Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large...

Area of Science:

• Ophthalmology
• Genetics
• Endocrinology

Background:

• Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness.
• The role of sex hormones, including testosterone, in POAG pathogenesis remains incompletely understood.
• Previous research indicated estrogen metabolism gene variants are associated with POAG in women.

Purpose of the Study:

• To investigate the association between gene variants in testosterone metabolism pathways and the risk of primary open-angle glaucoma (POAG).
• To examine these associations in a sex-stratified manner and across different POAG subtypes.
• To analyze data from two independent population-based cohorts.

Main Methods:

• Utilized two large datasets from the United States and Australia, comprising thousands of cases and controls.
• Employed pathway- and gene-based analyses using Pathway Analysis by Randomization Incorporating Structure (PARIS) software.
• Assessed single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and performed sex-stratified analyses for POAG and its subtypes (high-tension glaucoma [HTG] and normal tension glaucoma [NTG]).

Main Results:

• A panel of SNPs in testosterone metabolism genes showed a significant association with POAG in the Australian dataset (permuted P = 0.018) but not the US dataset (permuted P = 0.77).
• This association was consistently observed in men across both datasets (permuted P ≤ 0.033), but not in women (permuted P ≥ 0.42).
• The testosterone pathway was significantly associated with high-tension glaucoma (HTG) in both datasets (permuted P ≤ 0.011), though specific driver genes were not consistently identified.

Conclusions:

• Genetic variants in the testosterone metabolism pathway are collectively associated with primary open-angle glaucoma (POAG).
• The association is particularly significant for the high-tension glaucoma (HTG) subtype and appears more pronounced in men.
• These findings highlight a potential role for testosterone in the development of HTG.