Molecular and Phenotypic Associations in the Open Angle Glaucomas.

Author: Alex W Hewitt

Hewitt, Alex W, 2009 Molecular and Phenotypic Associations in the Open Angle Glaucomas., Flinders University, School of Medicine

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Glaucoma is the commonest cause for irreversible optic neuropathy worldwide. Being a complex heterogeneous disease, Primary Open Angle Glaucoma (OAG) is likely to manifest due to the collision of germ-line, somatic, environmental and stochastic factors. This thesis explores both the phenotypic features and genetic mechanisms of the glaucomatous process. Investigation of the myocilin gene, which has been unequivocally associated with OAG, demonstrated firm genotype-phenotype correlations. Possibly reflecting the association between myocilin-related glaucoma and elevated intraocular pressure, myocilin mutation carriers were found to have a lower prevalence of optic disc haemorrhages, compared to individuals with non-myocilin OAG. No structural differences of the optic nerve head were identified in young people known to carry myocilin mutations, but who do not have manifest glaucoma. At the phenotypic level the role of OAG as a systemic disease and the biometric associations of advanced OAG were investigated. Using mortality data from over 27,000 people of whom 741 were known to have OAG, adjusted for gender and age at death, we identified a statistically significant association between death due to ischaemic heart disease and OAG. In a separate study investigating the systemic associations of OAG in 1,700 patients, a past history of migraine or presence of atherosclerosis was identified as being more common in patients with familial forms of OAG compared to people with sporadic disease. Biometric investigation of patients who had definitive end-stage glaucomatous visual field loss, confirmed that central corneal thickness was a significant risk factor for disease progression. Automatic optic disc imaging, which was performed on a subset of this end-stage cohort, revealed that the Stratus optical coherence tomography retinal nerve fibre layer clock hour scan was most sensitive in detecting advanced disease. These findings may have important ramifications on phenotype-based screening programs. At the genotypic level, the Asp658Gly variant in the Winged Domain 40- repeat 36 gene was found, in a relatively small case-control study, to be a neutral variant in the Australian population and meta-analysis of the common optineurin Met98Lys, variant confirmed that its association with OAG, although weak, is highly statistically significant. Replicating previous work, two nonsynonymous variants in exon 1 of lysyl oxidase–like 1 (Arg141Leu; Gly153Asp) were found to be strongly associated with pseudoexfoliative glaucoma. After validating a novel method of genome-wide association using equimolar DNA pools, where we were easily able to identify a strong association between markers at the complement factor H locus and age-related macular degeneration, genetic risk variants for OAG on chromosomes 3q21, 6p25, 14q13 and Xq25 were found. Nonetheless, further work is required before the association of variants at the novel OAG loci are definitively proven. Accurate phenotypic descriptions, when compiled with relevant genetic information should enhance clinicians’ understanding of the specific natural history of an individual patient's disease. Ongoing work investigating the clinical natural history and outcome to available therapy is required to correlate specific disease-causing variants with the phenotype, thereby bridging the clinician to the laboratory.

Keywords: Glaucoma,genetics,genome-wide association

Subject: Ophthalmology thesis

Thesis type: Doctor of Philosophy
Completed: 2009
School: School of Medicine
Supervisor: Jamie E Craig