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