Researchers from Harvard Medical School, Massachusetts Eye and Ear and Case Western Reserve University School of Medicine have led an international effort to identify three genetic associations that influence susceptibility to primary open-angle glaucoma—the most common form of adult-onset glaucoma and the leading cause of irreversible blindness in the world. In the largest genome-wide association study of its kind, the investigators studied more than 4,000 cases and 30,000 controls for primary open-angle glaucoma using human genomes collected through the NEIGHBORHOOD consortium, a National Eye Institute collaborative. The researchers identified relationships between primary open-angle glaucoma and three genetic associations:TXNRD2, ATXN2 and FOXC1. The findings, published in Nature Genetics, provide key insights that may ultimately be used to develop gene-based testing and treatment strategies for glaucoma.
“We have identified three new genetic associations for primary open-angle glaucoma, and each one tells an interesting story about the disease,” said Janey Wiggs, the HMS Paul Austin Chandler Professor of Ophthalmology and co-director of the Ocular Genomics Institute at Mass. Eye and Ear, and a principal investigator on the study. “Previously, we have had very little insight into the actual molecular events that contribute to this disease.”
Glaucoma is characterized by a rise in eye pressure that can lead to irreparable damage of the optic nerve, which connects the eye to the brain. The increase in pressure is caused by dysfunctional drainage in the front of the eye. As fluid accumulates in the eye, intraocular pressure rises, and when that pressure rises above a certain level, it damages the optic nerve. In advanced stages of the disease, patients become completely blind. Primary open-angle glaucoma is the most common form of the disease and refers to glaucoma that progresses quietly as the drainage canals become damaged over time. Current treatment for glaucoma is limited to preventing permanent damage to the optic nerve; therefore, early detection and regular monitoring are essential to preserving eye health in glaucoma patients. However, glaucoma often progresses to advanced stages without any noticeable symptoms.
“The goal of this work is not only to increase our ability for early detection, but also to define molecules that, when they are dysfunctional, can contribute to disease. This is the critical insight that we need before we can develop gene-based screening tests to identify genetic risk factors and, ultimately, any gene-based therapy,” said Jonathan Haines, chair of the Department of Epidemiology and Biostatistics and the Mary W. Sheldon, MD, Professor of Genomic Sciences at Case Western Reserve University School of Medicine.
The three genetic associations for primary open-angle glaucoma identified in the study include:
TXNRD2: The researchers found an association between primary open-angle glaucoma and reduced levels of TXNRD2, a mitochondrial protein that naturally regulates the production of reactive oxygen species in cells. Without enough TXNRD2, reactive oxygen species can accumulate to the point of causing the mitochondria to die prematurely, ultimately destroying the cell. This evidence suggests that mitochondrial dysfunction can lead to glaucoma.
ATXN2: It is known that expansions of a CAG repeat in ATXN2 causes spinocerebellar atrophy 2 and intermediate expansions can increase risk of other neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). The researchers found that genetic variants located in regions that regulate ATXN2 expression are associated with primary open-angle glaucoma. This finding suggests that there may be an emerging relationship between glaucoma and other neurodegenerative diseases, particularly ALS.
FOXC1: Mutations in the protein FOXC1 are known to cause an early-onset type of glaucoma caused by abnormal development of the eye. The researchers found that genetic variation in a region necessary for regulation of gene expression is associated with primary open-angle glaucoma, which is an adult-onset disease. The finding suggests that moderate changes in gene expression influence risk of later-onset disease, while mutations disrupting protein function cause more severe early-onset disease.
The researchers hope to use this new knowledge to develop gene-based screening to promote early detection and, eventually, gene therapy strategies for patients with glaucoma.
“These studies are beginning to define the molecular events that underlie disease risk, and this is the first step toward gene-based diagnostics and therapies,” said Wiggs.