Interaction Between Smoking and Polymorphism in the Promoter Region of the VEGFA Gene Is Associated with Ischemic Heart Disease and Myocardial Infarction in Rheumatoid Arthritis

Objective. To determine whether variants in the vascular endothelial growth factor A (VEGFA) gene are associated with ischemic heart disease (IHD) and/or myocardial infarction (MI) in patients with rheumatoid arthritis (RA), and whether there is evidence of a gene-smoking interaction. Methods. PCR-RFLP assays were used to determine the genotypes of VEGFA single-nucleotide polymorphisms (SNP) including VEGFA-2578A/C (rs699947), -460C/T (rs833061), +405C/G (rs2010963), and +936C/T (rs3025039) in 418 subjects with RA. Smoking history was obtained on each patient, and IHD and MI status was recorded. Associations with IHD/MI were assessed using contingency tables and logistic regression analyses. Results. Strong linkage disequilibrium was detected among VEGFA-2578, -460, and +405. SNP located in the VEGFA promoter region (-2578,-460) were found to be associated with IHD and MI, whereas +405 and +936, in the 5'-untranslated region (UTR) and 3'-UTR, respectively, were not. Haplotype analysis suggested that the A/C/G haplotype was associated with increased risk of IHD (OR 2.37, 95% CI 1.22-4.62) and MI (OR 4.10, 95% CI 1.45-11.49). Smoking was also independently associated with IHD and MI, and evidence of interaction between smoking and the VEGFA promoter SNP was found. Multivariate analyses indicated that the strongest associations with IHD and MI were due to the combined effect of the VEGFA-2578 A allele and smoking (OR 3.52 and 7.11, respectively), independent of risk factors such as age, sex, diabetes, C-reactive protein, hyper-cholesterolemia, and hypertension. Conclusion. Interaction between smoking and polymorphism in the VEGFA gene is associated with IHD and MI in patients with RA. (First Release March 1 2011: J Rheumatol 2011;38:802-9; doi:10.3899/jrheum.101095)