TY - JOUR
T1 - Genetic Susceptibility Loci for Cardiovascular Disease and Their Impact on Atherosclerotic Plaques
AU - METASTROKE Collaboration of the International Stroke Genetics Consortium
AU - van der Laan, Sander W.
AU - Siemelink, Marten A.
AU - Haitjema, Saskia
AU - Foroughi Asl, Hassan
AU - Perisic, Ljubica
AU - Mokry, Michal
AU - van Setten, Jessica
AU - Malik, Rainer
AU - Dichgans, Martin
AU - Worrall, Bradford B.
AU - Samani, Nilesh J.
AU - Schunkert, Heribert
AU - Erdmann, Jeanette
AU - Hedin, Ulf
AU - Paulsson-Berne, Gabrielle
AU - Björkegrenn, Johan L.M.
AU - de Borst, Gert J.
AU - Asselbergs, Folkert W.
AU - den Ruijter, Folkert W.
AU - de Bakker, Paul I.W.
AU - Pasterkamp, Gerard
PY - 2018/9/1
Y1 - 2018/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85055611703&partnerID=8YFLogxK
U2 - 10.1161/CIRCGEN.118.002115
DO - 10.1161/CIRCGEN.118.002115
M3 - Journal articles
C2 - 30354329
AN - SCOPUS:85055611703
SN - 2574-8300
VL - 11
SP - e002115
JO - Circulation. Genomic and precision medicine
JF - Circulation. Genomic and precision medicine
IS - 9
ER -