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

Jessica N. Cooke Bailey , Puya Gharahkhani, Jae H. Kang, Mariusz Butkiewicz, David A. Sullivan, Robert N. Weinreb, Hugues Aschard, R. Rand Allingham, Allison Ashley-Koch, Richard K. Lee, Sayoko E. Moroi, Murray H. Brilliant, Gadi Wollstein, Joel S. Schuman, John H. Fingert, Donald L. Budenz, Tony Realini, Terry Gaasterland, William K. Scott, Kuldev SinghArthur J. Sit, Robert P. Igo, Jr., Yeunjoo E. Song, Lisa Hark, Robert Ritch, Douglas J. Rhee, Douglas Vollrath, Donald J. Zack, Felipe Medeiros, Thasarat S. Vajaranant, Daniel I. Chasman, William G. Christen, Margaret A. Pericak-Vance, Yutao Liu, Peter Kraft, Julia E. Richards, Bernard A. Rosner, Michael A. Hauser, Jamie E. Craig, Kathryn P. Burdon, Alex W. Hewitt, David A. Mackey, Jonathan L. Haines, Stuart Macgregor, Janey Wiggs, Louis R. Pasquale

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Abstract

Purpose: 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. Methods: 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]). Results: 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. Conclusions: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.

Original languageEnglish
Pages (from-to)629-636
Number of pages8
JournalInvestigative Ophthalmology and Visual Science
Volume59
Issue number2
DOIs
Publication statusPublished - Feb 2018

Bibliographical note

Copyright 2018 The Authors
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Keywords

  • Glaucoma
  • slit lamp biomicroscopy
  • angle closure
  • cup-disc ratio

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    Cooke Bailey , J. N., Gharahkhani, P., Kang, J. H., Butkiewicz, M., Sullivan, D. A., Weinreb, R. N., Aschard, H., Allingham, R. R., Ashley-Koch, A., Lee, R. K., Moroi, S. E., Brilliant, M. H., Wollstein, G., Schuman, J. S., Fingert, J. H., Budenz, D. L., Realini, T., Gaasterland, T., Scott, W. K., ... Pasquale, L. R. (2018). Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets. Investigative Ophthalmology and Visual Science, 59(2), 629-636. https://doi.org/10.1167/iovs.17-22708