Association Between Coronary Artery Disease Genetic Variants and Subclinical Atherosclerosis: An Association Study and Meta-analysis

Rev Esp Cardiol (Engl Ed). 2015 Oct;68(10):869-77. doi: 10.1016/j.rec.2014.10.023. Epub 2015 Mar 21.


Introduction and objectives: Recent studies have identified several genetic variants associated with coronary artery disease. Some of these genetic variants are not associated with classical cardiovascular risk factors and the mechanism of such associations is unclear. The aim of the study was to determine whether these genetic variants are related to subclinical atherosclerosis measured by carotid intima media thickness, carotid stiffness, and ankle brachial index.

Methods: A cross-sectional study nested in the follow-up of the REGICOR cohort was undertaken. The study included 2667 individuals. Subclinical atherosclerosis measurements were performed with standardized methods. Nine genetic variants were genotyped to assess associations with subclinical atherosclerosis, individually and in a weighted genetic risk score. A systematic review and meta-analysis of previous studies that analyzed these associations was undertaken.

Results: Neither the selected genetic variants nor the genetic risk score were significantly associated with subclinical atherosclerosis. In the meta-analysis, the rs1746048 (CXCL12; n = 10581) risk allele was directly associated with carotid intima-media thickness (β = 0.008; 95% confidence interval, 0.001-0.015), whereas the rs6725887 (WDR12; n = 7801) risk allele was inversely associated with this thickness (β = -0.013; 95% confidence interval, -0.024 to -0.003).

Conclusions: The analyzed genetic variants seem to mediate their association with coronary artery disease through different mechanisms. Our results generate the hypothesis that the CXCL12 variant appears to influence coronary artery disease risk through arterial remodeling and thickening, whereas the WDR12 risk variant could be related to higher plaque vulnerability.

Keywords: Ankle-brachial index; Aterosclerosis; Atherosclerosis; Carotid intima media thickness; Carotid stiffness; Genetic variants; Grosor intimomedial carotídeo; Meta-analysis; Metanálisis; Rigidez carotídea; Subclinical; Subclínica; Variantes genéticas; Índice tobillo-brazo.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Alleles
  • Atherosclerosis* / complications
  • Atherosclerosis* / diagnosis
  • Atherosclerosis* / genetics
  • Cell Cycle Proteins
  • Chemokine CXCL12 / genetics*
  • Chemokine CXCL12 / metabolism
  • Coronary Artery Disease* / diagnosis
  • Coronary Artery Disease* / etiology
  • Coronary Artery Disease* / genetics
  • Coronary Vessels / diagnostic imaging*
  • Genetic Predisposition to Disease*
  • Genotype
  • Humans
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • RNA-Binding Proteins
  • Risk Factors


  • CXCL12 protein, human
  • Cell Cycle Proteins
  • Chemokine CXCL12
  • Nuclear Proteins
  • RNA-Binding Proteins
  • WDR12 protein, human