Estrogen Pathway Polymorphisms in Relation to Primary Open Angle Glaucoma: A Gender-Specific Analysis from Patients in the United States

Abstract

Purpose: Altered estrogen metabolism has been strongly implicated in the pathogenesis of primary open-angle glaucoma (POAG). We assessed the association between a panel of estrogen metabolism single nucleotide polymorphisms (SNPs) in relation to POAG using a gender specific approach.

Methods: We included 3,146 POAG cases and 3,487 controls from the combined Glaucoma Genes and Environment (GLAUGEN) study and NEI Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium in this analysis. We assembled all SNPs from the estrogen metabolism pathway available on the Illumina 660W-Quad array platform. We assessed whether this aggregate of SNPs was associated with POAG overall and then by gender using the Pathway Analysis by Randomization Incorporating Structure (PARIS) analysis software package in our combined dataset. In secondary analysis we assessed associations between estrogen SNP pathway and POAG in women stratified by intraocular pressure (IOP) ≥ 22 mm Hg (HPG) or IOP < 22 mm Hg (NPG) at diagnosis. In addition, we determined which SNPs in the pathway accounted for any significant associations.

Results: The estrogen SNP pathway was not associated with POAG, NPG or HPG overall (p≥0.11). While the estrogen SNP pathway was not associated with POAG in males (permuted p=1.0) it was associated with POAG among women (permuted p=0.02). Among women, the estrogen SNP pathway was associated with HPG only (permuted p=0.004). The association between the estrogen SNP pathway and HPG in women was driven by polymorphisms in the following genes in the pathway: COMT, ESR1, AKR1C4, ESR2, CYP1A2, CYP3A4, SRDSA1 on autosomes and STS on the X chromosome. The COMT SNPs showed the strongest association with POAG across the spectrum of IOP (permuted p<0.001 for HPG and p=0.01 for NTG) among women.

Conclusions: The estrogen SNP pathway was strongly associated with HPG in women. These data provide insight regarding how common variants in the estrogen metabolism pathway contribute to POAG in women.

Keywords: 539 genetics • 464 clinical (human) or epidemiologic studies: risk factor assessment