciphering their underlying mechanisms are challenging. Histological studies identified destabilizing characteristics in human atherosclerotic plaques that associate with clinical outcome. To what extent established susceptibility loci for large artery ischemic stroke and coronary artery disease relate to plaque characteristics is thus far unknown but may point to novel mechanisms. METHODS: We studied the associations of 61 established cardiovascular risk loci with 7 histological plaque characteristics assessed in 1443 carotid plaque specimens from the Athero-Express Biobank Study. We also assessed if the genotyped cardiovascular risk loci impact the tissue-specific gene expression in 2 independent biobanks, Biobank of Karolinska Endarterectomy and Stockholm Atherosclerosis Gene Expression. RESULTS: A total of 21 established risk variants (out of 61) nominally associated to a plaque characteristic. One variant (rs12539895, risk allele A) at 7q22 associated to a reduction of intraplaque fat, P=5.09×10(−6) after correction for multiple testing. We further characterized this 7q22 Locus and show tissue-specific effects of rs12539895 on HBP1 expression in plaques and COG5 expression in whole blood and provide data from public resources showing an association with decreased LDL (low-density lipoprotein) and increase HDL (high-density lipoprotein) in the blood. CONCLUSIONS: Our study supports the view that cardiovascular susceptibility loci may exert their effect by influencing the atherosclerotic plaque characteristics. Lippincott Williams & Wilkins 2018-09 2018-09-17 /pmc/articles/PMC7664607/ /pubmed/30354329 http://dx.doi.org/10.1161/CIRCGEN.118.002115 Text en © 2018 The Authors. Circulation: Genomic and Precision Medicine is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made. |
spellingShingle | Original Articles van der Laan, Sander W. Siemelink, Marten A. Haitjema, Saskia Foroughi Asl, Hassan Perisic, Ljubica Mokry, Michal van Setten, Jessica Malik, Rainer Dichgans, Martin Worrall, Bradford B Samani, Nilesh J Schunkert, Heribert Erdmann, Jeanette Hedin, Ulf Paulsson-Berne, Gabrielle Björkegrenn, Johan L.M de Borst, Gert J. Asselbergs, Folkert W den Ruijter, Folkert W de Bakker, Paul I.W Pasterkamp, Gerard Genetic Susceptibility Loci for Cardiovascular Disease and Their Impact on Atherosclerotic Plaques |
title | Genetic Susceptibility Loci for Cardiovascular Disease and Their Impact on Atherosclerotic Plaques |
title_full | Genetic Susceptibility Loci for Cardiovascular Disease and Their Impact on Atherosclerotic Plaques |
title_fullStr | Genetic Susceptibility Loci for Cardiovascular Disease and Their Impact on Atherosclerotic Plaques |
title_full_unstemmed | Genetic Susceptibility Loci for Cardiovascular Disease and Their Impact on Atherosclerotic Plaques |
title_short | Genetic Susceptibility Loci for Cardiovascular Disease and Their Impact on Atherosclerotic Plaques |
title_sort | genetic susceptibility loci for cardiovascular disease and their impact on atherosclerotic plaques |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664607/ https://www.ncbi.nlm.nih.gov/pubmed/30354329 http://dx.doi.org/10.1161/CIRCGEN.118.002115 |
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