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Editors Selection IGR 11-2

Basic Research: OPA1 gene and risk of glaucoma

Jonathan Crowston

Comment by Jonathan Crowston on:

25275 OPA1 increases the risk of normal but not high tension glaucoma, Yu-Wai-Man P; Stewart J D; Hudson G et al., Journal of Medical Genetics, 2010; 47: 120-125


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POAG is a complex disease with a strong genetic influence. Four causative genes have been identified so far (optineurin, myocilin, CYP1B1, WDR36) although these only account around 10% of adult onset open-angle glaucoma. Accumulating evidence points to mitochondrial abnormalities contributing to glaucoma pathogenesis. To this end, Yu-Wai-Man et al. (61) investigated whether subtle genetic variations in the OPA1 gene increase the risk of developing openangle glaucoma.

The OPA1 gene encodes an inner mitochondrial membrane protein that is critical in the maintenance of the mitochondrial network and mitochondrial ATP production through oxidative phosphorylation (OXPHOS). Pathogenic mutations in the OPA1 gene are known to cause autosomal dominant optic atrophy , which, like glaucoma, results in the selective loss of retinal ganglion cells RGCs. Two singlenucleotide polymorphisms (SNPs) within intron 8 of the OPA1 have been linked with an increased risk of developing POAG in some, but not all populations.

To further clarify the influence of OPA1 in modulating glaucoma susceptibility, the authors analyzed three single-nucleotide polymorphisms in 137 Caucasian patients with primary open-angle glaucoma and 75 controls. In addition the entire OPA1 coding region was sequenced in 24 individuals.

The study identified a strong association between OPA1 polymorphisms at IVS8+4c/t and IVS8+32t/c and the risk of glaucoma. Further subgroup analysis based upon pre-treatment IOPs demonstrated that this association was largely restricted to the NTG group (OR = 2.04, 95% CI = 1.10 to 3.81, p = 0.004). It is interesting to note that the prior studies reporting significant associations between OPA1 and NTG all identified different high-risk compound genotypes from the one identified in this study. In addition, the authors are quick to point out that these associations do not necessarily imply causation and additional functional evidence of mitochondrial dysfunction in patients with the high risk genotype is required.



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