Polymorphism in the vascular endothelial growth factor A (VEGFA) gene is associated with serum VEGF-A level and disease activity in rheumatoid arthritis: Differential effect of cigarette smoking

ObjectiveTo assess the impact of common genetic variants in the vascular endothelial growth factor A (VEGFA) gene on circulating VEGF-A levels and disease activity in patients with rheumatoid arthritis (RA).MethodsA cohort (n = 419) of consecutively recruited RA patients of Caucasian origin was studied. Disease activity (DAS28) was recorded on a regular basis (0, 12 and 24 months). Smoking history (never, past and current) was obtained. PCR–RFLP assays were used to determine the genotypes of VEGFA single-nucleotide polymorphisms (SNP) including VEGFA-2578 (rs699947), −460 (rs833061), +405 (rs2010963) and +936 (rs3025039). Circulating levels of VEGF-A were measured in serum samples using a fluorescent bead-based assay system (Luminex®). Associations were analyzed using univariate and multivariate statistics.ResultsVEGFA-2578 AA genotype was associated with lower serum VEGF-A levels, as was the most frequent haplotype (A−2578–C−460–G+405, 48.1%) within the 5′-flanking region of the gene. The same genotype and haplotype were also associated with decreased disease activity in RA. This was seen only in patients who had never smoked. In multivariate multiple regression models, the VEGFA-2578 SNP was shown to be associated with disease activity at presentation (p = 0.029) and over time (p = 0.016) in patients who never smoked, independent of serum VEGF-A levels and other confounding factors.ConclusionGenetic variation in the VEGFA gene is associated with serum VEGF-A levels in RA, and shows an association with disease activity in RA patients who have never smoked, independent of serum VEGF-A levels.

► Genetic variation in the VEGFA gene is associated with serum VEGF-A levels in RA.
► The genotype associated with lower levels is associated with lower disease activity.
► The genetic association with activity occurs only in patients who have never smoked.
► The genetic association is independent of the serum level association with activity.