Coronary artery disease (CAD), a leading cause of death worldwide, has a complex etiology comprising both traditional risk factors (type 2 diabetes, dyslipidemia, arterial hypertension, and cigarette smoking) and genetic factors. Vascular endothelial growth factor (VEGF) notably contributes to angiogenesis and endothelial homeostasis. However, little is known about the relationship between CAD and VEGF polymorphisms in Koreans. The aim of this study is to investigate the associations of 2 VEGF promoter region polymorphisms (−1154G>A [rs1570360], −1498T>C [rs833061]) and 4 VEGF 3′-UTR polymorphisms (+936C>T [rs3025039], +1451C>T [rs3025040], +1612G>A [rs10434], and +1725G>A [rs3025053]) with CAD susceptibility in Koreans. We studied 885 subjects: 463 CAD patients and 422 controls. Genotyping was conducted with polymerase chain reaction-restriction fragment length polymorphism analysis and TaqMan allelic discrimination assays, and the genotype frequencies were calculated. We then performed haplotype and genotype combination analyses and measured the associations between VEGF polymorphisms and clinical variables in both the CAD patients and control subjects. We detected statistically significant associations between CAD and certain VEGF allele combinations. In the haplotypes of 5 single-nucleotide polymorphisms, the VEGF allele combination −1154A/+936T was associated with a decreased prevalence of CAD (A-T-T-G-G of VEGF −1154G>A/−1498T>C/+936C>T/+1612G>A/+1725G>A, AOR = 0.077, p = 0.021). In contrast, the VEGF allele combinations −1498T/+1725A and −1498T/+1612A/+1725A were associated with an increased prevalence of CAD (G-T-C-C-A of VEGF −1154G>A/−1498T>C/+936C>T/+1451C>T/+1725G>A, AOR = 1.602, p = 0.047; T-C-C-A-A of VEGF −1498T>C/+936C>T/+1451C>T/+1612G>A/+1725G>A, AOR = 1.582, p = 0.045). Gene−environment combinatorial analysis showed that the combination of the VEGF +1725AA genotype and several clinical factors (e.g., body mass index, hemoglobin A1c, and low-density lipoprotein cholesterol) increased the risk of CAD. Therefore, we suggest that VEGF polymorphisms and clinical factors may impact CAD prevalence.
Keywords: 3′-untranslated region; VEGF; angiogenesis; coronary artery disease; endothelial homeostasis; promoter region.