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. 2015 Jun;35(6):1526-31.
doi: 10.1161/ATVBAHA.114.304985. Epub 2015 Apr 16.

Common Sequence Variants Associated With Coronary Artery Disease Correlate With the Extent of Coronary Atherosclerosis

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Free PMC article

Common Sequence Variants Associated With Coronary Artery Disease Correlate With the Extent of Coronary Atherosclerosis

Eythor Bjornsson et al. Arterioscler Thromb Vasc Biol. .
Free PMC article

Abstract

Objective: Single-nucleotide polymorphisms predisposing to coronary artery disease (CAD) have been shown to predict cardiovascular risk in healthy individuals when combined into a genetic risk score (GRS). We examined whether the cumulative burden of known genetic risk variants associated with risk of CAD influences the development and progression of coronary atherosclerosis.

Approach and results: We investigated the combined effects of all known CAD variants in a cross-sectional study of 8622 Icelandic patients with angiographically significant CAD (≥ 50% diameter stenosis). We constructed a GRS based on 50 CAD variants and tested for association with the number of diseased coronary arteries on angiography. In models adjusted for traditional cardiovascular risk factors, the GRS associated significantly with CAD extent (difference per SD increase in GRS, 0.076; P=7.3 × 10(-17)). When compared with the bottom GRS quintile, patients in the top GRS quintile were roughly 1.67× more likely to have multivessel disease (odds ratio, 1.67; 95% confidence interval, 1.45-1.94). The GRS significantly improved prediction of multivessel disease over traditional cardiovascular risk factors (χ(2) likelihood ratio 48.1; P<0.0001) and modestly improved discrimination, as estimated by the C-statistic (without GRS versus with GRS, 64.0% versus 64.8%) and the integrated discrimination improvement (0.52%). Furthermore, the GRS associated with an earlier age at diagnosis of angiographic CAD. These findings were replicated in an independent sample from the Emory Biobank study (n=1853).

Conclusions: When combined into a single GRS, known genetic risk variants for CAD contribute significantly to the extent of coronary atherosclerosis in patients with significant angiographic disease.

Keywords: atherosclerosis; coronary disease; genetics.

Figures

Figure 1
Figure 1
The effects of 50 single nucleotide polymorphisms (SNPs) on the extent of coronary artery disease (CAD), expressed as the increase in number of diseased coronary vessels (with at least 50% stenosis) per SNP risk allele, plotted against their respective effect on CAD risk (odds ratio), previously reported in meta-analyses of genome-wide association studies (Table I in the online-only Data Supplement for references). Combined effect sizes in the Icelandic and Emory Biobank samples are presented where available (Table I in the online-only Data Supplement). The solid line denotes best linear fit, the dashed lines indicate 95% confidence limits.
Figure 2
Figure 2
Adjusted odds ratios for multivessel disease by quintiles of the genetic risk score (GRS) in the Icelandic (black) and Emory Biobank (grey) samples. Odds ratios are referenced to the bottom GRS quintile and presented with 95% confidence intervals.

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