A common variant near TGFBR3 is associated with primary open angle glaucoma.

Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10(-33)), we observed one SNP showing significant association to POAG (CDC7-TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10(-8)). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis.

ABCC5, a gene that influences the anterior chamber depth, is associated with primary angle closure glaucoma.

Anterior chamber depth (ACD) is a key anatomical risk factor for primary angle closure glaucoma (PACG). We conducted a genome-wide association study (GWAS) on ACD to discover novel genes for PACG on a total of 5,308 population-based individuals of Asian descent. Genome-wide significant association was observed at a sequence variant within ABCC5 (rs1401999; per-allele effect size =  -0.045 mm, P = 8.17 × 10(-9)). This locus was associated with an increase in risk of PACG in a separate case-control study of 4,276 PACG cases and 18,801 controls (per-allele OR = 1.13 [95% CI: 1.06-1.22], P = 0.00046). The association was strengthened when a sub-group of controls with open angles were included in the analysis (per-allele OR = 1.30, P = 7.45 × 10(-9); 3,458 cases vs. 3,831 controls). Our findings suggest that the increase in PACG risk could in part be mediated by genetic sequence variants influencing anterior chamber dimensions.

Argon Laser Peripheral Iridoplasty for Primary Angle-Closure Glaucoma: A Randomized Controlled Trial.

PURPOSE: To determine the effectiveness of argon laser peripheral iridoplasty (ALPI) in primary angle closure (PAC) and primary angle-closure glaucoma (PACG). DESIGN: Randomized controlled trial. PARTICIPANTS: Eighty PAC or PACG subjects who underwent laser iridotomy (LI) and had at least 180° of persistent appositional angle closure and intraocular pressure (IOP) of more than 21 mmHg were enrolled. METHODS: Subjects were randomized to receive either 360° ALPI (Visulas 532s; Carl Zeiss Meditec, Jena, Germany) or medical therapy (Travoprost 0.004%; Alcon-Couvreur, Puurs, Antwerp, Belgium). Repeat ALPI was performed if the IOP reduction was less than 20% from baseline along with inadequate angle widening at the month 1 or month 3 visit. Intraocular pressure was controlled with systematic addition of medications when required. MAIN OUTCOME MEASURES: The primary outcome measure was success rates after ALPI at 1 year. Complete success was defined as an IOP of 21 mmHg or less without medication, and qualified success was defined as an IOP of 21 mmHg or less with medication. Failure was defined as an IOP more than 21 mmHg despite additional medications or requiring glaucoma surgery. RESULTS: Forty subjects (51 eyes) were randomized to ALPI and 40 subjects (55 eyes) were randomized to medical therapy. Complete success (IOP ≤21 mmHg without medication) was achieved in 35.0% eyes of the ALPI group compared with 85.0% of eyes in the prostaglandin analog (PGA) group (P < 0.001), and qualified success (IOP ≤21 mmHg with medication) was achieved in 35.0% and 7.5%, respectively (P = 0.003). The IOP decreased by 4.9 mmHg (95% confidence interval [CI], 3.5-6.3 mmHg) in the ALPI group (P < 0.001) and by 6.1 mmHg (95% CI, 5.1-7.1 mmHg) in the medication group (P < 0.001). A failure rate of 30.0% was noted in the ALPI group compared with 7.5% in the medication group (P = 0.01). No treatment-related complications were recorded in either group. CONCLUSIONS: After 1 year, ALPI was associated with higher failure rates and lower IOP reduction compared with PGA therapy in eyes with persistent appositional angle closure and raised IOP after LI.

Angle-closure glaucoma in Asians: comparison of biometric and anterior segment parameters between Japanese and Chinese subjects.

PURPOSE: To compare anterior segment parameters in Chinese and Japanese subjects with angle closure using anterior segment optical coherence tomography (ASOCT). METHODS: One hundred and forty-two Japanese and one hundred and ninety-two Chinese subjects with primary angle closure (PAC) or primary angle-closure glaucoma (PACG) were recruited. All participants underwent A-scan biometry and ASOCT imaging (Visante, Carl Zeiss Meditec, Dublin, CA, USA). Customized software was used to measure ASOCT parameters in horizontal ASOCT scans. The parameters were compared, and multivariate analysis was performed to determine predictors of angle opening distance at 750 µm from the scleral spur (AOD750). RESULTS: Ethnic difference evaluated by multiple linear regression adjusted for age, gender, spherical equivalent, pupil diameter, and axial length showed that Japanese angle-closure subjects had significantly shallower anterior chamber depth (ACD;ß = -0.3, p < 0.001), smaller anterior chamber area (ACA; ß = -0.21, p = 0.02) and volume (ACV; ß = -0.19, p = 0.01), greater lens vault (LV, ß = 0.3, p < 0.001), lens thickness (LT; ß = 0.48, p < 0.001), greater iris area (IArea; ß = 0.19, p = 0.01), and more curved iris (ICurv; ß = 0.16, p = 0.04). The significant determinants of AOD750 were iris thickness (IT; ß = -0.21, p = 0.04), ICurv (ß = -0.17, p = 0.04), pupil diameter (PD; ß = -0.34, p = 0.001) and ACV (ß = 0.32, p < 0.001) in Japanese; and IT (ß = -0.25, p = 0.001), ACV (ß = 0.37, p < 0.001), PD (ß = -0.26, p = 0.001), and LV (ß = -0.18, p = 0.03) in Chinese. CONCLUSIONS: Compared to Chinese, Japanese angle-closure eyes have smaller and more crowded anterior segment with thicker lenses. ACV, IT, and PD are important factors for angle width in both races. These results suggest possible ethnic differences in angle-closure mechanism(s).

