A Genetic Study of Primary Angle-Closure Glaucoma and Nanophthalmos

Author: Mona Awadalla

Awadalla, Mona, 2013 A Genetic Study of Primary Angle-Closure Glaucoma and Nanophthalmos, Flinders University, School of Medicine

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Glaucoma is a term describing a group of ocular disorders with multi-factorial etiology united by a clinically characteristic intraocular pressure-associated optic neuropathy. Collectively, they are the leading cause of irreversible blindness worldwide. Primary angle-closure glaucoma is a subtype of glaucoma characterised by irido-trabecular contact and elevated intraocular pressure. Almost half of individuals who reach legal blindness due to glaucoma have PACG. PACG may be clinically divided into acute and chronic forms, and the pathogenesis is multifactorial. Short axial length and a crowded anterior segment are established risk factors in the development of PACG. Similar but more extreme clinical findings are found in a rare developmental disorder known as nanophthalmos. Recent studies have highlighted the heritable component of both nanophthalmos and PACG. The aim of this thesis was to further explore genetic risk factors in the development of nanophthalmos and PACG. This study identified a novel variant located in exon 8 of Transmembrane protein 98 gene in a large family with autosomal dominant nanophthalmos, and reports variants of Membrane frizzled-related protein and Protease serine 56 in two other families with nanophthalmos. These three genes were further analysed for association with PACG and borderline significance was identified, motivating further study on a larger cohort. We then conducted a genome-wide association study, which is an approach that involves scanning the whole genomes of many people to find genetic variations associated with a particular disease, on patients with PACG from two different cohorts available at the time of the study from Australia and Nepal. We chose different cohorts to investigate the differences in the allele frequencies and the genetic risks between these two cohorts. Unfortunately no significant single nucleotide polymorphisms reaching genome-wide significance were detected from this GWA study, so we aimed to build up the PACG cohort for the next larger GWAS. Meanwhile, analyses of previously published candidate gene studies for PACG were undertaken. This study shows that common variation within Matrix metalloproteinase-9, and Endothelial nitric oxide synthase genes were significantly associated with PACG in the Australian cohort, while the Hepatocyte growth factor gene was associated with the disease in the Nepalese cohort. Finally, replication of three novel loci rs11024102 in PLEKHA7, rs3753841 in COL11A1, and rs1015213 located between PCMTD1 and ST18 from a recent GWAS indicates replicated association of these candidate loci with PACG. Data from this thesis advance understanding of the genes involved in the pathogenesis of nanophthalmos and PACG. It may assist in refining of the genetic screening programs to identify individuals at particularly high risk, especially in families with nanophthalmos, as they develop blindness at a younger age. Identification of TMEM98 as a gene for autosomal dominant nanophthalmos is also a finding of significance, which requires further functional work to unveil the role of this gene in the human eye.

Keywords: Glaucoma,Nanophthalmos,gene
Subject: Ophthalmology thesis, Medicine thesis

Thesis type: Doctor of Philosophy
Completed: 2013
School: School of Medicine
Supervisor: A/Prof Jamie E Craig