Search

Purpose: To elucidate a potential association between the apolipoprotein E (APOE) E4 allele and glaucoma prevalence in large cohorts. Design: A cross-sectional analysis of baseline and prospectively collected cohort data. Participants: UK Biobank (UKBB) participants of genetically determined European ancestry (n = 438 711). Replication analyses were performed using clinical and genotyping data collected from European participants recruited to the Canadian Longitudinal Study of Aging (CLSA; n = 18 199), the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG; n = 1970), and the Blue Mountains Eye Study (BMES; n = 2440). Methods: Apolipoprotein E alleles and genotypes were determined, and their distributions were compared on the basis of glaucoma status. Similar analyses were performed using positive control outcomes associated with the APOE E4 allele (death, dementia, age-related macular degeneration) and negative control outcomes not associated with the APOE E4 allele (cataract, diabetic eye disease). Outcome phenotypes were also correlated with Alzheimer’s dementia (AD), a clinical outcome highly associated with the APOE E4 allele. Main Outcome Measures: Results of APOE E4 genotype-phenotype comparisons were reported as odds ratios (ORs) with 95% confidence intervals (CIs). Replication analyses investigated APOE E4 associations in 2 replication cohorts (CLSA and ANZRAG/BMES). Results: The APOE E4 allele was inversely associated with glaucoma (OR, 0.96; 95% CI, 0.93–0.99; P = 0.016) and both negative controls (cataract: OR, 0.98; 95% CI, 0.96–0.99; P = 0.015; diabetic eye disease: OR, 0.92; 95% CI, 0.87–0.97; P = 0.003) in the UKBB cohort. A paradoxical positive association was observed between AD and both glaucoma (OR, 1.30; 95% CI, 1.08–1.54; P < 0.01) and cataract (OR, 1.15; 1.04–1.28; P = 0.018). No association between the APOE E4 allele and glaucoma was observed in either replication cohort (CLSA: OR, 1.03; 95% CI, 0.89–1.19; P = 0.66; ANZRAG/BMES: OR, 0.97; 95% CI, 0.84–1.12; P = 0.65). Conclusions: A small negative association observed between APOE E4 and glaucoma within the UKBB was not evident in either replication cohort and may represent an artifact of glaucoma underdiagnosis in APOE E4 carriers. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Glaucoma is a highly heritable disease that is a leading cause of blindness worldwide. Here, we identified heterozygous thrombospondin 1 (THBS1) missense alleles altering p.Arg1034, a highly evolutionarily conserved amino acid, in 3 unrelated and ethnically diverse families affected by congenital glaucoma, a severe form of glaucoma affecting children. Thbs1R1034C-mutant mice had elevated intraocular pressure (IOP), reduced ocular fluid outflow, and retinal ganglion cell loss. Histology revealed an abundant, abnormal extracellular accumulation of THBS1 with abnormal morphology of juxtacanalicular trabecular meshwork (TM), an ocular tissue critical for aqueous fluid outflow. Functional characterization showed that the THBS1 missense alleles found in affected individuals destabilized the THBS1 C-terminus, causing protein misfolding and extracellular aggregation. Analysis using a range of amino acid substitutions at position R1034 showed that the extent of aggregation was correlated with the change in protein-folding free energy caused by variations in amino acid structure. Extracellular matrix (ECM) proteins, especially fibronectin, which bind to THBS1, also accumulated within THBS1 deposits. These results show that missense variants altering THBS1 p.Arg1034 can cause elevated IOP through a mechanism involving impaired TM fluid outflow in association with accumulation of aggregated THBS1 in the ECM of juxtacanalicular meshwork with altered morphology.

