Abstract

Background: Primary open angle glaucoma (POAG) is a progressive optic neuropathy characterised by the selective loss of retinal ganglion cells (RGCs), pathological optic disc cupping and visual field defects. The OPA1 gene encodes for an inner mitochondrial membrane protein crucial for normal mitochondrial function and pathogenic mutations cause autosomal dominant optic atrophy (DOA) by specifically targeting RGCs. This raises the distinct possibility that more subtle genetic variations in OPA1 could alter the risk of developing glaucoma.

Methods: We studied 137 POAG patients, 67 patients with high tension glaucoma (HTG), 70 patients with normal tension glaucoma (NTG), and 75 controls from the North East of England. Three single nucleotide polymorphisms (SNPs) in intron 8 (IVS8+4c>t and IVS8+32t>c) and exon 4 (c.473A>G) of the OPA1 gene were genotyped in our study group. In addition, the entire OPA1 coding region was sequenced in 24 individuals with the CT/TT compound genotype using standard BigDyeTM chemistries.

Results: There was no difference in either allele or genotype frequency for the IVS8+32t>c SNP between patients and controls, but there was a significant association between the T allele at IVS8+4c>t and the risk of developing NTG (Odds ratio (OR) = 2.04, 95% confidence interval (CI) = 1.10-3.81, P = 0.004), but not HTG. Logistic regression analysis also confirmed a strong association between the CT/TT compound genotype at IVS8+4 and IVS8+32 with NTG (OR = 29.75, 95% CI = 3.83-231.21, P = 0.001).

Conclusions: The CT/TT compound genotype at IVS8+4 and IVS8+32 is a strong genetic risk determinant for NTG but not HTG.