Genetic Susceptibility Loci for Cardiovascular Disease and Their Impact on Atherosclerotic Plaques

Abstract

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.

Keywords: atherosclerosis; cardiovascular disease; coronary artery disease; genetic loci; plaque, atherosclerotic; quantitative trait loci; stroke.

Figure 1.

Associations of genetic variants in 7q22 with carotid intraplaque fat. Rs12539895 was previously associated with coronary artery disease (CAD; purple). The strongest association was for a deletion chr7:106901393 (triglycerides [TG] >T; P=2.14×10⁻⁷; pink). The x axis shows the chromosomal position relative to 1000G (March 2012, Hg19). The lower shows refSeq canonical genes from UCSC (the black arrow indicates the direction of transcription). The left y axis shows the −log₁₀(P value) of the association with intraplaque fat. The right y axis shows the recombination rate (gray line in the middle). The middle shows each associated variant colored by the r² relative to rs12539895. The legend in the upper right corner shows the r² color scale. The per variant annotation key is depicted in the bottom left corner. Made using LocusZoom version 1.3 and SNiPA.^, COG5 indicates component of oligomeric Golgi complex 5; CpG, cytosine-guanine dinucleotide; eQTL, expression quantitative trait loci; HBP1, HMG-box transcription factor 1; and mQTL, methylation quantitative trait loci.

Figure 2.

Association of rs3815148 with HBP1 expression in carotid plaques. Rs3815148 is a proxy (LD r²=0.91) for rs12539895 and associated (P=7.0×10⁻⁶) with HBP1 expression in carotid plaques from BiKE. A, Regional association of variants with HBP1 expression in carotid plaques. The x axis shows the chromosomal position relative to 1000G (March 2012, Hg19) and refSeq canonical genes (green) from UCSC (the black arrow indicates the direction of transcription). The left y axis shows the −log₁₀ P value of the association with HBP1 expression. The right y axis shows the recombination rate (gray line). The middle shows each associated variant colored by the r² relative to rs12539895. The legend in the upper right corner shows the r² color scale. B, Boxplot of the association of rs3815148 with HBP1 expression. Proxy data based on 1000G phase 3, version 5 data from SNiPA. Made using LocusZoom version 1.3.

Figure 3.

Polygenic scores of coronary artery disease (CAD; dark pink) and large artery stroke (LAS; blue) associate with different plaque characteristics. Polygenic scores for CAD associate with intraplaque fat (A), whereas polygenic scores for LAS associate with intraplaque hemorrhage (B) and smooth muscle cells (C). Scores were constructed based on GWAS (Genome-Wide Association Study) summary statistics using increasingly liberal P value thresholds (P_T, see also Information in the Data Supplement; Table II in the Data Supplement). Each P_T bin is depicted on the x axis. The y axis indicate the r² of the association; please note the different scales. *P<0.05 for association of the score with the plaque characteristic. PGC indicates bipolar disorder from the Psychiatric Genetics Consortium (green).