Glaucoma risk stratification using novel genetic and clinical risk factors

Author: Ayub Qassim

Qassim, Ayub, 2021 Glaucoma risk stratification using novel genetic and clinical risk factors, Flinders University, College of Medicine and Public Health

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Primary open-angle glaucoma (POAG) is one of the most heritable common human diseases. POAG remains the leading cause of irreversible blindness worldwide, despite the ongoing advances in the medical and surgical treatment options of glaucoma. This is largely due to its asymptomatic and progressive natural history as treatment cannot restore an already lost vision. Nonetheless, treatment — via reduction of intraocular pressure (IOP) — is highly effective in slowing down disease progression, and in most cases, halting vision loss. There is no established cost-effective screening strategy for glaucoma in Australia, and there is currently no way of knowing which glaucoma suspect will progress to a blinding disease. Thus, the current national guidelines recommend routine follow-up of all ‘at-risk’ individuals, which adds a significant burden to health care resources since the majority of glaucoma suspects will not need any intervention.

This thesis addressed this gap in knowledge by investigating novel risk factors of glaucoma development and progression. Leveraging ‘big data’ from population studies and genetic consortia, several novel genetic risk variants were identified to be associated with POAG and glaucoma-related phenotypes, improving our understanding of the biological pathways involved in POAG pathogenesis. The aggregate effects of these genetic risk variants were demonstrated (using polygenic risk scores) to be highly predictive of the risk of glaucoma development, progression, treatment intensity, and diurnal IOP variations. Since IOP remains the only modifiable risk factor for glaucoma, the IOP-lowering benefits of cataract surgery and selective laser trabeculoplasty were ascertained, with a focus on predictive factors for individuals who would most likely benefit from these interventions. A novel approach to monitor IOP change post-intervention was piloted using a cloud-connected and patient-administered home tonometer. Finally, a novel glaucoma progression risk prediction was developed using corneal biomechanical properties — namely, corneal stiffness parameter, in synergy with central corneal thickness.

The outcomes of this thesis have markedly enhanced our capacity in glaucoma risk stratification via genetic and clinical biomarkers of disease progression. The insights gained from this research will lead to translational implications for policy development and rational deployment of an evidence-based glaucoma suspect monitoring both in Australia and internationally. This can be facilitated by further research implementing a risk-stratified monitoring and treatment strategy such that these decisions are personalised for each patient, substantially reducing the cost of follow-up and reducing unnecessary treatment, and that fewer patients will irreversibly lose vision.

Keywords: glaucoma, polygenic risk score, risk stratification, corneal biomechanics, personalised medicine, PRS, POAG, IOP, OCT, progression, GWAS

Subject: Ophthalmology thesis

Thesis type: Doctor of Philosophy
Completed: 2021
School: College of Medicine and Public Health
Supervisor: Jamie Craig