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ARRA Investments in Primary Open Angle Glaucoma (POAG)

Public Health Burden
Glaucoma refers to a heterogeneous group of diseases characterized by progressive optic nerve degeneration that results in irreversible blindness, and is a major cause of blindness worldwide. Primary open-angle glaucoma (POAG), a condition whose prevalence increases sharply with increasing age, represents the most common glaucoma subtype in the Western world. It is estimated that by the year 2020, 5.9 million people will be bilaterally blinded from POAG. Among those older than 70 years, the prevalence of open-angle glaucoma is 6% in white populations, 16% in black populations and 3% in Asians. An enhanced understanding of the pathophysiologic bases of glaucoma holds considerable promise for improving glaucoma management and allowing a more rational allocation of limited healthcare resources.

Currently there is no treatment that prevents retinal ganglion cell apoptosis (programmed cell death) triggered by POAG. Since POAG optic nerve degeneration is frequently associated with elevated intraocular pressure (IOP), current therapy is directed at lowering the IOP. However, IOP lowering therapy is expensive -- the mean1-year healthcare charge attributable to POAG in 2004 was $1449, a charge which is above the per-capita income of 70 out of 171 countries evaluated in that year. But more importantly, costly IOP lowering treatments only slow the progression of POAG and do not halt the disease process. Moreover, as IOP is only a risk factor, incidence studies report that many newly diagnosed POAG patients present with IOP in the normal range. Collectively these data suggest that factors other than elevated IOP contribute to optic nerve degeneration in POAG. Therapy targeted to the underlying molecular mechanisms responsible for elevated IOP and/or optic nerve degeneration cannot currently be given because the molecular pathogenesis of the disease is not known. Clearly, an improved understanding of POAG pathogenesis is needed before effective treatment strategies can be implemented.  

Basic Research on the Genetics of POAG
Despite many decades of research, little is known about its pathogenesis on a molecular level. However, a significant genetic predisposition for POAG in the family history of glaucoma is a major risk factor for POAG and the prevalence of POAG in first-degree relatives of affected patients is 7 to 10 times that of the general population. Although glaucoma-related genes have been identified from linkage studies using large families affected with the disease, it is absolutely required to conduct an adequately powered genome-wide association study (GWAS) to discover the full spectrum of genes that impact this complex disease.

NIH ARRA funds support genetic investigations aimed at elucidating the pathogenesis of POAG.
  • Large-scale whole genome association (WGA) studies are needed to identify genetic variants that are biologically relevant. The NEIGHBOR (NEI Glaucoma Human genetics collaBORation) consortium is a unique collaborative effort, involving 22 investigators at 12 institutions throughout the United States, to collect 2000 POAG cases and 2000 controls to sufficiently power a genome-wide association study. A multidisciplinary team of investigators with a wide range of expertise oversee and coordinate the entire NEIGHBOR GWAS project1-3.
  • The results of NEIGHBOR GWAS will be evaluated in parallel with the GENEVA (gene-environment) study of glaucoma (GLAUGEN) which includes an additional 1200 cases and 1200 controls selected using the same POAG definition.
  • Another ARRA grant leverages the work of the NEIGHBOR and GENEVA GWAS consortia to takes genetic study of POAG beyond GWAS4. Using a subset of the samples from the NEIGHBOR consortium, this study aims to find rare genetic variants associated with POAG with cutting-edge high-throughput genomic sequencing technologies.
Once genetic factors contributing to POAG are confirmed, gene-environment and gene-gene interactions can be further investigated which will lead to the implementation of effective screening and prevention strategies, and to the development of novel therapies.

  1. 3R01EY015872-05S1 -- Genetic Etiologies of Primary Open Angle Glaucoma -- Wiggs, Janey L (MA)
  2. 3R01EY019126-02S1 -- Admixture Mapping of Glaucoma Genes in African Americans -- Hauser, Michael A (NC)
  3. 3R01EY015473-05S1 -- Gene-Environment Interactions in Glaucoma -- Pasquale, Louis R (MA)
  4. 1RC2EY020678-01 -- Genome-Wide Targeted Gene Resequencing in Glaucoma -- Gaasterland, Theresa (CA)

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