Primary open angle glaucoma (POAG) is a significant cause of blindness worldwide. Compelling evidence supports the hypothesis that specific genes influence susceptibility to the disease. The objective of this proposal is to identify POAG susceptibility genes and determine the relationships between specific genetic defects and clinical phenotype. In addition to providing insight into disease related molecular pathology, this information will lead to new treatment and diagnostic modalities. Using 103 sibpairs affected by POAG, an initial screen of the human genome has been completed, and sixteen genomic regions demonstrating initially promising linkage results have been identified. The goals of the current proposal are to confirm the initial POAG linkage results with a second set of affected pedigrees, examine candidate genes located in the confirmed regions, and identify genes that confer risk to POAG. To achieve these goals, a second pedigree set of 200 affected sibpairs will be collected and used to confirm the initial linkage results. Follow-up studies will include additional genotyping of new markers located in the regions of interest, and genotyping the initial markers in the second pedigree set. Candidate genes mapped within the confirmed genomic regions will be tested for POAG associations using both linkage analysis and family based association studies using the S-TDT. Genes that show positive associations will be screened for responsible DNA sequence alterations. Specific genetic defects will be correlated with clinical phenotype by investigating familial aggregation of clinical parameters and looking for evidence of gene/gene interactions and how these interactions may influence phenotype. Initial genome screens to identify genes responsible for two POAG risk factors, ocular hypertension (OHT) and pseudoexfoliation (PEX), will be performed.
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