The relationship between Family History and Genetic susceptibility to open angle glaucoma

Abstract

Purpose : Glaucoma family history is a risk factor for open-angle glaucoma (OAG) and thought to be a surrogate for an inherited genetic risk. We have previously reported that 6 single nucleotide polymorphisms (SNPs) are associated with increased glaucoma risk in a dose-dependent manner. Here we assess the interaction between these SNPs and OAG family history

Methods : The Blue Mountains Eye Study is a population-based cohort of older Australians followed from 1990-2007. Glaucoma family history was obtained via standardized questionnaire. OAG diagnosis was by masked expert panel assessment, based on glaucomatous visual field loss and matching optic disc appearance, independent of intraocular pressure. DNA was analyzed using Illumina HumanHap670 quad arrays for rs4656461 (TMCO1), rs4619890 (AFAP1), rs11969985 (GMDS), rs4977756 (CDKN2B_AS1), rs2472493 (ABCA1) and rs10483727 (SIX1/SIX6). After ensuring no inter-SNP interactions, allele load scores were constructed and the relationship with family history explored using logistic regression.

Results : Of 2471 participants with complete data, 85 had OAG (3.44%). OAG family history was reported by 345 participants (14%) and associated with female gender and OAG. After adjusting for gender, age and intraocular pressure (highest of the two eyes) participants with an OAG family history were 3 times more likely to have OAG.

No association was found in between glaucoma family history and individual SNPs or allele load, for either single risk alleles or homozygous high-risk genotypes, after adjusting for gender or in men and women separately. Nor was any associations found between these genetic risk measures and other previously identified OAG risk factors.

The final multivariate model contained allele load, OAG family history, intraocular pressure, age and gender. The odds of OAG increased 1.43 times (95CI 1.23-1.67) for each additional risk allele. This represents an interquartile odds for allele load (OR 2.9 p<0.0001) of approximately the same magnitude as family history (OR 3.1 p<0.0001).

Conclusions : Allele load confers a substantial increase in odds of OAG for these 6 alleles in this population, but independently of glaucoma family history. While the gender associations of family history point to recall bias in this measure, the lack of association with these SNPs suggests many more OAG risk alleles are yet to be identified.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.