期刊
CIRCULATION-GENOMIC AND PRECISION MEDICINE
卷 11, 期 9, 页码 -出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGEN.118.002115
关键词
atherosclerosis; cardiovascular disease; coronary artery disease; genetic loci; plaque, atherosclerotic; quantitative trait loci; stroke
资金
- Netherlands CardioVascular Research Initiative of the Netherlands Heart Foundation [CVON 2011/B019, CVON 2017-20]
- Interuniversity Cardiology Institute of the Netherlands (ICIN) [09.001]
- FP7 EU project CVgenes@target [HEALTH-F2-2013-601456]
- European Union (BiomarCaRE) [HEALTH-2011-278913]
- technology foundation Stichting voor de Technische Wetenschappen through the Danone partnership program [11679]
- UCL Hospitals NIHR Biomedical Research Centre
- Dutch Heart Foundation [2014T001]
- Swedish Heart and Lung Foundation
- Swedish Research Council [K2009-65X-2233-01-3, K2013-65X-06816-30-4, 349-2007-8703]
- Uppdrag Besegra Stroke [P581/2011-123]
- Strategic Cardiovascular Programs of Karolinska Institutet
- Stockholm County Council [ALF2011-0260, ALF-2011-0279]
- Foundation for Strategic Research
- European Commission (CarTarDis)
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=5.09x10(-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.
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