Shamira A. Perera

Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR) = 1.22; P = 5.33 × 10−12), rs3753841 in COL11A1 (per-allele OR = 1.20; P = 9.22 × 10−10) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR = 1.50; P = 3.29 × 10−9). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG.

Refractive error, axial dimensions, and primary open-angle glaucoma: the Singapore Malay Eye Study.

OBJECTIVE To explore the relationship of refractive error and ocular biometry with primary open-angle glaucoma (POAG) in the Malay population. METHODS The Singapore Malay Eye Study is a population-based cross-sectional survey that examined 3280 persons (78.7% response) aged 40 to 80 years. Participants underwent a standardized clinical examination including slitlamp biomicroscopy, Goldmann applanation tonometry, refraction, dilated optic disc assessment, and measurement of axial length (AL) and central corneal thickness (CCT). Glaucoma was defined according to International Society for Geographical and Epidemiological Ophthalmology criteria. RESULTS After adjusting for possible confounders, persons with moderate or high myopia (less than -4.0 diopters, right eyes) were more likely to have POAG (odds ratio [OR], 2.87; 95% confidence interval, 1.09-7.53); this association remained significant after controlling for CCT (2.80; 1.07-7.37). Longer AL was associated with POAG (ORs, 2.49, 3.61, and 2.88, comparing quartiles 2, 3, and 4, respectively, with quartile 1 of AL; P = .03 for trend). If CCT was controlled for, persons with AL in quartile 4 were 3 times more likely to have POAG (OR, 3.00; 95% confidence interval, 1.09-8.24) than those in quartile 1. CONCLUSION This population-based study in Singapore shows an association of moderate myopia and increasing AL with POAG independent of other factors, including CCT.

Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10−11) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10−10); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10−10). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.

Anterior segment optical coherence tomography parameters in subtypes of primary angle closure.

PURPOSE To compare anterior segment parameters, assessed by anterior segment optical coherence tomography (ASOCT), in subjects categorized as primary angle closure suspect (PACS), primary angle closure (PAC), primary angle closure glaucoma (PACG), and previous acute PAC (APAC); and to identify factors associated with APAC. METHODS This was a prospective ASOCT study of 425 subjects with angle closure (176 PACS, 66 PAC, 125 PACG, and 58 APAC). Customized software was used to measure ASOCT parameters, including angle opening distance (AOD750), trabecular-iris space area (TISA750), anterior chamber depth, width, area and volume (ACD, ACW, ACA, ACV), iris thickness (IT750), iris area (IAREA), and lens vault (LV). Mean differences in anterior segment parameters were evaluated by analysis of covariance (ANCOVA) adjusted for age, sex, and pupil diameter (PD). RESULTS Comparison among the different subgroups showed that ACD, ACA, and ACV were smallest, and IT750 thickest in the APAC group compared with the other subgroups (P < 0.001). LV was greatest in the APAC group (1218 ± 34 μm) followed by PAC (860 ± 31 μm), PACG (845 ± 23 μm), and PACS (804 ± 19 μm), respectively (P = <0.001). While the APAC group had the narrowest angles, the PACS group had the widest (P < 0.001 for both AOD750 and TISA750). Logistic regression showed that greater LV (P = <0.001), narrower TISA750 (P = <0.001), and thicker IT750 (P = 0.007) were the major determinants of APAC. CONCLUSIONS Eyes with APAC had the narrowest angles, smallest anterior segment dimensions, thickest iris, and largest LV compared with PACS, PAC, and PACG. LV, TISA750, and IT750 were the major determinants of APAC.

