Primary Open-Angle Glaucoma Linked to 2 Genetic Variations

Laurie Barclay, MD

April 30, 2012

April 30, 2012 — Two genetic variations associated with primary open-angle glaucoma (POAG) involve genes on chromosomes 9 and 14 that may interact with transforming growth factor-beta (TGF-beta), according to the results of a study reported online April 26 in PLoS Genetics. In addition, the locus on chromosome 9 was associated with normal-pressure glaucoma (NPG) in a subgroup analysis, as was a locus on chromosome 8.

"Tens of millions of people worldwide have vision loss or blindness due to glaucoma, [so] there is a critical need for better diagnostic tools and better treatments for patients with this disease," John Fingert, MD, PhD, associate professor of ophthalmology and visual sciences, Carver College of Medicine at the University of Iowa, Iowa City, told Medscape Medical News in an email interview when asked for independent comment.

Prevalence of glaucoma in the United States is approximately 2.2 million. About two thirds of patients with POAG have increased intraocular pressure, and the remainder have NPG, for which no cure is available.

"[This study] has identified genetic factors that help determine why some develop glaucoma and others do not, [and] has also provided further evidence that the [TGF-beta] signaling pathway is important in glaucoma pathogenesis," Dr. Fingert said. "These discoveries have provided some new insights into the molecular mechanisms at work in glaucoma biology and may also represent a major step towards the development of novel diagnostic tools and therapies to prevent vision loss from this blinding disorder."

In the current meta-analysis, Janey L. Wiggs, MD, PhD, from Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, and colleagues studied data from 2 independent genome-wide association studies for POAG. A total of 6633 participants enrolled in the Glaucoma Genes and Environment (GLAUGEN) study and in the NEI Glaucoma Human genetics collaboration (NEIGHBOR) study at 12 sites in the United States. All participants underwent DNA sequencing. Nearly half of the participants had POAG (3146 case-patients and 3487 control participants).

Additionally, the investigators performed a genome-wide association study on the subgroup of patients with NPG. They also retested the single-nucleotide polymorphisms that showed the most significant associations with NPG for association with a second form of glaucoma, exfoliation-syndrome glaucoma.

"Dr. Wiggs and coworkers have conducted one of the world's largest genetic studies of glaucoma," Dr. Fingert said. "One of the research team's major strengths was the great size of the patient populations that were under study, which empowered them to discover important genetic risk factors for glaucoma."

Study Findings

The investigators identified genetic variations associated with POAG, including NPG. These are the first genetic variations identified known to be commonly associated with NPG. The first variant involves the CDKN2BAS gene located on chromosome 9 (9p21), and a second variant affects the SIX1/SIX6 gene region on chromosome 14 (14q23).

The team also found that the CDKN2BAS variant was associated with NPG, as was a variant on a region of chromosome 8 (8q22). The chromosome 8 variant is in a likely regulatory region and may modulate the expression of genes LRP12 or ZFPM2. Both NPG loci were also nominally associated with exfoliation syndrome glaucoma.

"In the future, when more environmental and genetic factors (like CDKN2BAS) are discovered, physicians may be able to use genetic tests to accurately predict who is at greatest risk for developing glaucoma and target treatments to those who need them most," Dr. Fingert concluded.

The 8q22 genomic region associated with NPG contains regulatory sites that may affect 2 cell types that could contribute to glaucoma-related optic nerve disease. These are choroid plexus epithelial cells, involved in formation of cerebral spinal fluid, and nonpigmented ciliary body epithelial cells, which affect ocular intraocular pressure through the production of aqueous humor.

"This study shows that specific genes can contribute to susceptibility of optic nerve degeneration in glaucoma," Dr. Wiggs and coauthor Louis R. Pasquale, MD, also from the Harvard Medical School and Massachusetts Eye and Ear Infirmary, told Medscape Medical News in an email interview. "This is important because the deterioration of the optic nerve is the cause of blindness in patients affected by the disease."

TGF-beta Linked to Pathogenesis of POAG

A genomic pathway analysis showed an association between the TGF-beta pathway and NPG (permuted P = .009). Previous studies have also implicated the TGF-beta pathway in glaucoma. Researchers suspect that the pathway plays a pathogenetic role in glaucoma through its effects on cell growth and survival.

"Both of the genomic regions identified in this study influence the activity of TGF-beta, an important cytokine that participates in a number of cellular processes, including cell division, apoptosis, and developmental processes," Dr. Wiggs and Dr. Pasquale explained. "Although we are not yet sure which of these processes is influencing optic nerve disease in glaucoma, it is intriguing to speculate about apoptosis, as it known that retinal ganglion cells [in] the optic nerve die by an apoptotic process. Our results suggest that TGF-beta has an important role in glaucoma pathogenesis, and in particular in the optic nerve deterioration that is the cause of blindness."

This findings not only have clarified mechanisms underlying glaucoma but may ultimately have clinical and treatment implications, according to Dr. Wiggs and Dr. Pasquale. Both are co-directors of the Harvard Glaucoma Center of Excellence, and Dr. Pasquale is also director of the Glaucoma Service at Massachusetts Eye and Ear Infirmary.

"This result identifies this pathway as a target for pharmacotherapy, as we would predict that modulation of the pathway could protect the optic nerve from damage, thus preserving its function and preventing loss of sight from the disease," they added.

However, Dr. Wiggs and Dr. Pasquale note that only a few genes are known to influence susceptibility to adult-onset glaucoma, and these account for only a small fraction of the heritability of the disease. Therefore, many more genes must be awaiting identification.

"We are currently embarking on a second study that is expected to be nearly twice as large as this one, with the goal of finding these additional genes," Dr. Wiggs and Dr. Pasquale concluded. "Another important area of future research is to understand how the genes currently known to contribute to the disease interact with other genes (gene-gene interactions) as well as environmental risk factors (gene-environment interactions). The gene-environment studies are particularly important because environmental risk factors may be modifiable, leading to strategies to avoid risky behaviors with subsequent preservation of sight."

Funding sources for this research include the National Eye Institute, the National Human Genome Research Institute, Lions Eye Research Fund, Glaucoma Center of Excellence, the Margolis Fund, and Research to Prevent Blindness. Dr. Wiggs, Dr. Pasquale, and Dr. Fingert have disclosed no relevant financial relationships.

PLoS Genet. Published online April 26, 2012. Full text