Genetic variants associated with glaucomatous visual field loss in primary open-angle glaucoma.

Primary open-angle glaucoma (POAG) is characterized by a progressive optic neuropathy with visual field loss. To investigate the genetic variants associated with visual field loss in POAG, Japanese POAG patients (n = 426) and control subjects (n = 246) were genotyped for 22 genetic variants predisposing to POAG that can be classified into those associated with intraocular pressure (IOP) elevation (IOP-related genetic variants) and optic nerve vulnerability independent of IOP (optic nerve-related genetic variants). The genetic risk score (GRS) of the 17 IOP-related and five optic nerve-related genetic variants was calculated, and the associations between the GRS and the mean deviation (MD) of automated static perimetry as an indicator of the severity of visual field loss and pattern standard deviation (PSD) as an indicator of the focal disturbance were evaluated. There was a significant association (Beta = - 0.51, P = 0.0012) between the IOP-related GRS and MD. The severity of visual field loss may depend on the magnitude of IOP elevation induced by additive effects of IOP-related genetic variants. A significant association (n = 135, Beta = 0.65, P = 0.0097) was found between the optic nerve-related, but not IOP-related, GRS and PSD. The optic nerve-related (optic nerve vulnerability) and IOP-related (IOP elevation) genetic variants may play an important role in the focal and diffuse visual field loss respectively. To our knowledge, this is the first report to show an association between additive effects of genetic variants predisposing to POAG and glaucomatous visual field loss, including severity and focal/diffuse disturbance of visual field loss, in POAG.

Genetic Variants Associated With the Onset and Progression of Primary Open-Angle Glaucoma.

PURPOSE: We sought to investigate the genetic variants associated with the onset and progression of primary open-angle glaucoma (POAG). DESIGN: Case-control genetic association study. METHODS: Japanese POAG patients (n = 505) and control subjects (n = 246) were genotyped for 22 genetic variants predisposing to POAG that can be classified into those associated with intraocular pressure (IOP) elevation (IOP-related genetic variants) and optic nerve vulnerability independent of IOP (non-IOP-related genetic variants). The total number of risk alleles of the 17 IOP-related and 5 non-IOP-related genetic variants were calculated as the genetic risk score (GRS), and the associations between the GRS and family history of glaucoma as an indicator of POAG onset and age at the diagnosis of glaucoma as an indicator of POAG progression were evaluated. RESULTS: There was a significant association (P = .014; odds ratio 1.26 per GRS) between the non-IOP-related GRS, but not IOP-related GRS, and a family history of glaucoma in POAG. As the non-IOP-related GRS increased, the risk of a family history of glaucoma increased. In contrast, a significant association (P = .0014; ß = -0.14) was found between the IOP-related GRS, but not non-IOP-related GRS, and age at the diagnosis of glaucoma. As the IOP-related GRS increased, age at the diagnosis of glaucoma decreased. CONCLUSION: The results indicate that non-IOP-related (optic nerve vulnerability) rather than IOP-related (IOP elevation) genetic variants may play an important role in the onset of POAG (family history of glaucoma) and that IOP-related rather than non-IOP-related genetic variants may play an important role in its progression (age at the diagnosis of glaucoma).

Genetic Variant Near PLXDC2 Influences the Risk of Primary Open-angle Glaucoma by Increasing Intraocular Pressure in the Japanese Population.

PURPOSE: The purpose of this study is to assess the association between the genetic variants that were previously reported to be associated with primary open-angle glaucoma (POAG) in the Japanese population and the phenotypic features. METHODS: A total of 661 Japanese patients including 417 patients with POAG [normal tension glaucoma (NTG), n=210; high tension glaucoma (HTG), n=207] and 244 control subjects without glaucoma were analyzed for 3 genetic variants: rs547984 (near gene: ZP4), rs7081455 (PLXDC2), and rs7961953 (TMTC2). The allele frequency differences between POAG (NTG or HTG) patients and control subjects were estimated. The association between these genetic variants and the phenotypic features, including the maximum intraocular pressure (IOP) and the vertical cup-to-disc ratio, was evaluated. RESULTS: There was a significant difference in the rs7081455 (PLXDC2) allele frequencies between the POAG (P=0.0050) patients and the control subjects. An almost 1.5 increase in the risk of POAG (P=0.0042, odds ratio 1.52) was found with a G allele of rs7081455 (PLXDC2). The maximum IOP [23.5±10.3 mm Hg (mean±SD)] in patients with the GG genotype of rs7081455 (PLXDC2) was significantly higher (P=0.0037) than that (19.9±7.4 mm Hg) in patients with the TT genotype. CONCLUSIONS: The genetic variant near the PLXDC2 gene was found to influence the risk of POAG by increasing IOP in the Japanese population.

Additive effects of genetic variants associated with intraocular pressure in primary open-angle glaucoma.

To investigate the association between the additive effects of genetic variants associated with intraocular pressure (IOP) and IOP, vertical cup-to-disc ratio (VCDR), and high tension glaucoma (HTG) or normal tension glaucoma (NTG) as phenotypic features of primary open-angle glaucoma (POAG), and to evaluate the clinical usefulness of the additive effects of IOP-related genetic variants for predicting IOP elevation, Japanese patients with HTG (n = 255) and NTG (n = 261) and 246 control subjects were genotyped for nine IOP-related genetic variants near CAV2, GAS7, GLCCI1/ICA1, ABCA1, ARHGEF12, FAM125B, FNDC3B, ABO, and PTPRJ/AGBL2. The total number of risk alleles of these genetic variants was calculated for each participant as a genetic risk score (GRS), and the association between the GRS and the maximum IOP, mean VCDR, and phenotype (HTG or NTG) of POAG was evaluated. As the GRS increased, the maximum IOP (P = 0.012) and VCDR (P = 0.010) significantly increased. The GRS (9.1±1.9) in patients with HTG was significantly higher (P = 0.011) than that (8.7±1.8) in control subjects. The patients with GRS≥12 as a cut-off value had a 2.54 times higher (P = 0.0085) risk on HTG (maximum IOP≥22mmHg) compared with all patients. The IOP-related GRS approach substantiated that the IOP and VCDR were increased by the additive effects of IOP-related genetic variants in POAG. The high IOP-related GRS in patients with HTG but not NTG shows that there are differences in the genetic background between HTG and NTG and supports the notion that the phenotype (HTG or NTG) in patients with POAG depends on the additive effects of IOP-related genetic variants. The above-mentioned cut-off value of IOP-related GRS may be clinically useful for predicting the risk of IOP elevation.