BAX and BCL-2 genes in patients with Retinal Detachment with and without Proliferative Vitreoretinopathy. The Retina 4 project.

Abstract

Purpose: To compare the distribution of BCL-2 C(-938)A, and BAX G(-248)A genotypes among European subjects undergoing rhegmatogenous retinal detachment (RRD) surgery in relation to the further development of proliferative vitreoretinopathy (PVR).

Methods: A case-control gene association study as part of the Retina 4 Project (European multicenter study) was designed. Two promoter single nucleotide polymorphisms (SNP) (rs2279115 and rs4645878) were analysed by TaqMan 5'exonuclease allelic discrimination assay, using a StepOne®system in 134 samples from patients with PVR secondary to RRD and 421 with RRD without PVR. Proportions of genotypes and AA homozygote groups of BCL-2 and BAX polymorphisms between sub-samples were analysed in 2 phases. First, samples from Spain and Portugal were analysed. Once significant results were found, samples from United Kingdom and Netherlands were analysed in a second phase. Genotypic and allelic frequencies were compared in global sample and in sub-samples.

Results: -BAX gene: Significant differences were observed regarding genotype frequencies between cases (AA: 5.2%, GA: 31.3%, GG: 63.4 %) and controls (AA: 2.1%, GA: 21.8%, GG: 76.0%) and in A allelic homozygote carriers (AA) between controls (95% CI: 10.9 to 15.5) and cases (95% CI: 16.2 to 26.3) in the global series. The odds ratio (OR) of A carriers in the global sample was 1.7 (95% CI: 1.23-2.51). Also, in the comparison of proportions of genotypes in Spain+Portugal, significant differences were found. The OR of A carriers from Spain and Portugal was 1.8 (95% CI: 1.11-2.95). - BCL-2 gene: No significant differences were observed in genotype frequencies and in A allelic homozygote carriers (AA) in global sample and in sub-samples from different countries. However, the comparison of proportions of genotypes in Spain+Portugal, was statistically significant. In addition, a protective effect was found in the analysis of A carriers from Spain and Portugal with an OR of 0.6 (95% CI: 0.43-0.96).

Conclusions: The A allele of BAX is associated with a higher risk of developing PVR in patients undergoing a RRD surgery, suggesting that a down-regulation in the apoptosis pathway could be an important key in PVR pathogenesis. Also, this study highlights the role of the SNP rs 2279115 in the BCL-2 gene (inhibitor of necroptosis pathway) as a possible new target in PVR prophylaxis.

Keywords: 655 proliferative vitreoretinopathy • 539 genetics • 426 apoptosis/cell death