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Gene-environment Initiative in Primary Open Angle Glaucoma

Louis Robert Pasquale, M.D.

Assistant Professor of Ophthalmology Harvard Medical School

Permanent vision loss from POAG is a condition of public health significance. Current evidence suggests that POAG is a polygenetic disease modified by environmental influences. We hypothesize that the identification and characterization of POAG susceptibility genes via a genome-wide association study (GWAS) will reveal significant environmental determinants that influence the disease process, as well as a better understanding of how gene-environment and gene-gene interactions contribute to this complex disease. For this study we have formulated a case-control study population from three cohorts: the Nurses Health Study (NHS); Health Professionals Follow-up Study (HPFS); and Massachusetts Eye and Ear Infirmary (MEEI). The cohort consists of 1200 cases and 1200 controls with DNA. Members of the NHS and HPFS also have repeated environmental exposure data over a 16 to 24 year period. We will perform a single-stage GWAS and carry out the appropriate statistical analyses to find genetic markers with the strongest association with POAG. For the cuurent application, we will submit data on a myriad of environmental exposures (from members of NHS and HPFS) that could modify genetic predisposition for POAG to a central data repository. Thus this work will generate a valuable collection of genotype, phenotype and environment exposure data, allowing scientists to test numerous hypotheses regarding how genes and enviroment relate to incident POAG. We will collaborate with Dr. Michael Hauser at Duke University who is planning an admixture study to identify genetic loci associated with POAG among African Americans. We will seek to find concordance between genetic markers identified in his study and those identified in our stage I scan. Fine gene mapping and assessment of gene-gene and gene-environemnt interactions will be deferred until genetic markers associated with POAG are confirmed in a replication WGAS. Discovery of the various combinations of gene and environment interactions involved in POAG could lead to genotype-specific primary prevention strategies for this disease.