Determinants of Angle Width in Chinese Singaporeans

PURPOSE To investigate determinants of angle width and derive mathematic models to best predict angle width. DESIGN Population-based, cross-sectional study. PARTICIPANTS A total of 1067 Chinese subjects aged ≥40 years. METHODS Participants underwent gonioscopy, A-scan biometry, and imaging by anterior segment optical coherence tomography (ASOCT, Carl Zeiss Meditec, Dublin, CA). Customized software (Zhongshan Angle Assessment Program, Guangzhou, China) was used to measure ASOCT parameters. Linear regression modeling was performed with trabecular-iris space area at 750 μm (TISA750) and angle opening distance at 750 μm (AOD750) from the scleral spur as the 2 dependent angle width variables. By using a combination of ASOCT and biometric parameters, an optimal model that was predictive of angle width was determined by a forward selection regression algorithm. Validation of the results was performed in a separate set of community-based clinic study of 1293 persons aged ≥50 years. MAIN OUTCOME MEASURES Angle width and biometric parameters. RESULTS The mean age (standard deviation) of the population-based subjects was 56.9 (8.5) years, and 50.2% were male. For TISA750, the strongest determinants among ASOCT and A-scan independent variables were anterior chamber volume (ACV, R(2)=0.51), followed by anterior chamber area (ACA, R(2)=0.49) and lens vault (LV, R(2)=0.47); for AOD750, these were LV (R(2)=0.56), ACA (R(2)=0.55), and ACV (R(2)=0.54). The R(2) values for anterior chamber depth and axial length were 0.39 and 0.27 for TISA750, respectively, and 0.46 and 0.30 for AOD750, respectively. An optimal model consisting of 6 variables (ACV, ACA, LV, anterior chamber width [ACW], iris thickness at 750 μm, and iris area) explained 81.4% of the variability in TISA750 and 85.5% of the variability in AOD750. The results of the population-based study were validated in the community-based clinic study, where the strongest determinants of angle width (ACA, ACV, and LV) and the optimal model with 6 variables were similar. CONCLUSIONS Angle width is largely dependent on variations in ACA, ACV, and LV. A predictive model comprising 6 quantitative ASOCT parameters explained more than 80% of the variability of angle width and may have implications for screening for angle closure.

Lamina cribrosa visibility using optical coherence tomography: comparison of devices and effects of image enhancement techniques.

PURPOSE To compare the visibility of the lamina cribrosa (LC) in optic disc images acquired from 60 glaucoma and 60 control subjects using three optical coherence tomography (OCT) devices, with and without enhanced depth imaging (EDI) and adaptive compensation (AC). METHODS A horizontal B-scan was acquired through the center of the disc using two spectral-domain (Spectralis and Cirrus; with and without EDI) and a swept-source (DRI) OCT. Adaptive compensation was applied post acquisition to improve image quality. To assess LC visibility, four masked observers graded the 1200 images in a randomized sequence. The anterior LC was graded from 0 to 4, the LC insertions from 0 to 2, and the posterior LC either 0 or 1. The effect of EDI, AC, glaucoma severity, and other clinical/demographic factors on LC visibility was assessed using generalized estimating equations. RESULTS The anterior LC was the most detectable feature, followed by the LC insertions. Adaptive compensation improved anterior LC visibility independent of EDI. Cirrus+EDI+AC generated the greatest anterior LC visibility grades (2.79/4). For LC insertions visibility, DRI+AC was the best method (1.10/2). Visibility of the posterior LC was consistently poor. Neither glaucoma severity nor clinical/demographic factors consistently affected LC visibility. CONCLUSIONS Adaptive compensation is superior to EDI in improving LC visibility. Visibility of the posterior LC remains poor suggesting impracticality in using LC thickness as a glaucoma biomarker.

Subgrouping of Primary Angle-Closure Suspects Based on Anterior Segment Optical Coherence Tomography Parameters

PURPOSE To identify subgroups of primary angle-closure suspects (PACS) based on anterior segment optical coherence tomography (AS-OCT) and biometric parameters. DESIGN Cross-sectional study. PARTICIPANTS We evaluated 243 PACS subjects in the primary group and 165 subjects in the validation group. METHODS Participants underwent gonioscopy and AS-OCT (Carl Zeiss Meditec, Dublin, CA). Customized software (Zhongshan Angle Assessment Program, Guangzhou, China) was used to measure AS-OCT parameters. An agglomerative hierarchical clustering method was first used to determine the optimum number of parameters to be included in the determination of subgroups. The best number of subgroups was then determined using Akaike Information Criterion (AIC) and Gaussian Mixture Model (GMM) methods. MAIN OUTCOME MEASURES Subgroups of PACS. RESULTS The mean age of the subjects was 64.8 years, and 65.02% were female. After hierarchical clustering, 1 or 2 parameters from each cluster were chosen to ensure representativeness of the parameters and yet keep a minimum of redundancy. The parameters included were iris area, anterior chamber depth (ACD), anterior chamber width (ACW), and lens vault (LV). With the use of GMM, the optimal number of subgroups as given by AIC was 3. Subgroup 1 was characterized by a large iris area, subgroup 2 was characterized by a large LV and a shallow ACD, and subgroup 3 was characterized by elements of both subgroups 1 and 2. The results were replicated in a second independent group of 165 PACS subjects. CONCLUSIONS Clustering analysis identified 3 distinct subgroups of PACS subjects based on AS-OCT and biometric parameters. These findings may be relevant for understanding angle-closure pathogenesis and management.

