Estrogen, POAG link explored

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Data analyses found a strong association in women between estrogen metabolism pathway single-nucleotide polymorphisms and high-pressure, open-angle glaucoma.

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Seattle–Common variants in estrogen metabolizing genes collectively contribute to primary open-angle glaucoma (POAG) in women, according to researchers at the annual meeting of the Association for Research in Vision and Ophthalmology.

Dr. PasqualeLouis R. Pasquale, MD, and co-workers investigated associations between the disease and a panel made up of about 900 single-nucleotide polymorphisms (SNPs) from the estrogen metabolism pathway using samples from more than 6,600 patients with POAG and unaffected controls. Using sophisticated software to perform complex analyses, no associations were found between the estrogen SNP pathway and POAG overall, high-pressure glaucoma (IOP ≥22 mm Hg) or normal-pressure glaucoma (IOP <22 mm Hg) when looking at the entire study population.

However, when the study group was divided by gender, an association was found between the estrogen SNP pathway and POAG in women. Findings from an IOP-based subgroup analysis showed the association in women was only with high-pressure glaucoma.

“The findings from this study provide additional support for the concept that variations in estrogen levels play a role in glaucoma risk,” said Dr. Pasquale, HMS Distinguished Ophthalmology Scholar and associate professor of ophthalmology, Harvard Medical School, Boston. “As a next step, we hope to establish that estrogen levels are different [when] comparing women who go on to develop open-angle glaucoma (OAG) and those who do not, as that would provide definitive evidence that declining estrogen levels are important in determining a woman’s risk for developing OAG.”

Currently, Dr. Pasquale is writing a grant application to the NIH for a case-control study that would use banked blood and participant data from the Nurses’ Health Study (NHS) to compare circulating estrogen levels in women with and without glaucoma while taking into account menopause status, type (natural or surgical), and use of hormone replacement therapy.

Building the estrogen story

Interest in investigating a role of circulating estrogen in the pathogenesis of glaucoma derives from several observations, beginning with the fact that estrogen receptors are present on retinal ganglion cells. In addition, studies have shown IOP decreases during pregnancy and in postmenopausal women using hormone replacement therapy. There is evidence that neuroretinal rim thickness as well as visual field performance vary as a function of the menstrual cycle.

In addition, analyzing NHS data, Dr. Pasquale and co-workers previously reported an increased risk of POAG among women using oral contraceptives for 5 or more years but a reduced risk of the high-tension variant in women with menopause onset at a later age. Consistent with the latter finding, Dutch researchers found that early-age menopause was associated with an increased risk of OAG. In an Australian study, investigators found the incidence of OAG in women lagged behind that of men during the 5th and 6th decades of life and caught up thereafter, consistent with the idea that women were protected early after menopause by waning estrogen levels.

Previous studies have also investigated whether a genetic component might explain variations in declining estrogen levels and glaucoma risk, but they yielded conflicting results, noted Dr. Pasquale, who is also director of the glaucoma service, Massachusetts Eye and Ear Infirmary, Boston.

“However, the prior studies did not look at a full complement of estrogen metabolizing genes,” he said.

To address the latter limitation, Dr. Pasquale’s colleague, Stephanie Loomis, BA, MPH, glaucoma genetics research coordinator, Massachusetts Eye and Ear Infirmary, Boston, conducted a thorough literature search to identify enzymes responsible for controlling circulating estrogen levels. Her review found 23 genes on 15 chromosomes and a total of 903 common variants of those genes that were used for the analyses in the present study.

Implications for improved care

In the future, Dr. Pasquale expects it will be possible to develop a genomic-based risk calculator for predicting the likelihood that a woman will develop POAG. Such a tool will depend on the identification of at least 50 genes that contribute to glaucoma risk, he said.

“So far, we have identified only a handful of associated genes, but we expect that number to double soon and firmly believe that we will be using genetic information to identify susceptibility to POAG in women in the future,” he said.

Knowledge about genes associated with glaucoma development can also open the door to new understanding of disease pathogenesis and the identification of novel therapeutic targets. For example, the finding that polymorphisms in the gene for catechol-O-methyl transferase had the strongest association with POAG suggests the possibility that a topical therapy modulating the activity of this gene or the enzyme itself might be effective for reducing the likelihood of glaucoma development in at-risk women or as a treatment for early or moderate disease.

Louis R. Pasquale, MD

E: louis_pasquale@meei.harvard.edu

Dr. Pasquale did not indicate a proprietary interest in the subject matter.

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