Kathryn P. Burdon

Description: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.

Description:Genetic testing for paediatric cataract detects a cause in 50%-70% of affected children but is as low as 20% in some reports. We screened 180 cataract-related genes in 22 children (from 20 families) with paediatric cataract from Myanmar using whole-exome sequencing. Pathogenic or likely pathogenic variants were identified in 45% (9/20) of probands in genes MIP, COL2A1, NHS, GJA8, GJA3, CRYGC, CRYBB2, PAX6 and SLC7A8. Variants of uncertain significance likely to be important were identified in three children for a maximum diagnostic rate of 12/20 probands (60%) comparable to other reports. This is the first study to examine the genetics of paediatric cataract in Myanmar.

Description:Objective: Pseudoexfoliation syndrome (PEX) is a known risk factor for glaucoma, but its individual clinical course ranges from no glaucoma to total blindness. This study investigated whether polygenic risk scores (PRSs) built from variants collectively associated with open-angle glaucoma, intraocular pressure (IOP), and vertical cup-to-disc ratio (VCDR) can stratify individuals with pseudoexfoliation for the risk of glaucoma development. Methods: Retrospective multicohort study of 2 glaucoma registries and 1 population-based cohort. Methods: For the primary analysis, participants (n = 828) were classified as having PEX with glaucoma, PEX with suspected glaucoma, or PEX with no glaucoma. For the secondary analysis, a cohort of participants (n = 2460) were classified as having PEX with glaucoma, having PEX with no glaucoma, and being unaffected, and an independent cohort of participants (n = 3372) were classified as having primary open-angle glaucoma (POAG) or suspected POAG. Methods: Previously published and validated PRSs for open-angle glaucoma, IOP, and VCDR were expressed as a percentile, decile, or tertile of an ancestrally matched healthy population. Multivariable logistic and linear regressions and survival analyses were performed. Methods: The main outcome measures were odds of pseudoexfoliative glaucoma (PEX-G) and odds of clinically relevant outcomes. Results: Participants in the top tertile of the glaucoma PRS showed greater odds of receiving a PEX-G diagnosis (adjusted odds ratio [aOR], 4.22; 95% confidence interval [CI], 2.62-6.88; P < 0.001), greater odds of bilateral central vision loss (aOR, 3.43; 95% CI, 1.49-8.99; P = 0.007), and greater odds of bilateral incisional surgery (aOR, 3.35; 95% CI, 1.33-10.24; P = 0.018). Age at PEX-G diagnosis was 1 year younger with each increasing glaucoma PRS decile (1.06 years; 95% CI, 0.59-1.53 years; P < 0.001). Participants with manifest glaucoma and pseudoexfoliation showed a comparatively lower glaucoma PRS than counterparts with POAG. Conclusions: The PRSs for open-angle glaucoma, IOP, and VCDR stratify risk of glaucoma development and disease severity among individuals with PEX.

Description:Objective: Pseudoexfoliation syndrome (PEX) is a known risk factor for glaucoma, but its individual clinical course ranges from no glaucoma to total blindness. This study investigated whether polygenic risk scores (PRS) built from variants collectively associated with open-angle glaucoma, intraocular pressure (IOP) and vertical cup:disc ratio (VCDR) can stratify individuals with pseudoexfoliation for their risk of glaucoma development. Methods: Retrospective multicohort study of two glaucoma registries and one population-based cohort. Methods: For the primary analysis, participants (n=828) were classified as PEX-Glaucoma, PEX-Glaucoma Suspect, and PEX-No Glaucoma. For the secondary analysis, a cohort of participants (n=2459) were classified as PEX-Glaucoma, PEX-No Glaucoma, and Unaffected, and an independent cohort of participants (n=3360) were classified as primary open-angle glaucoma (POAG) and POAG-Suspect. Methods: Previously published and validated PRS for open-angle glaucoma, IOP and VCDR were expressed as a percentile, decile or tertile of an ancestrally-matched normal population. Multivariable logistic and linear regressions, and survival analyses were performed. Methods: Odds of pseudoexfoliative glaucoma, and odds of clinically-relevant outcomes. Results: Participants in the top tertile of the Glaucoma-PRS had greater odds of pseudoexfoliative glaucoma diagnosis (adjusted OR 4.22, 95% CI 2.62 - 6.88, p<0.001), greater odds of bilateral central vision loss (adjusted OR 3.43, 95% CI 1.49 - 8.99, p=0.007), and greater odds of bilateral incisional surgery (adjusted OR 3.35, 95% CI 1.33 - 10.24, p=0.018). Age of pseudoexfoliative glaucoma diagnosis was 1 year younger with each increasing Glaucoma-PRS decile (1.06 years, 95% CI 0.59-1.53, p<0.001). Manifest glaucoma participants with pseudoexfoliation had a comparatively lower Glaucoma-PRS than primary open-angle glaucoma counterparts. Conclusions: PRS for open-angle glaucoma, IOP and VCDR stratify risk of glaucoma development and disease severity amongst individuals with pseudoexfoliation syndrome.

Description:Background: An ongoing challenge with rare diseases is limited data and, consequently, limited knowledge about the collective prevalence and impact of these conditions on individuals, families, and the health system, particularly in rural and regional areas. Using existing datasets, this project aimed to examine the epidemiology of and hospital activity for Tasmanians with rare diseases. Methods: Rare diseases were defined as non-infectious diseases with a prevalence of less than 1 in 2000. An initial resource set of 1028 ICD-10-AM diagnostic codes was used to identify a cohort of Tasmanians with rare diseases in Tasmanian Health datasets (1 January 2007 until 31 December 2020). Validating the resource set using a small group with known rare diseases revealed limitations in ascertainment, and so an expanded set of 1940 ICD-10-AM diagnostic codes was developed by cross-referencing ICD-10-AM codes with Orphanet data. Cohort hospital activity and admission costs were compared to statewide data for the final year of the study, 01 January 2020 to 31 December 2020. Results: Using the resource set of 1028 ICD-10-AM diagnostic codes, the period prevalence of rare diseases in Tasmania across all age groups was estimated at 3.5%, with a point prevalence of 1.5% in December 2020. In 2020, 3384 individuals within the Tasmanian rare disease cohort, representing 0.6% of the Tasmanian population, accessed the public hospital system and accounted for 5.6% of all admissions. The mean length of stay for rare disease-related hospital admissions was 5.0 days, compared to 3.3 days for non-rare disease-related admissions. The mean cost per admission for the rare disease cohort was AUD$11,310, compared to AUD$6475 for all admissions statewide. In 2020, using the expanded resource set, the total cost of public hospital admissions in Tasmania was estimated to be AUD$979 million, with rare disease-related hospital admissions accounting for 9.1% of this cost, increasing to 19.0% when the costs for all admissions for the rare disease patients were included. Conclusions: Patients with rare diseases had more admissions, longer length of stay, and a higher average cost per admission. Patients with rare diseases have a disproportionate impact on statewide hospital activity and costs in Tasmania.