Purpose: To study the association of selected polymorphism in genes related to vitamin E, vitamin C, and glutathione peroxidase with these biomarkers and primary open-angle glaucoma (POAG) risk.
Methods: A case-control study matched for age, sex, and bodyweight was undertaken. Two hundred fifty POAG cases and 250 controls were recruited from a Mediterranean population. Plasma concentrations of vitamin C, vitamin E, and glutathione peroxidase (GPx) activity were measured. We analyzed the polymorphisms rs1279683 in the Na(+)-dependent L-ascorbic acid transporter 2 (SLC23A2) gene, rs6994076 in the tocopherol alpha transfer protein (TTPA) gene, rs737723 in the tocopherol-associated protein (SEC14L2/TAP) gene, and rs757228 in the glutathione peroxidase 4 (GPX4) gene. We also analyzed expression of the SLC23A2 gene in a subsample.
Results: We found a novel association between the rs737723 polymorphism and POAG risk. Homozygous subjects for the C allele had a higher POAG risk than carriers of the ancestral G allele (adjusted odds ratio 1.73, 95% confidence interval 1.13-2.65, p=0.011). This association remained statistically significant after adjustment for multiple comparisons. We also confirmed the association between the rs1279683 polymorphism and a higher POAG risk in GG homozygous subjects and detected statistically significant differences in SLC23A2 gene expression between POAG cases and controls, even after adjustment for multiple testing. We observed a nominally significant (p<0.05) gene-gene interaction between the SEC14L2/TAP and SLC23A2 polymorphisms in determining POAG risk, increasing POAG risk in those subjects who had both risk genotypes at the same time (p<0.01). This increase was statistically significant even after adjustment for multiple comparisons. We did not detect any association with POAG risk for the rs6994076 or rs757228 polymorphisms. We also found that POAG patients had statistically significant (after correction for multiple testing) lower plasma vitamin E (p<0.001) and vitamin C (p<0.001) concentrations than control subjects. However, we detected a higher plasma GPx activity in POAG cases than in controls (p<0.001). The rs6994076 and rs1279683 polymorphisms were significantly (p<0.001) associated with plasma vitamin E and vitamin C, respectively. However, the rs757228 polymorphism in the GPX4 gene was not associated with plasma GPx activity.
Conclusions: We have described a novel association between the rs737723 polymorphism (SEC14L2/TAP) and higher POAG risk and confirmed the association between rs1279683 (SLC23A2) and POAG. Our results also suggested a gene-gene interaction between both polymorphisms that increases POAG risk.