Abstract

Glaucoma is one of the leading causes of blindness in America, and affects over 15 million individuals. Loss of vision is caused by degeneration of the optic nerve, often accompanied by elevated intraocular pressure. There is a large genetic component to this disease, but the specific genes involved are not yet known. Current treatments are aimed at slowing vision loss by reducing intraocular pressure, but do not address the molecular basis of the disease. The goal of this project is to investigate differential gene expression in the trabecular meshwork, in order to identify genes that affect the drainage of fluid, and in turn, intraocular pressure. We hypothesize that the abnormal functioning of trabecular meshwork tissue in patients with primary open angle glaucoma (POAG) is associated with altered patterns of gene expression in this tissue. We will use Serial Analysis of Gene Expression (SAGE) to profile transcription patterns in trabecular meshwork from POAG patients as well as from young (20-40 years) and age-matched (50-70 years) controls. Genes whose expression levels are significantly up- or down-regulated in affected individuals will be investigated as candidate genes for POAG. We will also investigate genes whose expression levels changes significantly with age in normal individuals. These genes will be mapped, providing an excellent resource for future positional cloning of disease genes that affect the trabecular meshwork. Candidate genes will then be tested for association with POAG by family-based association analysis. This double screen-differential expression in affected tissue and statistical association with disease-will provide a powerful mechanism for the identification of candidate susceptibility genes. The most promising candidates will then be characterized at the molecular level and screened for mutations and polymorphisms. The identification of POAG susceptibility genes could provide the basis for diagnostic tests and lead to earlier detection of POAG and a greatly improved prognosis for the millions of patients affected with this debilitating disease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013315-04
Application #
6751518
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Chin, Hemin R
Project Start
2001-07-02
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
4
Fiscal Year
2004
Total Cost
$346,500
Indirect Cost

  Institution

Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705

  Publications

Bailey, Jessica N Cooke; Gharahkhani, Puya; Kang, Jae H et al. (2018) Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets. Invest Ophthalmol Vis Sci 59:629-636
Khawaja, Anthony P; Cooke Bailey, Jessica N; Wareham, Nicholas J et al. (2018) Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma. Nat Genet 50:778-782
Liu, Yutao; Allingham, R Rand (2017) Major review: Molecular genetics of primary open-angle glaucoma. Exp Eye Res 160:62-84
Pasquale, Louis R (2016) Vascular and autonomic dysregulation in primary open-angle glaucoma. Curr Opin Ophthalmol 27:94-101
Hauser, Michael A; Aboobakar, Inas F; Liu, Yutao et al. (2015) Genetic variants and cellular stressors associated with exfoliation syndrome modulate promoter activity of a lncRNA within the LOXL1 locus. Hum Mol Genet 24:6552-63
Li, Zheng; Allingham, R Rand; Nakano, Masakazu et al. (2015) A common variant near TGFBR3 is associated with primary open angle glaucoma. Hum Mol Genet 24:3880-92
Liu, Yutao; Garrett, Melanie E; Yaspan, Brian L et al. (2014) DNA copy number variants of known glaucoma genes in relation to primary open-angle glaucoma. Invest Ophthalmol Vis Sci 55:8251-8
Bailey, Jessica N Cooke; Yaspan, Brian L; Pasquale, Louis R et al. (2014) Hypothesis-independent pathway analysis implicates GABA and acetyl-CoA metabolism in primary open-angle glaucoma and normal-pressure glaucoma. Hum Genet 133:1319-30
Carnes, Megan Ulmer; Liu, Yangfan P; Allingham, R Rand et al. (2014) Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma. PLoS Genet 10:e1004372
Ozel, A Bilge; Moroi, Sayoko E; Reed, David M et al. (2014) Genome-wide association study and meta-analysis of intraocular pressure. Hum Genet 133:41-57

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