Genetic susceptibility to open angle glaucoma: the Blue Mountains Eye Study

Abstract

 

Purpose

 

Six single nucleotide polymorphisms (SNPs); rs4656461 (TMCO1), rs4619890 (AFAP1), rs11969985 (GMDS), rs4977756 (CDKN2B_AS1), rs2472493 (ABCA1) and rs10483727 (SIX1/SIX6); have recently been reported to be associated with the development of primary open angle glaucoma (OAG). We aimed to determine whether these risk alleles are independently associated with an increased risk of primary open angle glaucoma (POAG) in at least one eye in the Blue Mountains Eye Study (BMES) cohort, and evaluate genetic risk scores for POAG.

 

Methods

 

OAG diagnosis by expert panel was based on masked glaucomatous visual field loss and matching optic disc appearance, independent of intraocular pressure. Genetic analysis was performed using Illumina HumanHap670 quad arrays. Logistic regression models were used to assess associations between the genetic loci and POAG, adjusting for age and gender. Risk scores were constructed quantifying the effect of each additional risk allele among SNPs significant together in multivariable modeling.

 

Results

 

A total of 2481 participants in the BMES cohort had data on SNPs and glaucoma status. Of these, 85 had POAG (cases) and 2396 did not (controls).<br /> <br /> When analyzed individually, four SNPs, rs4656461 (risk allele G), rs4977756 (risk allele A), rs10483727 (risk allele A) and rs2472493 (risk allele G) all conferred increased risk of OAG (p=0.047, 0.004, 0.04 and 0.006 respectively) (Table 1). Corresponding risk allele frequencies were 0.12, 0.60, 0.39 and 0.43.<br /> <br /> In multivariable modeling, 3 SNPs (rs4656461, rs4977756 and rs2472493) remained significantly associated with OAG (OR 1.61-1.67, p<0.05). These effects appeared largely independent of each other. Proportions of participants developing OAG were 1.7%, 2.7%, 4.3% or 6.0% among those carrying 0-1, 2, 3 or 4-6 risk alleles from these three SNPs.

 

Conclusions

 

These recently discovered SNPs were associated with OAG in a European-derived older population, each conferring about a 50% increased risk. Increasing number of risk alleles was associated with increasing glaucoma risk in a dose-dependent manner. Genetic risk scoring may have clinical utility by providing a glaucoma-enriched population for screening.  

 

Table 1