Association between Genetic Variants Associated with Vertical Cup-to-Disc Ratio and Phenotypic Features of Primary Open-Angle Glaucoma

Purpose: To assess the association between the genetic variants associated with the optic nerve vertical cup-to-disc ratio (VCDR) and the phenotypic features in patients with primary open-angle glaucoma (POAG), including normal-tension glaucoma (NTG) and high-tension glaucoma (HTG). Design: Case-control study. Participants and Controls: Japanese patients with NTG (n = 213) and HTG (n = 212) and 191 control subjects without glaucoma. Methods: DNA samples were genotyped for 7 single nucleotide polymorphisms (SNPs) associated with VCDR: rs1063192 (near gene: CDKN2B), rs10483727 (SIX1), rs17146964 (SCYL1), rs1547014 (CHEK2), rs1900004 (ATOH7), rs1926320 (DCLK1), and rs12015126 (RERE). Main Outcome Measures: The VCDR was compared between genotypes, and allele frequency differences were compared between NTG or HTG subjects and control subjects. Demographic and clinical features were compared between alleles in patients with NTG or HTG. Results: There were significant VCDR differences (P = 0.0077 and P = 0.019) between the genotypes for rs1063192 (CDKN2B) and rs1547014 (CHEK2), respectively. There were significant differences in the rs1063192 (CDKN2B) and rs1900004 (ATOH7) allele frequencies between the NTG subjects and control subjects (P = 0.0023 and P = 0.028, respectively) and a significant difference (P = 0.013) in the rs1547014 (CHEK2) allele frequencies between the HTG subjects and control subjects. Ages at diagnosis were significantly different in the NTG subjects with and without the rs10483727 (SIX1) C allele (P = 0.017) or the rs1926320 (DCLK1) T allele (P = 0.040). Likewise, the age at diagnosis was significantly different (P = 0.037) in the HTG subjects with and without the rs12025126 (RERE) T allele. There were no significant associations between the maximum intraocular pressure (IOP) and 7 genotyped SNP alleles in patients with NTG or HTG. Conclusions: The rs1063192 (CDKN2B) and rs1900004 (ATOH7) seem to be non-IOP-related genetic risk factors for NTG, and the rs1547014 (CHEK2) is a genetic risk factor for HTG. Although the rs10483727 (SIX1), rs1926320 (DCLK1), or rs12025126 (RERE) alone may not be sufficient for the development of POAG, the association of these SNPs with a phenotypic feature in patients with NTG or HTG suggests that these loci contribute to the pathogenesis of POAG. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2012; 119: 1819-1825 (C) 2012 by the American Academy of Ophthalmology.