Diabetes, hyperglycemia, and central corneal thickness: the Singapore Malay Eye Study.

PURPOSE: To examine the relationship of diabetes and hyperglycemia with central corneal thickness (CCT) in Malay adults in Singapore. DESIGN: Population-based cross-sectional study. PARTICIPANTS: Three thousand two hundred eighty Malay adults ages 40-80 years living in Singapore. METHODS: The study population was selected using an age-stratified random sampling procedure of Malay 40- to 80-year-olds living in the southwestern part of Singapore. Participants had a standardized interview, examination, and ocular imaging at a centralized study clinic. Central corneal thickness was measured with an ultrasound pachymeter, and nonfasting serum glucose and glycosylated hemoglobin (Hb A(1C)) was obtained from all participants. Diabetes was defined as having nonfasting glucose levels of > or =200 mg/dl (11.1 mmol/l), a self-report of diabetic medication use, or physician diagnosis of diabetes. MAIN OUTCOME MEASURES: Central corneal thickness. RESULTS: Of the 3280 (78.7% response) participants, data on CCT were available on 3239 right eyes. Central corneal thickness was normally distributed, with a mean of 541.2 microm. There were 748 persons with diabetes (23.0%). After controlling for age and gender, central corneas were significantly thicker in persons with diabetes than in those without diabetes (547.2 microm vs. 539.3 microm, P<0.001) and, in the total population, with higher serum glucose (539.6, 540.2, 541.3, and 544.4, comparing increasing glucose quartiles; P = 0.023) and higher Hb A(1C) (537.8, 541.0, 541.4, and 545.5, comparing increasing Hb A(1C) quartiles; P<0.001) levels. In multiple linear regression models adjusting for age, intraocular pressure (IOP), body mass index, and axial length, persons with diabetes had, on average, central corneas 6.50 microm thicker than those of persons without diabetes. CONCLUSIONS: This population-based study among Malays showed that diabetes and hyperglycemia are associated with thicker central corneas, independent of age and IOP levels. These findings may have implications for understanding the relationship between diabetes and glaucoma.

Genome-wide association study identifies five 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 (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10(-12)). We also confirmed significant association at three previously described loci (P < 5 × 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG.

Efficacy of selective laser trabeculoplasty in primary angle-closure glaucoma: a randomized clinical trial.

IMPORTANCE: Selective laser trabeculoplasty (SLT) should be explored as a therapeutic option in eyes with angle closure. OBJECTIVE: To assess the intraocular pressure (IOP)-lowering efficacy of SLT in eyes with primary angle closure (PAC) and PAC glaucoma (PACG). DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial at tertiary eye care institutions of 100 patients diagnosed as having PAC or PAC glaucoma in which the angles had opened at least 180° (visible posterior trabecular meshwork on gonioscopy) after laser iridotomy. Recruitment and baseline were completed from June 2009 to April 2012 and 6-month follow-up was completed from December 2009 to November 2012. INTERVENTIONS: Eligible patients with a baseline IOP greater than 21 mm Hg were randomized to either SLT or prostaglandin analog (PGA; travoprost, 0.004%). The SLT was repeated if the IOP reduction was less than 20.0% from baseline at the 1- or 3-month follow-up visit. MAIN OUTCOMES AND MEASURES: The primary outcome measure was the change in IOP from baseline to the final follow-up visit (at 6 months). The frequency of additional postoperative treatments and complications were secondary outcomes. RESULTS: Fifty patients (96 eyes) were randomized to SLT and 50 patients (99 eyes) to PGA medical therapy. At 6 months, 49 patients in the SLT group and 47 in the PGA group completed follow-up. Analysis was based on intent to treat. At 6 months, IOP decreased by 4.0 mm Hg (95% CI, 3.2-4.8) in the SLT group (P < .001) and by 4.2 mm Hg (95% CI, 3.5-4.9) in the PGA group (P < .001). There were no differences between the SLT and PGA groups in the absolute mean reduction of IOP (4.0 vs 4.2 mm Hg, respectively; P = .78) or in the percentage of reduction in IOP (16.9% vs 18.5%, respectively; P = .52). Complete success (IOP ≤21 mm Hg without medications) was achieved in 60.0% eyes of the SLT group, compared with 84.0% of eyes in the PGA group (P = .008). No patients required glaucoma surgery. Additional medications were required in 22.0% of patients in the SLT group compared with 8.0% in the PGA group (P = .05). One patient in the SLT group (2.0%) had a transient posttreatment IOP spike greater than 5 mm Hg. The mean endothelial cell count showed a significant decrease from baseline in the SLT arm (4.8% decrease; P = .001). No other events such as persistent uveitis or increase in peripheral anterior synechiae were noted in eyes that underwent SLT. Two patients in the PGA group exited owing to drug-related complications (1 patient with uveitis and 1 with allergic conjunctivitis). CONCLUSIONS AND RELEVANCE: Eyes with PAC or PACG respond to SLT in the short term, but the overall long-term therapeutic effectiveness needs further evaluation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01004900.