Reliability and Determinants of Retinal Vessel Oximetry Measurements in Healthy Eyes

PURPOSE To assess the reliability and determinants of retinal vessel oximetry measurements with the Oxymap T1 Retinal Oximeter in normal Asian eyes. METHODS Subjects older than 40 years without a history of stroke and heart disease were recruited from a community-based clinic. Subjects underwent standardized systemic and ocular examinations. Normal eyes were defined as eyes without major eye diseases such as age-related macular degeneration, glaucoma, or retinopathy. Retinal vessel oximetry levels were measured by using the Oxymap T1 Retinal Oximeter. Intra- and intergrader reliability of retinal vessel oximetry measurements were assessed by using 50 images. Intravisit repeatability of retinal vessel oximetry measurements was assessed by using 20 paired images. Univariable linear regression was performed to examine the associations between retinal vessel oximetry measurements and systemic determinants. RESULTS A total of 118 retinal oximetry images were included in the final analysis. Intra- (intraclass correlation coefficient [ICC] values: 0.89-0.99) and intergrader (ICC values: 0.77-0.94) reliability, and intravisit (ICC values: 0.85-0.96) repeatability were both high. In the linear regression analysis, older age was associated with reduced overall retinal venular oximetry levels (β: -2.61%; 95% confidence interval [CI]: -4.92 to -0.29) and reduced inferior-nasal retinal venular oximetry levels (β: -3.53%; 95% CI: -6.07 to -0.99). CONCLUSIONS The Oxymap Retinal Oximeter allows reliable and repeatable retinal vessel oximetry measurements. Age is the main factor that influences retinal venular oximetry levels and should be taken into account when retinal oximetry measurements are interpreted.

Finite Element Analysis Predicts Large Optic Nerve Head Strains During Horizontal Eye Movements.

PURPOSE We combined finite element (FE) analysis and dynamic magnetic resonance imaging (MRI) to estimate optic nerve head (ONH) strains during horizontal eye movements, and identified factors influencing such strains. We also compared ONH strains (prelamina, lamina cribrosa, and retrolamina strains) induced by eye movements to those induced by IOP. METHODS The ocular globes and orbits of a healthy subject were visualized during horizontal eye movements (up to 13°), using dynamic MRI. A baseline FE model of one eye was reconstructed in the primary gaze position, including details from the orbital and ONH tissues. Finite element-derived ONH strains induced by eye movements were compared to those resulting from an IOP of 50 mm Hg. Finally, a FE sensitivity study was performed, in which we varied the stiffness of all ONH connective tissues, to understand their influence on ONH strains. RESULTS Our models predicted that, during horizontal eye movements, the optic nerve pulled the ONH posteriorly. Optic nerve head strains following a lateral eye movement of 13° were large and higher than those resulting from an IOP of 50 mm Hg. These results held true even with variations in connective tissue stiffness. We also found that stiff sclerae reduced lamina cribrosa and prelamina strains during eye movements, but stiff optic nerve sheaths significantly increased those strains. CONCLUSIONS Our models predicted high ONH strains during eye movements, which were aggravated with stiffer optic nerve sheaths. Further studies are needed to explore links between ONH strains induced by eye movements and axonal loss in glaucoma.

Blindness and long-term progression of visual field defects in Chinese patients with primary angle-closure glaucoma.

PURPOSE To investigate the long-term rates of blindness and visual field (VF) progression in treated primary angle-closure glaucoma (PACG) patients. DESIGN Retrospective observational case series. METHODS PACG patients with ≥10 years of follow-up were analyzed. All VFs (static automated perimetry, central 24-2 threshold test) performed were reviewed and reliable VFs (fixation losses <20%, false positives and false negatives <33%) were scored using the Advanced Glaucoma Intervention Study (AGIS) system. Progression of a VF defect was defined as a change of ≥4 from baseline on 2 consecutive VF tests. RESULTS From the 137 eyes of 87 patients with PACG with ≥10 years of follow-up identified, 6% and 30.1% were blind based on initial visual acuity (VA) and VF criteria respectively and 12.0% had an initial AGIS score of 20; these were excluded. Eighty-three eyes from 57 patients (all Chinese, mean age 59.9 ± 8.2 years, 67.5% female) were analyzed. The mean AGIS score was 5.14 ± 4.37 at baseline. VF deterioration was detected in 27 eyes (32.5%) of 21 patients, with 4.8% and 7.2% of eyes progressing to blindness based on VA and VF criteria respectively. On Cox regression, eyes with VF progression had higher mean overall IOP (P < .001), and higher prevalence of previous acute angle closure (AAC, P = .008). CONCLUSIONS Over 10 years, a third of PACG patients were found to have VF progression, with 7% progressing to blindness while on treatment. Eyes with higher mean overall IOP and a history of previous AAC were more likely to have VF progression.