Dataset Information

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

ABSTRACT: Sex 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.We 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]).In 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.Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.

SUBMITTER: Bailey JNC

PROVIDER: S-EPMC5795896 | biostudies-other | 2018 Feb

REPOSITORIES: biostudies-other

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

Bailey Jessica N Cooke JNC Gharahkhani Puya P Kang Jae H JH Butkiewicz Mariusz M Sullivan David A DA Weinreb Robert N RN Aschard Hugues H Allingham R Rand RR Ashley-Koch Allison A Lee Richard K RK Moroi Sayoko E SE Brilliant Murray H MH Wollstein Gadi G Schuman Joel S JS Fingert John H JH Budenz Donald L DL Realini Tony T Gaasterland Terry T Scott William K WK Singh Kuldev K Sit Arthur J AJ Igo Robert P RP Song Yeunjoo E YE Hark Lisa L Ritch Robert R Rhee Douglas J DJ Vollrath Douglas D Zack Donald J DJ Medeiros Felipe F Vajaranant Thasarat S TS Chasman Daniel I DI Christen William G WG Pericak-Vance Margaret A MA Liu Yutao Y Kraft Peter P Richards Julia E JE Rosner Bernard A BA Hauser Michael A MA Craig Jamie E JE Burdon Kathryn P KP Hewitt Alex W AW Mackey David A DA Haines Jonathan L JL MacGregor Stuart S Wiggs Janey L JL Pasquale Louis R LR

Investigative ophthalmology & visual science 20180201 2

<h4>Purpose</h4>Sex 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.<h4>Methods</h4>We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 ...[more]

PMID: 29392307

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Project description:BackgroundTestosterone may be a possible modifiable risk factor for open-angle glaucoma (OAG) and intraocular pressure (IOP), but evidence has been scarce and conflicting. In this study we evaluated the association of testosterone and its genetic predisposition with incident (i) OAG, IOP, retinal nerve fiber layer (RNFL), and ganglion cell-inner plexiform layer (GCL +).MethodsParticipants aged 45-100 years were derived from the prospective, population-based Rotterdam Study. Ophthalmic examinations and serum testosterone measurements (including bioavailable and free testosterone) were performed from 1991 onwards. Follow-up took place every 4-5 years. A total of 187 out of 7898 participants were diagnosed with incident (i) OAG during follow-up. Genotyping was performed in 165 glaucoma cases and 6708 controls. We calculated sex-specific weighted genetic risk scores (GRS) for total and bioavailable testosterone. Associations with iOAG were analyzed using multivariable logistic regression. Associations with IOP, RNFL, and GCL + were analyzed with multivariable linear regression. Analyses were stratified on sex and adjusted for at least age, body mass index, and follow-up duration.ResultsIn men, testosterone was not associated with iOAG. However, the GRS for higher total testosterone was associated with an increased iOAG risk (odds ratio [OR] with 95% confidence interval [95% CI]: 2.48 [1.18; 5.22], per unit). In women, higher values of bioavailable testosterone (2.05 [1.00; 4.18] per nmol/L) and free testosterone (1.79 [1.00; 3.20] per ng/dL) were significantly associated with increased risk of iOAG. Moreover, the GRS for higher bioavailable testosterone was associated with an increased iOAG risk (2.48 [1.09; 5.65], per unit). Higher bioavailable and free testosterone were adversely associated with IOP (0.58 [0.05; 1.10] per nmol/L and 0.47 [0.04; 0.90] per ng/dL). Higher total testosterone was inversely associated with peripapillary RNFL and GCL + (Beta [95% CI]: - 3.54 [- 7.02; - 0.06] per nmol/L and - 2.18 [- 4.11; - 0.25] per nmol/L, respectively).ConclusionsIn women, higher testosterone levels increased the risk of iOAG. Both IOP-dependent and IOP-independent mechanisms may underlie this association. Managing testosterone levels may be particularly relevant for the prevention of neurodegeneration in the eye. Future research should confirm these findings.

Dataset Information

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

Publications

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

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