A comparison of applanation tonometry using conventional reusable goldmann prisms and disposable prisms.

PURPOSE: To determine the agreement between intraocular pressure (IOP) measurements using conventional Goldmann applanation tonometry (GAT) and Tonosafe disposable prisms, and also to provide a comprehensive cost analysis of the use of both types of prisms METHODS: : In this prospective observational study, 198 eyes of 100 glaucoma patients had their IOPs measured by 5 consultant ophthalmologists. Data were analyzed using the Bland-Altman method of differences, and correlation was measured using the Pearson coefficient. An analysis of the cost incurred using the 2 methods over a 6-month period was performed. RESULTS: The majority were Chinese (82%), with a male preponderance (57%). The range of IOPs as measured by GAT was 4 to 34 mm Hg. Using the Bland-Altman method to compare GAT and disposable prisms, the bias was 0.2 mm Hg. Tonosafe overestimated the IOP by 0.2 mm Hg in the right eye and underestimated it by 0.2 mm Hg in the left eye. The Tonosafe IOP correlated well with GAT, with a Pearson coefficient of correlation(r) of 0.91 (P<0.0005) for the right eye and 0.92 (P<0.0005) for the left eye, respectively. For those with GAT IOP≥21 mm Hg (n=26), Tonosafe underestimated the IOP by 0.35 mm Hg. The cost incurred by Tonosafe prisms was approximately 8 times that of GAT, but the cost differential reverses when GAT had to be replaced after every 100 cycles of disinfection. CONCLUSIONS: We found a good correlation between Tonosafe prisms and conventional GAT in measuring the IOP. Tonosafe prisms may be of use, especially if the risk of transmission of infection is high. However, cost may limit its more widespread use.

Patient acceptance and attitude toward an alternative method of subconjunctival injection for the medical treatment of glaucoma.

PURPOSE: Nonadherence to glaucoma medications may be a major cause of treatment failure. We examined the acceptance of glaucoma patients toward a possible new route of administering glaucoma medication by subconjunctival injection. PATIENTS AND METHODS: Patients were recruited from specialist glaucoma clinics on a voluntary basis. Trained interviewers administered a 30-item questionnaire and an information sheet with details of an alternative subconjunctival injection route involving injections at 3-month intervals. Outcome measures regarding acceptance of the new procedure, social situational factors, disease factors, and treatment factors were assessed. RESULTS: A total of 151 patients participated in this study. Of the 151 patients 112 (74.2%) were willing to have their glaucoma medication given by the new method of subconjunctival injection, 101 of 112 (90.2%) were willing to accept it at the same cost as their present medication, and 87 of 101 (86.1%) were willing to accept it even at a higher cost. These patients tended to be on a greater number of medications (P=0.006), and medicating more frequently in a day (P=0.003). Nine of 10 (90%) patients who were admitted to nonadherence were willing to accept subconjunctival injections at 3-month intervals in place of their topical medication. CONCLUSIONS: Our study found that 74% of glaucoma patients were willing to accept an alternative form of glaucoma treatment through 3-monthly subconjunctival injections. A large proportion of patients who were admitted to nonadherence to topical medication were willing to consider this alternative method of medication. Our findings are helpful when developing patient-acceptable drug-delivery regimes, which may alleviate the need for daily medication.

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.

Central corneal thickness in Chinese subjects with primary angle closure glaucoma.

