GWAS-identified loci for coronary heart disease are associated with intima-media thickness and plaque presence at the carotid artery bulb

Abstract

Background: Large-scale genome-wide association studies (GWAS) have so far identified 45 loci that are robustly associated with coronary heart disease (CHD) in data from adult men and women of European descent.

Objectives: To examine whether the CHD-associated loci are associated with measures of atherosclerosis in data from up to 9582 individuals of European ancestry.

Methods: Forty-five SNPs representing the CHD-associated loci were genotyped in middle-aged to elderly individuals of European descent from four independent population-based studies (IMPROVE, MDC-CC, ULSAM and PIVUS). Intima-media thickness (IMT) was measured by external B-mode ultrasonography at the far wall of the bulb (sinus) and common carotid artery. Plaque presence was defined as a maximal IMT of the bulb >1.5 mm. We meta-analysed single-SNP associations across the four studies, and combined them in a genetic predisposition score. We subsequently examined the association of the genetic predisposition score with prevalent CHD and the three indices of atherosclerosis, adjusting for sex, age and Framingham risk factors.

Results: As anticipated, the genetic predisposition score was associated with prevalent CHD, with each additional risk allele increasing the odds of disease by 5.5% (p = 4.1 × 10(-6)). Moreover, each additional CHD-risk allele across the 45 loci was associated with a 0.24% increase in IMT (p = 4.0 × 10(-3)), and with a 2.8% increased odds of plaque presence (p = 7.4 × 10(-6)) at the far wall of the bulb. The genetic predisposition score was not associated with IMT of the common carotid artery (p = 0.47).

Conclusions: Our results suggest that the association between the 45 previously identified loci and CHD at least partly acts through atherosclerosis.

Keywords: Atherogenic plaque; Atherosclerosis; Carotid artery; Genome-wide association; Intima-media thickness.

Figure 1. Association of the 45 CHD-associated loci with carotid atherosclerosis

Summary statistics for the association of a genetic predisposition score of 45 coronary heart disease (CHD)-associated loci with CHD risk, plaque presence and intima-media thickness (IMT) of the bulb – also known as sinus - and common carotid artery (CCA) in the IMPROVE, MDC-CC, ULSAM and PIVUS studies, as well as after fixed effects, inverse variance weighted meta-analysis. OR and 95% confidence intervals per additional risk allele were provided for associations with dichotomous outcomes, beta and SE expressed in % increase per additional risk allele were provided for continuous outcomes. Weights in % were based on the inverse of the variance. P-values were provided for associations in individual studies, as well as after meta-analysis. I² and p-values for heterogeneity in effect size across studies were provided for results of the meta-analysis. Studies were ordered by sample size.