Glaucoma is a common, blinding disease affecting 2% of Americans over the age of 40 with primary open- angle glaucoma being the most common form (70-90% of all patients). Population surveys indicate that less than half of those with glaucomatous damage have received an appropriate diagnosis or treatment. At least seven genes for POAG have been mapped, however, they represent only a small proportion of all cases. The majority of POAG results from an interaction between a person's genetic background and their environment. Identifying genes involved in complex traits, such as POAG, has been facilitated by the significant progress made by the human genome project. To tease out the potentially important genes from this complex disorder, the general phenotype of POAG will be simplified into specific endophenotypes, e.g., corneal thickness, intraocular pressure, and optic nerve cup parameters. These more discrete components will be examined within POAG families and will allow the inclusion of related members, who may not yet have POAG but have one of the above risk factors. The long-term goal of this proposal is to detect and map polymorphic genes that influence variation in risk factors for glaucoma. To provide adequate power to detect and map POAG risk factor genes, we have recruited 1500 members of 37 extended families from Northwestern US, Australia and Greece. The heritabilities will be estimated for the POAG risk factors including IOP, optic nerve and corneal thickness. An eight centimorgan map will be generated including genotyping of 500 microsatellite markers in each of the 1500 individuals. The phenotypes will be screened for linkage using the standard analysis, as well as, variance component approach. Finer scale mapping with microsatellite markers and single nucleotide poly-morphisms will more precisely localize quantitative trait loci within targeted chromosomal regions. Candidate genes within these regions will be sequenced in the 37 families to identify variations associated with specific risk factors. This study will form the basis for future studies aimed at identifying and characterizing the genes that influence POAG risk factors.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010555-12
Application #
7802108
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Chin, Hemin R
Project Start
1994-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
12
Fiscal Year
2010
Total Cost
$531,175
Indirect Cost
Name
Oregon Health and Science University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Keller, Kate E; Yang, Yong-Feng; Sun, Ying Ying et al. (2014) Interleukin-20 receptor expression in the trabecular meshwork and its implication in glaucoma. J Ocul Pharmacol Ther 30:267-76
Pasutto, Francesca; Keller, Kate E; Weisschuh, Nicole et al. (2012) Variants in ASB10 are associated with open-angle glaucoma. Hum Mol Genet 21:1336-49
Charlesworth, Jac; Kramer, Patricia L; Dyer, Tom et al. (2010) The path to open-angle glaucoma gene discovery: endophenotypic status of intraocular pressure, cup-to-disc ratio, and central corneal thickness. Invest Ophthalmol Vis Sci 51:3509-14
Wirtz, Mary K; Samples, John R; Toumanidou, Victoria et al. (2010) Association of POAG risk factors and the Thr377Met MYOC mutation in an isolated Greek population. Invest Ophthalmol Vis Sci 51:3055-60
Wirtz, Mary K; Konstas, Anastasios G P; Samples, John R et al. (2008) Myocilin variations and familial glaucoma in Taxiarchis, a small Greek village. Mol Vis 14:774-81
Wirtz, Mary K; Samples, John R; Xu, Hong et al. (2002) Expression profile and genome location of cDNA clones from an infant human trabecular meshwork cell library. Invest Ophthalmol Vis Sci 43:3698-704
Xu, H; Acott, T S; Wirtz, M K (2000) Identification and expression of a novel type I procollagen C-proteinase enhancer protein gene from the glaucoma candidate region on 3q21-q24. Genomics 66:264-73
Wirtz, M K; Samples, J R; Rust, K et al. (1999) GLC1F, a new primary open-angle glaucoma locus, maps to 7q35-q36. Arch Ophthalmol 117:237-41
Wirtz, M K; Xu, H; Rust, K et al. (1998) Insulin-like growth factor binding protein-5 expression by human trabecular meshwork. Invest Ophthalmol Vis Sci 39:45-53
Wirtz, M K; Bradley, J M; Xu, H et al. (1997) Proteoglycan expression by human trabecular meshworks. Curr Eye Res 16:412-21

Showing the most recent 10 out of 12 publications