Genetics: 49. Polymorphism in the Promoter Region of the Vascular Endothelial Growth Factor Gene is Associated with Serum Vegf Level and Disease Activity in RA

Background: Previous studies have demonstrated that the vascular endothelial growth factor (VEGF) level is associated with disease activity and severity in rheumatoid arthritis (RA). Polymorphism in the VEGF gene has also been associated with susceptibility to RA, but the relationship of VEGF genetic variants with RA activity and severity measures is unclear. The aim of this study was to determine whether common VEGF polymorphisms (VEGF-2578/-460/+405/+936) are associated with serum levels of VEGF in patients with RA, and to assess whether these genetic variants are associated with disease activity and/or severity of RA. Methods: Serum levels of VEGF were measured using a fluorescent bead-based assay system in a cohort (n = 410) of consecutively recruited RA patients of Caucasian origin. Genotyping of the four VEGF SNPs in the same patients was carried out using PCR-RFLP methods. RA clinical variables such as IgM RF (+/-), anti-CCP (+/-), ESR, DAS-28, HAQ and serum levels of CRP, MMP-1 and −3 were obtained for each patient. Demographic characteristics were also recorded. Associations were first analyzed using univariate statistics. Thereafter, multivariate multiple regression was applied to assess the independence of associations and to adjust for possible confounding factors. Results: We confirmed in this patient group that serum VEGF level was correlated with various markers such as ESR (r = 0.12, p = 0.015), CRP (r = 0.14, p = 0.004), MMP-1 (r = 0.15, p = 0.003) and MMP-3 (r = 0.13, p = 0.009). It was also strongly associated with disease activity (as measured by DAS-28, p < 0.0001) and functional outcome (as measured by HAQ score, p = 0.001), independent of age, sex and disease duration. Serum VEGF levels were significantly lower in patients carrying the AA genotype of VEGF-2578, compared to that in subjects with a C allele (74.0 vs 85.7 pg/ml, p = 0.033). Other VEGF SNPs or haplotypes were not associated with serum VEGF levels. VEGF-2578 AA was found to be associated with lower DAS-28 (p = 0.046) after adjustment for age, sex, RA duration, and levels of VEGF, MMP-1 and −3. Haplotype analysis demonstrated that A-C-G (-2578/-460/+405), the most frequent haplotype (48.3%), was associated with lower DAS-28 (p = 0.017). Regression analyses suggested that VEGF-2578 SNP associations were independent of VEGF serum level associations. Conclusions: The VEGF-2578 SNP is associated with the serum VEGF level in RA, and may play an additional role in RA disease activity apart from its influence on VEGF expression. Disclosure statement: The authors have declared no conflicts of interest.