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Invest Ophthalmol Vis Sci. 2018 Feb 1;59(2):629-636. doi: 10.1167/iovs.17-22708.

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

Author information

1
Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States.
2
Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States.
3
Statistical Genetics, QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, Australia.
4
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States.
5
Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States.
6
Department of Ophthalmology, Hamilton Glaucoma Center and Shiley Eye Institute, University of California at San Diego, La Jolla, California, United States.
7
Department of Epidemiology, Harvard T. H. Chan School of Public Health, Harvard Medical School, Boston, Massachusetts, United States.
8
Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States.
9
Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States.
10
Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, United States.
11
Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States.
12
Center for Human Genetics, Marshfield Clinic Research Institute, Marshfield, Wisconsin, United States.
13
Department of Ophthalmology, NYU Langone Medical Center, NYU School of Medicine, New York, New York, United States.
14
Departments of Ophthalmology and Anatomy/Cell Biology, University of Iowa, College of Medicine, Iowa City, Iowa, United States.
15
Department of Ophthalmology, University of North Carolina, Chapel Hill, North Carolina, United States.
16
Department of Ophthalmology, WVU Eye Institute, Morgantown, West Virginia, United States.
17
Scripps Genome Center, University of California at San Diego, San Diego, California, United States.
18
Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States.
19
Department of Ophthalmology, Stanford University, Palo Alto, California, United States.
20
Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, United States.
21
Wills Eye Hospital, Glaucoma Research Center, Philadelphia, Pennsylvania, United States.
22
Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York, New York, United States.
23
Department of Ophthalmology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States.
24
Department of Genetics, Stanford University, Palo Alto, California, United States.
25
Wilmer Eye Institute, Johns Hopkins University Hospital, Baltimore, Maryland, United States.
26
Department of Ophthalmology, University of Illinois College of Medicine at Chicago, Chicago, Illinois, United States.
27
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States.
28
Department of Cellular Biology and Anatomy, Augusta University, Augusta, Georgia, United States.
29
Department of Biostatistics, Harvard T. H. Chan School of Public Health, Harvard Medical School, Boston, Massachusetts, United States.
30
Department of Ophthalmology, Flinders University, Adelaide, SA, Australia.
31
School of Medicine, Menzies Research Institute of Tasmania, Hobart, Australia.
32
Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia.
33
Department of Ophthalmology, Mass Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States.

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.

PMID:
29392307
PMCID:
PMC5795896
DOI:
10.1167/iovs.17-22708
[Indexed for MEDLINE]
Free PMC Article

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