Jamie E. Craig

Diabetic maculopathy (including diabetic macular edema [DME]) is the leading cause of vision loss in people with diabetes. We aimed to identify the genetic determinants of diabetic maculopathy. We conducted a genome-wide association study (GWAS) in two cohorts with a meta-analysis. The Australian cohort comprised 551 cases of DME and 599 controls recruited from the states of South Australia and Tasmania. The Scottish cohort comprised 1951 cases of diabetic maculopathy and 6541 controls from the Genetics of Diabetes Audit and Research in Tayside Scotland study (GoDARTS). Genotyping, imputation, and association analysis using logistic regression were conducted in each cohort, before combining summary statistics in a meta-analysis using the GWAMA package. A locus on chromosome 7 reached genome-wide significance in GoDARTS but showed the opposite direction of effect in the Australian cohort. The meta-analysis identified two suggestive associations (P < 5 × 10-6) for diabetic maculopathy risk with similar effect direction; one at chromosome 1 close to the RNU5E-1 gene and one at chromosome 13 upstream of the ERICH6B gene. The two loci were evaluated in silico for potential functional links to diabetic maculopathy. Both are located in regulatory regions and have annotations indicating regulatory functions. They are also expression quantitative trait locus (eQTLs) for genes plausibly involved in diabetic maculopathy pathogenesis, with links to folate metabolism and the regulation of VEGF. The study suggests several promising SNPs and genes related to diabetic maculopathy risk. Despite being the largest genetic study of diabetic maculopathy to date, larger, homogeneous cohorts will be required to identify robust genetic risk loci for the disease.

Axenfeld-Rieger Syndrome (ARS) is an autosomal dominant condition with both ocular and non-ocular manifestations. ARS is primarily caused by coding variants at the PITX2 or FOXC1 loci, yet many cases still remain undiagnosed. Here we used whole-genome sequencing to identify two non-coding structural variants associated with a typical presentation of PITX2 -associated ARS: one with a 450 kb deletion removing a series of conserved enhancer elements distal to PITX2 , and the second with a 12.5 Mb inversion displacing the PITX2 gene from these same enhancer elements. Neither variant disrupted the PITX2 gene itself, and therefore both were expected to reduce PITX2 expression by disrupting its proximity or access to enhancer elements. Enhancer-disrupting intergenic inversions therefore represent a unique genetic mechanism for the development of ARS, which should be carefully considered in the context of ARS and other conditions without a conclusive genetic diagnosis.

Objective: To assess the early safety and effectiveness outcomes of the PreserFlo MicroShunt with and without an intraluminal suture stent. Methods: Multicenter observational retrospective study using data from the Fight Glaucoma Blindness registry. Methods: A total of 183 eyes in 172 patients, with a mean age of 73 ± 14 years, who underwent PreserFlo MicroShunt surgery with/without intraluminal stent suture placement, and with at least 6 months of follow-up. Eyes were divided into 2 groups: stent (68 eyes) and no-stent (115 eyes). Methods: Baseline and postoperative measurements of intraocular pressure (IOP), visual acuity (VA), number of glaucoma medications, and adverse events were recorded at 1, 3, and 6 months. Outcomes were compared between stent and no-stent groups using t tests for continuous variables and Fisher exact tests for categorical variables. Methods: The primary outcome measures were the incidence of numerical hypotony (IOP ≤ 5 mmHg) and symptomatic hypotony (numerical hypotony plus ≥10 letters of VA loss) within 1 month, 1 to 3 months, and 3 to 6 months postoperatively. Secondary outcome measures included surgical success rates (defined as IOP ≤12, ≤15, ≤18, or ≤21 mmHg and ≥20% IOP reduction without hypotony and without additional glaucoma medications) and the need for secondary surgical interventions. Results: In the first postoperative month, the stent group had significantly lower rates of numerical hypotony (24% vs. 44%; P = 0.007) and symptomatic hypotony (13% vs. 28%; P = 0.027) than the no-stent group. The rate of device revision, explant, or replacement with an alternative shunt was also significantly lower in the stent group (3 eyes; 4.4%) than in the no-stent group (17 eyes; 14.8%; P = 0.047). No significant differences in hypotony rates were observed in the later follow-up windows (1-3 and 3-6 months), nor were there significant differences in surgical success rates between the stent and no-stent groups at any time point. Conclusions: The use of an intraluminal suture stent in PreserFlo MicroShunt surgery reduces the incidence of early hypotony without compromising surgical success. These findings suggest that routine use of intraluminal sutures may improve early postoperative safety.

Glaucoma is the leading cause of irreversible blindness with early detection and intervention critical to slowing disease progression. However, half of those affected are undiagnosed. This is largely due to the early stages of disease being asymptomatic; current population-based screening measures being unsupported; and a lack of current efficient prediction models. Research investigating polygenic risk scores (PRS) for glaucoma have shown predictive ability to identify individuals at higher risk. Potential clinical applications include identification of high-risk individuals, resulting in earlier diagnosis and treatment to prevent glaucoma blindness, and adjusted monitoring for low-risk individuals. However, the psychological impact of receiving glaucoma PRS is unknown. There is a critical need to evaluate risk information communication and assess the impact of receiving results, to support clinical implementation of glaucoma PRS testing. In this prospective study, 300 individuals from the GRADE (Genetic Risk Assessment of Degenerative Eye disease) study will be recruited to investigate the psychosocial impact of disclosing polygenic risk results for glaucoma. GRADE aimed to apply PRS testing on 1,000 unexamined individuals aged 50 years or older from the general population and examine a subset of these individuals to assess the clinical validity of PRS to detect glaucoma. In this study, individuals each from the bottom decile (10%), top decile (10%), and middle (45-55%) of the PRS distributions will be invited to receive research glaucoma PRS results. Participants who choose to receive their results will complete up to four questionnaires (prior to receiving their results, and subsequently two-weeks, six- and 12-months after receiving their result). The questionnaires will include health belief model measures and assess glaucoma anxiety, general anxiety and depression, test-related distress, decisional regret, and recall and understanding of results. This research will provide guidance for the implementation of polygenic risk testing into clinical practice and inform delivery strategies.

Precision medicine is paving the way for personalised risk assessment, and its translation into glaucoma clinics holds potential to change current management paradigms. Our understanding of glaucoma's genetic architecture has expanded in recent years, recognising both monogenic and polygenic contributions. Genetic testing within glaucoma populations can provide additional information for clinicians to support decision-making. Here, we review the evidence base for genetic variants strongly associated with glaucoma and outline a vision for translating these learnings into the clinic. Integrating clinical and genetic information will provide clinicians and patients with the strongest evidence to deliver personalised glaucoma management.