Purpose: To investigate the association between the apolipoprotein E (APOE) E4 dementia-risk allele and prospective longitudinal retinal thinning in a cohort study of suspect and early manifest glaucoma. Design: Retrospective analysis of prospective cohort data. Participants: This study included all available eyes from participants recruited to the Progression Risk of Glaucoma: Relevant SNPs [single nucleotide polymorphisms] with Significant Association (PROGRESSA) study with genotyping data from which APOE genotypes could be determined. Methods: Apolipoprotein E alleles and genotypes were determined in PROGRESSA, and their distributions were compared with an age-matched and ancestrally matched normative cohort, the Blue Mountains Eye Study. Structural parameters of neuroretinal atrophy measured using spectral-domain OCT were compared within the PROGRESSA cohort on the basis of APOE E4 allele status. Main Outcome Measures: Longitudinal rates of thinning in the macular ganglion cell–inner plexiform layer (mGCIPL) complex and the peripapillary retinal nerve fiber layer (pRNFL). Results: Rates of mGCIPL complex thinning were faster in participants harboring ≥1 copies of the APOE E4 allele (β = –0.13 μm/year; P ≤0.001). This finding was strongest in eyes affected by normal-tension glaucoma (NTG; β = –0.20 μm/year; P = 0.003). Apolipoprotein E E4 allele carriers were also more likely to be lost to follow-up (P = 0.01) and to demonstrate a thinner average mGCIPL complex (70.9 μm vs. 71.9 μm; P = 0.011) and pRNFL (77.6 μm vs. 79.2 μm; P = 0.045) after a minimum of 3 years of monitoring. Conclusions: The APOE E4 allele was associated with faster rates of mCGIPL complex thinning, particularly in eyes with NTG. These results suggest that the APOE E4 allele may be a risk factor for retinal ganglion cell degeneration in glaucoma.

Purpose: To evaluate the association between genetic risk for cardiovascular disease and retinal thinning in early glaucoma. Design: Prospective, observational genetic association study Participants: Multicohort study combining a cohort of patients with suspect and early manifest primary open-angle glaucoma (POAG), a cohort of patients with perimetric POAG, and an external normative control cohort. Methods: A cardiovascular disease genetic risk score was calculated for 828 participants from the Progression Risk of Glaucoma: Relevant SNPs [single nucleotide polymorphisms] with Significant Association (PROGRESSA) study. Participants were characterized as showing either predominantly macular ganglion cell–inner plexiform layer (GCIPL), predominantly peripapillary retinal nerve fiber layer (pRNFL) or equivalent macular GCIPL and pRNFL spectral-domain OCT thinning. The cardiovascular disease genetic risk scores for these groups were compared to an internal reference group of stable suspected glaucoma and of an external normative population. Replication was undertaken by comparing the phenotypes of participants from the Australia New Zealand Registry of Advanced Glaucoma (ANZRAG) with the normative control group. Main Outcome Measures: Spectral-domain OCT and Humphrey Visual Field (HVF) change. Results: After accounting for age, sex, and intraocular pressure (IOP), participants with predominantly macular GCIPL thinning showed a higher cardiovascular disease genetic risk score than reference participants (odds ratio [OR], 1.76/standard deviation [SD]; 95% confidence interval [CI], 1.18–2.62; P = 0.005) and than normative participants (OR, 1.32/SD; 95% CI, 1.12–1.54; P = 0.002). This finding was replicated by comparing ANZRAG participants with predominantly macular GCIPL change with the normative population (OR, 1.39/SD; 95% CI, 1.05–1.83; P = 0.022). Review of HVF data identified that participants with paracentral visual field defects also demonstrated a higher cardiovascular disease genetic risk score than reference participants (OR, 1.85/SD; 95% CI, 1.16–2.97; P = 0.010). Participants with predominantly macular GCIPL thinning exhibited a higher vertical cup-to-disc ratio genetic risk score (OR, 1.48/SD; 95% CI, 1.24–1.76; P < 0.001), but an IOP genetic risk score (OR, 1.12/SD; 95% CI, 0.95–1.33; P = 0.179) comparable with that of the normative population. Conclusions: This study highlighted the relationship between cardiovascular disease and retinal thinning in suspect and manifest glaucoma cases.