Researchers have identified three genetic associations that influence susceptibility to primary open angle glaucoma (POAG) – 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 POAG using human genomes collected through the NEIGHBORHOOD consortium, a National Eye Institute collaborative. The researchers identified relationships between POAG and three genetic associations: TXNRD2, ATXN2 and FOXC1. The findings, published in Nature Genetics, provide key insight that may ultimately be used to develop gene-based testing and treatment strategies for glaucoma.
Dr. Janey Wiggs, co-director of the Glaucoma Center of Excellence at Massachusetts Eye and Ear/Harvard Medical School, said each of the new genetic associations “tells an interesting story about the disease”.
“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 Dr. Jonathan L. Haineschair of Epidemiology and Biostatics and the Mary W. Sheldon, MD, Professor of Genomic Sciences Case Western Reserve University School of Medicine. The three genetic associations for POAG identified in the study include:
TXNRD2: A mitochondrial protein that naturally regulates the production of a reactive oxygen species in cells. Without enough TXNRD2, the reactive oxygen species can accumulate to the point of causing the mitochondria to prematurely die, ultimately destroying the cell. This evidence suggests that mitochondrial dysfunction can lead to glaucoma.
ATXN2: It is known that mutations in the gene ATXN2 cause severe neurodegenerative diseases, such as amyotrophic lateral sclerosis(ALS), and the variance in the gene that causes those diseases is the type of mutation that causes a severe early onset phenotype. The researchers found that genetic variants located in regions that regulate ATXN2 expression is associated with POAG. This finding suggests that there may be an emerging relationship between glaucoma and severe neurodegenerative diseases, and 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 POAG, which is an adult onset disease. The finding suggests that changes in expression of the gene may not lead to early onset glaucoma, but can instead contribute to a milder, later 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.
“The genetic studies are beginning to define molecules that, when they are dysfunctional, can contribute to disease. This is 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 Dr. Wiggs. “We hope to have the opportunity to understand enough about this basic molecular biology of the disease that we can begin to target critical molecular events with gene-based therapies”.