The underlying hypothesis of this proposal is that specific gene defects are responsible for the pseudoexfoliation syndrome and for the adult open angle glaucoma that is frequently found as part of this condition. In preliminary studies the PI has ascertained and collected 51 sibpairs affected by pseudoexfoliation and pseudoexfoliative glaucoma. Using 40 or these sibpairs she has performed preliminary genetic studies using microsatellite repeat markers located within genomic regions harboring candidate genes selected on the basis of their known expression and location in the eye and known ocular function. These studies identified 5 genomic regions that show interesting initial results. In this proposal, she plans to add to this preliminary work by performing a complete genome scan designed to identify susceptibility genes responsible for this condition.
The specific aims of the research plan are to: 1) collect an initial group of at least 100 sibling pairs (or other relative pairs) affected by pseudoexfoliation; 2) scan the human genome for susceptibility loci using DNA samples from the collected affected pedigree members, microsatellite repeat markers located at 1- cM intervals and analytical methods to identify genomic regions demonstrating nominal evidence for linkage; 3) perform follow-up studies using a second set of affected pedigree members and additional markers to confirm the initial linkage results; 4) identify candidate genes within the confirmed genomic regions using allelic association analyses (S-TDT) and SNPs; and 5) correlate specific genetic defects with particular aspects of the clinical phenotype, including the relationship between pseudoexfoliative material and glaucoma. Identifying the gene defects responsible for pseudoexfoliation syndrome and its associate glaucoma and understanding how these defects contribute to the development of adult onset glaucoma will lead to important new insights into the pathophysiology of this form of glaucoma and will add to our collective knowledge of glaucoma in general.
| Aung, Tin (see original citation for additional authors) (2017) Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci. Nat Genet 49:993-1004 |
| Aung, Tin; Ozaki, Mineo; Mizoguchi, Takanori et al. (2015) A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome. Nat Genet 47:387-92 |
| Fan, Bao J; Pasquale, Louis R; Kang, Jae H et al. (2015) Association of clusterin (CLU) variants and exfoliation syndrome: An analysis in two Caucasian studies and a meta-analysis. Exp Eye Res 139:115-22 |
| Wiggs, Janey L; Pasquale, Louis R (2014) Expression and regulation of LOXL1 and elastin-related genes in eyes with exfoliation syndrome. J Glaucoma 23:S62-3 |