PURPOSE: To characterize central corneal thickness (CCT) in Chinese eyes with primary angle closure glaucoma (PACG). METHODS: CCT was measured by ultrasound pachymetry in PACG eyes and compared with primary open-angle glaucoma (POAG) eyes. POAG eyes were further subdivided into high-tension glaucoma (HTG) and normal-tension glaucoma (NTG) for analysis. PACG eyes had glaucomatous optic neuropathy and visual field loss, an angle in which at least 180 degrees of angle in which the posterior trabecular meshwork was not visible, and raised intraocular pressure (IOP) and/or peripheral anterior synechiae. Both HTG (IOP >21 mm Hg) and NTG (IOP consistently <21 mm Hg) eyes had glaucomatous optic neuropathy with compatible visual field defects and open angles. Further comparison was made with CCT data of 1067 normal subjects previously enrolled in a population-based study. RESULTS: We enrolled 154 patients with PACG and 300 with POAG. Mean age of PACG patients was 68.1±8.3 years compared with 71.1±12.4 years in POAG patients (P=0.002). There was no difference in mean CCT of PACG eyes (541.28±33.95 µm) and POAG eyes (539.28±34.84 µm, P=0.56) or normal eyes of control subjects (536.74±31.08 µm) (P=0.07). However, mean CCT of NTG eyes (535.23±36.10 µm) was significantly lower than that of HTG eyes (543.44±33.10 µm, P=0.04), and HTG eyes had thicker CCT than normal eyes (P=0.01). CONCLUSIONS: PACG eyes had similar CCT as those with POAG or normal eyes in Chinese subjects.

Comparison of ocular response analyzer parameters in chinese subjects with primary angle-closure and primary open-angle glaucoma.

OBJECTIVES: To evaluate corneal hysteresis (CH) and intraocular pressure (IOP) measured by the Ocular Response Analyzer in Chinese subjects with primary angle-closure glaucoma (PACG), assess their relationship with Goldmann applanation tonometry (GAT) measurements, and compare this with subjects with primary open-angle glaucoma (POAG) and normal controls. METHODS: In this prospective observational study, consecutive subjects with PACG and POAG without prior intraocular surgery were enrolled from glaucoma clinics. Normal subjects were recruited from an ongoing population-based study. One eye of each subject underwent standardized ocular examination and IOP measurement by GAT and the Ocular Response Analyzer. Corneal hysteresis and corneal-compensated IOP were compared between groups. RESULTS: Of the 443 subjects recruited, 131 had PACG, 162 had POAG, and 150 were normal. Corneal hysteresis was lower in PACG (9.1 mm Hg; 95% confidence interval [CI], 8.7 to 9.4 mm Hg) and POAG (9.5 mm Hg; 95% CI, 9.2 to 9.5 mm Hg) eyes compared with control eyes (10.4 mm Hg; 95% CI, 10.1 to 10.6 mm Hg; P < .001 for both), with no difference (P = .16) in CH found between PACG and POAG eyes. After adjusting for age, sex, and IOP measurement by GAT, CH persisted to be lower only in eyes with PACG in comparison with control eyes (9.4 vs 10.1 mm Hg; P = .006). Eyes with POAG had lower CH than control eyes but the difference was not statistically significant (9.6 vs 10.1 mm Hg; P = .06). CONCLUSIONS: Corneal hysteresis was lower in eyes with glaucoma. After adjusting for age, sex, and IOP measurement by GAT, a persistently lower hysteresis was noted in eyes with PACG compared with other groups.

Central corneal thickness and its associations with ocular and systemic factors: the Singapore Malay Eye Study.

PURPOSE: To examine the association between central corneal thickness (CCT) and potential systemic and ocular factors affecting CCT in an Asian population. DESIGN: Population-based cross-sectional study. METHODS: A total of 3,280 (78.7% response) adults aged 40 to 80 years of Malay ethnicity living in Singapore underwent a standardized interview and ocular and systemic examination at a centralized study clinic. CCT was measured with an ultrasound pachymeter. Blood samples were obtained to determine serum glucose, cholesterol, and triglyceride levels, and urine samples to determine glomerular filtration rate. The presence of diabetes, hypertension, chronic kidney disease (CKD), and metabolic syndrome were defined based on a combination of investigation results and participant's history. RESULTS: CCT was obtained from 3,239 individuals. CCT was normally distributed with a mean of 541.2 microm in the right eye. While controlling for age and gender, CCT was greater in individuals with higher body mass index (BMI) (P = .038), greater intraocular pressure (IOP) (P < .001), greater axial length (P = .005), and greater radius of corneal curvature (P < .001). Individuals with CKD (P = 0.012) and metabolic syndrome (P < .001) also had greater CCT. CONCLUSION: CCT is associated with higher IOP, longer axial length, and greater radius of corneal curvature, as well as higher BMI, metabolic syndrome, and CKD.