Determinants of primary open-angle glaucoma : a genetic-epidemiologic approach

In the first part of this thesis, potential environmental and genetic risk factors for POAG are examined in the Rotterdam Study, a prospective population-based cohort study among subjects 55 years and older. In its second part, the population of a genetic isolate is investigated, using a combined test for linkage and linkage disequilibrium. Glaucoma cases with pseudoexfoliation were not specifically excluded in the baseline phase of the Rotterdam Study. Investigators disagree about whether pseudoexfoliative glaucoma should be named POAG and prevalence figures in glaucoma populations are reported up to 66°/o in Scandinavia, but also 12°/o in the US and Australia.B1 As we did not see any pseudoexfoliation during follow up, and because we specifically excluded pseudoexfoliative glaucoma in the POAG patients from the genetically isolated population, we refer to the disease status as POAG in this thesis. In chapter 2.1, a proposal for an international definition of POAG is presented as well as the prevalence of POAG in the Rotterdam Study based according to this definition. The association between early menopause and POAG is described in chapter 2.2, suggesting the involvement of hormonal factors in the disease etiology. In chapter 2.3, we investigate the relation bet\veen blood pressure, arterial stiffness, and POAG. A new method to estimate the genetic risk in an individual is demonstrated in chapter 3. This study was performed in a family study based on case and control probands derived from the Rotterdam population. In chapter 4, the prevalence of lvf'YOC mutations was studied in a sample of POAG cases from the population-based Rotterdam Study. In addition, we described a family retrieved from this population, where POAG co-segregated with a mutation in this gene. The exclusion of POAG candidate loci in a sample of patients from a genetically isolated population was reported in chapter 5.1. In chapter 5.2, a genome scan performed in this sample is described, two regions are proposed, and possible candidate genes are selected. Finally, the main findings and methodological issues of all studies described in this thesis are discussed in chapter 6, with recommendations for future research.

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