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

Abstract

PurposeSex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk.MethodsWe used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]).ResultsIn the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations.ConclusionsCollectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.

The Role of Chromosome X in Intraocular Pressure Variation and Sex-Specific Effects

“…Although there is evidence for sex-specific effects for IOP variation and POAG risk, 8 , 9 , 13 – 16 our results indicate that chromosome X genetics are most likely not a factor for any sex-specific effects. Previous literature indicates hormonal pathways as the most probable candidate for these effects 18 , 19 , 22 , 60 and androgen receptors are expressed in multiple ocular tissues. 61 …”

“…Reduced IOP is associated with estrogen treatment in post-menopausal women 18 – 21 and there is also evidence of association between POAG and testosterone pathways in men. 22 …”

Primary open angle glaucoma genetics: The common variants and their clinical associations (Review)

“…located on chromosome 9p21, in the CDKN2B-CDKN2A gene cluster, CDKN2B protein is expressed in the inner nuclear layers of the retina and the ganglion cell layer. CDKN2B-AS1 is detected in the retina, ciliary body and optic nerve and variants have been associated with VCDR changes and NTG especially in women, as well as various non-ocular disorders, namely myocardial infarction and intracranial aneurysms; an association of POAG risk and these conditions has not been made however (41)(42)(43)(44)(45)(46)(47).…”

“…It belongs to the family of flavoenzymes that catalyze redox reactions, thus controlling the levels of reactive oxygen species. TXNRD2 is found, among others, in the retina and optic nerve and sequence variants have been associated with PoaG, possibly through a protective effect of TXNRD2 against oxidative stress of the RGCs (41,61,62).…”

“…It encodes a protein that has been shown to play a role in the regulation of embryonic and ocular development. Although mainly linked to anterior segment dysgenesis and axenfeld-rieger syndrome, sequence variants within the GMDS gene as well as variants located upstream of FOXC1 have been associated with POAG (41,57).…”