Precision medicine coming to glaucoma via specific pathways

By Fred Gebhart; Reviewed by Joan M. O'Brien, MD

Emerging data from the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study recognizes glaucoma as a set of multiple diseases, said Joan M. O’Brien, MD.

POAAGG, a 5-year study funded by the National Eye Institute, is the largest genetic study of African Americans with primary open-angle glaucoma (POAG) to date. POAAGG researchers are beginning to identify distinct genetic variants associated with clinical phenotypes of POAG.

Characterizing the genetic elements linked to different types of glaucoma could help clinicians develop more precise and effective treatments.

“We are working to explore and exploit the genetic differences that underlie the phenotypic variation in glaucoma,” said Dr. O’Brien, chair of the University of Pennsylvania’s Department of Ophthalmology, Scheie Eye Institute, Philadelphia, and primary investigator of POAAGG.

Making an analogy

“We can consider an analogy between glaucoma and diseases, such as breast cancer,” Dr. O'Brien said. “Not so long ago, a person diagnosed with breast cancer simply had breast cancer. Now we know that breast cancer is a wide array of phenotypically and genetically distinct diseases.”

Knowledge of the genetics of breast cancer lets clinicians use precision medicine to treat the disease more effectively than ever, she explained.

“We are learning how to inhibit cancer-promoting pathways that shouldn’t be turned on or to kick-start inhibitory pathways that have been turned off,” Dr. O'Brien added. “That is the goal in glaucoma, to discover the specific pathways that underlie specific kinds of disease, then find ways to change that messaging in cells.”

The POAAGG study population consists of self-identified African Americans aged 35 years and older in the Philadelphia region. Every participant receives a clinical exam that includes a complete glaucoma evaluation and interview. Glaucoma cases, suspects, and controls are determined by glaucoma specialists based on specific clinical criteria.

Glaucoma suspects are particularly important. Some suspects have progressed to cases over the study duration, Dr. O’Brien noted.

“We want to look at the genetic risk factors for rapid progression,” she explained. “We know that in African American populations a good proportion of patients present at a younger age than we would expect in the general U.S. population and progress more rapidly.

“Our center is located in a predominantly African American neighborhood, and our neighbors are walking in already blind from glaucoma,” she added.

POAAGG has already enrolled more than 8,000 African American patients in the Philadelphia area. The 5-year study was launched in April 2014.

“African Americans are the group most adversely affected by POAG, yet they are the least-well studied,” Dr. O’Brien noted. “Only 3% of samples for all genome-wide association studies have been African American, with the vast majority of samples being European. This study is a first step to remedy a lack of understanding and move toward more effective screening, diagnosis, and treatment of POAG.”

Variety of clinical traits

Examinations of African Americans with POAG show a variety of clinical traits, including a range of visual field defects and differences in optic nerve appearance. The study is using 1.8 million single nucleotide polymorphisms to identify genes that are associated with POAG.

“Our comprehensive genetic analysis uses genome-wide, exome-wide, and mitochondrial association analysis to look at some of the genes that might be associated with glaucoma in this population,” Dr. O’Brien explained. “We suspect that those differences we see clinically will be related to some of the differences that occur genetically.”

Mitochondrial DNA analysis shows that African Americans are a widely diverse population with multiple ancestral branches, or haplogroups. A few of these haplogroups are over-represented in POAG cases within the study population.

Early analysis suggests some of these ancestral lineages may confer some degree of protection against POAG, while other lineages may increase the risk of developing POAG.

One of the clearest examples is a pair of missense variants in the mitochondrial cytochrome c oxidase subunit I (MT-CO1) gene that define a common African haplogroup. The presence of these two variants may elevate the risk of developing glaucoma and could result in more severe disease.

“Patients with this double-missense mutation appear to have worse visual field loss, higher cup-to-disc ratio, and lower IOP,” Dr. O’Brien said.”

Joan M. O’Brien, MD

e: Joan.O'Brien@uphs.upenn.edu

This article was adapted from Dr. O'Brien's presentation at the American Academy of Ophthalmology meeting. Research was supported by the National Eye Institute, Bethesda, MD.