A gene-centric study of common carotid artery remodelling

Abstract

Background: Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized.

Methods: Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA).

Results: rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08-0.18 mm, P = 8.2 × 10(-8)). A proxy SNP (rs4916251, R(2) = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case-control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03-1.17, p = 2.8 × 10(-3), I(2) = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling.

Conclusions: Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development.

Fig. 1

Analysis flow for this study.

Fig. 2

Manhattan plot for association results by chromosome between 127,998 SNPs and CCAD in the IMPROVE study (red-line = array-wide significance, 8.39 × 10⁻⁷). Each point on the plot represents the −log10 p-value for the association between individual SNPs and CCAD. Manhattan plot created in R statistical package (http://www.r-project.org/).

Fig. 3

Regional forest of the association between variants at 1q24.3 and ICCAD. The lead SNP value (rs3768445, β = 0.13, P = 8.2 × 10⁻⁸) is represented by the purple diamond, while the other points are colour coded by their LD with the lead SNP (as measured by R²). Plot was created using Locuszoom (http://csg.sph.umich.edu/locuszoom/).

Fig. 4

Meta-analysis of the association between rs4916251 and ICCAD by tertile of CIMT (1st tertile is the lowest, 3rd tertile the highest). Details of the individual study results are presentated in the Supplementary data.

Fig. 5

Forest-plot of association between rs4916251 and AAA. Combined OR (1.10, 95% CI 1.03–1.17, p = 2.8 × 10⁻³, I² = 18.8, Q = 0.295).

Fig. 6

Association between rs1023479 (proxy for rs4916251) and expression of PIGC in aortic media (P = 4.4 × 10⁻³). CC – n = 3, TC – n = 47, TT – n = 83.