Common sequence variation in the VEGF-C gene is associated with diabetic retinopathy and diabetic macular edema in Caucasian diabetic patients.

Abstract

Purpose: The interaction between Vascular Endothelial Growth Factor C (VEGF-C), VEFG-A and their common receptor, VEGFR-2, has been shown to play a functional role in the pathogenesis of diabetic retinopathy (DR). The aim of this study was to investigate associations between single nucleotide polymorphisms (SNPs) in the VEGF-C gene and the development of DR in Caucasian patients with either type 1 (T1DM) or type 2 (T2DM) diabetes mellitus.

Methods: 2907 Caucasian patients with T1DM or T2DM were recruited from ophthalmology and endocrine clinics in Australia and the United Kingdom. T2DM patients were required to have DM for a duration of at least 5 years, and be on oral hypoglycemic treatment or insulin. Participants were categorized according to their worst ever DR grading, as having ‘No DR’ (no history of non-proliferative DR (NPDR), proliferative DR (PDR) or diabetic macular edema (DME)), or ‘Any DR’ (further subclassified as NPDR, PDR, and/or DME). Clinical characteristics, diabetic control (HbA_1c), and the presence of diabetic complications were determined at the time of recruitment. Genotyping was successfully performed for 12 VEGF-C tag SNPs. Odds ratios (OR) were determined for associations of VEGF-C tag SNPs, individually and within haplotypes, with diabetic retinopathy. Logistic regression allowed for adjustment of clinical covariates including DM type, age, sex, duration of DM, hypertension, nephropathy and Hb_A1c.

Results: 1022 diabetic participants with No DR were compared with 1885 diabetic participants with Any DR. Three VEGF-C SNPs were associated with DR following logistic regression, and after correction for multiple SNP testing: rs17697419 (p=0.001; OR, 0.68; CI, 0.54-0.86), rs17697515 (p=0.001; OR, 0.65; CI, 0.50-0.84) and rs1485766 (p=0.005; OR, 1.22; CI, 1.06-1.40). rs17697515 was also specifically associated with DME (p=0.002; OR, 0.68; CI, 0.53-0.86). Haplotype analysis revealed 3 significant haplotypes, including 1 risk, and 2 protective haplotypes for DR development.

Conclusions: This study is the first to evaluate sequence variation with the VEGF-C gene in diabetic patients with and without DR. Significant associations were found between VEGF-C tag SNPs (individually, and within haplotypes) and the presence of any DR, and DME, in a large cohort of Caucasian participants with both T1DM and T2DM.