RESUMEN
Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], ORâ=â0.69 [95%CI 0.63-0.75], pâ=â1.86×10⻹8), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], ORâ=â1.32 [95%CI 1.21-1.43], pâ=â3.87×10⻹¹). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], ORâ=â0.58 [95% CI 0.50-0.67], pâ=â1.17×10⻹²) and a probable regulatory region on 8q22 (rs284489 [G], ORâ=â0.62 [95% CI 0.53-0.72], pâ=â8.88×10⻹°). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], ORâ=â0.59 [95% CI 0.41-0.87], pâ=â0.004 and rs284489 [G], ORâ=â0.76 [95% CI 0.54-1.06], pâ=â0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted pâ=â0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.
