In the largest study of its kind ever completed, researchers from Australia, the United Kingdom, The Netherlands, Finland, Germany, Singapore, Japan, Nigeria, Ghana, South Africa, Switzerland, Tanzania and the United States—led by principal investigator, Janey L. Wiggs, MD, PhD, associate chief of ophthalmology clinical research at Mass Eye and Ear, and the Paul Austin Chandler Professor of Ophthalmology and vice chair of clinical research at Harvard Medical School—compared the genes of 34,179 people with glaucoma to the genes of 349,321 control subjects. Their goal was to identify previously unknown gene loci (specific locations on a given gene) associated with the disease. Primary open-angle glaucoma is highly inheritable, making genetic variants a valuable treatment target.

This study, which included 10 times more glaucoma cases and controls than previous studies conducted by the group, uncovered 44 new genetic variants present only in the subjects with glaucoma. It also confirmed 83 genetic loci that had previously been identified.

One of the shortcomings of similar previous studies was a focus on people of European ancestry. Because of that narrow focus, it remained unclear whether the findings of those studies applied to other races—a notable irony given that rates of glaucoma are highest among people of African-American and Asian ancestry. For the first time in a study of this kind, the participants included members of all three groups, allowing the study to determine whether the same genetic variants appear in all groups. 

Remarkably, the data revealed that the majority of genetic variations associated with glaucoma were present in all three groups. “Seventy to 80 percent of the genetic associations had similar effects across all ancestries,” notes Dr. Wiggs. Asked whether the researchers believe the 20-percent difference between the groups might account for the difference in their disease rates and severities, Dr. Wiggs indicates it may be too early to know the answer. “The genetic associations that are not the same [between groups] are of interest,” she acknowledges. “This would be a fruitful area of investigation in the future.”

The study authors report that in addition to revealing new potential treatment targets, the new data suggest the presence of previously unknown biological processes that may contribute to the development of the disease. “Those new processes include vascular function and development,” explains Dr. Wiggs. “Blood vessels and blood flow have been thought to be important [in the development of glaucoma], but these results support a more primary role for vascular development and function in some patients. Additionally, some of the vascular-related genes, such as TEK and ANGPT1, are needed for Schlemm’s canal development, which is known to be a modified lymph vessel. 

“A second interesting area is ocular development,” she says. “We’ve known that mutation in the genes needed for ocular development can cause severe forms of childhood glaucoma, but several of these genes also appear to be able to contribute to adult-onset forms of glaucoma such as POAG.”

One possible use of this kind of genetic data would be to identify associations between specific genes and different types of glaucoma. “This was a study of POAG only,” notes Dr. Wiggs. “Other types of glaucoma weren’t included. However, we’re investigating associations with the high-tension and low-tension subgroups in the study, as well as some glaucoma-related ocular traits, such as IOP and cup-to-disc ratio.” Dr. Wiggs says it may take some time to uncover the purpose of the newly discovered genetic loci. “For some of these genetic associations we have some insight into mechanism and function,” she notes. “However, for the most part the role of these genes in disease pathogenesis is still unknown.” 

In addition to suggesting new targets for therapeutic intervention, this type of data has been used to develop polygenic risk scores, making it possible to estimate the likelihood that someone will manifest the disease. Adding the new list of genetic loci should make it possible to increase the specificity of that risk score significantly. The study authors are planning additional studies to see how individuals with higher risk scores, calculated with the addition of the new data, do in the real world. Hopefully this will provide guidance for clinicians in terms of deciding whether more proactive treatment is called for.

Of course, it would be exciting if this information were able to lead to direct genetic manipulation via current techniques such as CRISPR, preventing the disease from occurring or effecting a cure. However, Dr. Wiggs urges patience. “Some of these genes may be targets for new therapies—even gene-based therapies using approaches such as CRISPR/Cas9,” she says. “However, research using animal and cell models would be needed to demonstrate efficacy and safety. Furthermore, POAG is genetically complex, so a single gene isn’t responsible for the majority of these cases. That means that treatment of a single gene would be unlikely to be curative for all patients.”

BCBS Changes Eylea Stance

After pressure from the American Academy of Ophthalmology, Blue Cross/Blue Shield has decided to continue to cover treatment with aflibercept (Eylea, Regeneron) for patients who have lost three lines of vision.

Initially, BCBS’s policy was to deny coverage to such patients, which stirred the AAO and its members into action.

“Blue Cross Blue Shield has based its exclusion of Eylea treatment on two studies that were conducted to determine the drug’s efficacy prior to approval from the FDA,” the AAO said in a statement when the original policy was announced. “The insurer ignores the hundreds of studies completed after FDA approval that reflect the results seen in real-world ophthalmology practice and that are the basis for the treatment of patients.”