[Show abstract][Hide abstract] ABSTRACT: Selective laser trabeculoplasty (SLT) should be explored as a therapeutic option in eyes with angle closure.
To assess the intraocular pressure (IOP)-lowering efficacy of SLT in eyes with primary angle closure (PAC) and PAC glaucoma (PACG).
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.
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.
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.
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).
Eyes with PAC or PACG respond to SLT in the short term, but the overall long-term therapeutic effectiveness needs further evaluation.
clinicaltrials.gov Identifier: NCT01004900.
[Show abstract][Hide abstract] ABSTRACT: Enteric fever affects more than 25 million people annually and results from systemic infection with Salmonella enterica serovar Typhi or Paratyphi pathovars A, B or C(1). We conducted a genome-wide association study of 432 individuals with blood culture-confirmed enteric fever and 2,011 controls from Vietnam. We observed strong association at rs7765379 (odds ratio (OR) for the minor allele = 0.18, P = 4.5 × 10(-10)), a marker mapping to the HLA class II region, in proximity to HLA-DQB1 and HLA-DRB1. We replicated this association in 595 enteric fever cases and 386 controls from Nepal and also in a second independent collection of 151 cases and 668 controls from Vietnam. Imputation-based fine-mapping across the extended MHC region showed that the classical HLA-DRB1*04:05 allele (OR = 0.14, P = 2.60 × 10(-11)) could entirely explain the association at rs7765379, thus implicating HLA-DRB1 as a major contributor to resistance against enteric fever, presumably through antigen presentation.
[Show abstract][Hide abstract] ABSTRACT: To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.
[Show abstract][Hide abstract] ABSTRACT: Purpose:To examine the associations between iris surface features with anterior chamber angle width in Asian eyes. Methods:In this prospective cross-sectional study, we recruited 600 subjects from a large population-based study, the Singapore Epidemiology of Eye Diseases (SEED) study. We obtained standardized digital slit-lamp iris photographs and graded the iris crypts (by number and size), furrows (by number and circumferential extent), and color (higher grade denoting darker iris). Vertical and horizontal cross-sections of anterior chamber were imaged using anterior segment optical coherence tomography. Angle opening distance (AOD), angle recess area (ARA), and trabecular-iris space area (TISA) were measured using customized software. Associations of the angle width with the iris surface features in the subject's right eyes were assessed using linear regression analysis. Results:464 eyes of the 464 subjects (mean age: 57.5±8.6 years) had complete and gradable data for crypts and color, and 423 eyes had gradable data for furrows. After adjustment for age, gender, ethnicity, pupil size, and corneal arcus, higher crypt grade was independently associated with wider AOD750 (β [change in angle width per grade higher] = 0.018, P=0.023), ARA750 (β=0.022, P=0.049) and TISA750 (β=0.011, P=0.019), and darker iris was associated narrower ARA750 (β=-0.025, P=0.044) and TISA750 (β=-0.013, P=0.011). Conclusions:Iris surface features, assessed and measured from slit lamp photographs, correlated well with anterior chamber angle width; irises with more crypts and lighter color were associated with wider angle. These findings may provide another imaging modality to assess angle closure risk based on iris surface features.
[Show abstract][Hide abstract] ABSTRACT: Purpose:To evaluate a novel software capable of automatically grading angle closure on EyeCamTM (Clarity Medical Systems, Pleasanton, CA) angle images in comparison to manual grading of images, with gonioscopy as the reference standard. Methods:In this hospital-based, prospective study, subjects underwent gonioscopy by a single observer, and EyeCam imaging by a different operator. The anterior chamber angle in a quadrant was classified as closed if the posterior trabecular meshwork could not be seen. An eye was classified as having angle closure if there were 2 or more quadrants of closure. Automated grading of the angle images was performed using customized software. Agreement between the methods was ascertained by kappa statistic and comparison of area under receiver operating characteristic curves (AUC). Results:One hundred and forty subjects (140 eyes) were included, the majority of whom were Chinese (102/140, 72.9%) and females (72/140, 51.5%). Angle closure was detected in 61 eyes (43.6%) with gonioscopy in comparison to 59 eyes (42.1%, p=0.73) using manual grading and 67 eyes (47.9%, p=0.24) with automated grading of EyeCam images. The agreement for angle closure diagnosis between gonioscopy and both manual (k=0.88; 95% Confidence Interval (CI), 0.81-0.96) and automated grading of EyeCam images was good (k=0.74; 95% CI, 0.63-0.85). The AUC for detecting eyes with gonioscopic angle closure was comparable for manual and automated grading (AUC 0.974 vs 0.954, p = 0.31) of EyeCam image. Conclusions:Customized software for automated grading of EyeCam angle images was found to have good agreement with gonioscopy. Human observation of the EyeCam images may still be needed to avoid gross misclassification, especially in eyes with extensive angle closure.
[Show abstract][Hide abstract] ABSTRACT: Purpose: To test the association between the CTG18.1 trinucleotide repeat expansion of TCF4 gene and Fuchs' endothelial corneal dystrophy (FECD) in a Chinese population. Methods: The CTG18.1 trinucleotide repeat polymorphism was genotyped using short tandem repeat (STR) and triplet repeat primed polymerase chain reaction (TP-PCR) assays in 57 Chinese subjects with FECD and 121 controls. Statistical association of the expanded CTG18.1 allele and 18 single nucleotide polymorphisms (SNPs) across TCF4 with FECD was evaluated. To investigate the linkage disequilibrium structure of the TCF4 region, haplotype analysis was performed on our study subjects and compared to genotyping data of 97 Han Chinese and 85 Caucasians in the 1000 Genomes Project. Results: The expanded CTG18.1 allele was associated with FECD (P = 4.7 X 10-14) with the odds ratio of each copy of the expanded allele estimated to be 66.5 (95% confidence interval: 12.6-350.1). Five TCF4 SNPs showed association with FECD at a nominal level (P < 5.0 X 10-2); however, conditional on the expanded CTG18.1 polymorphism, none of the SNPs showed association with FECD. The only haplotype associated with the disease was the one with the expansion at the CTG18.1 locus. Conclusions: Trans-ethnic replication of the association between the CTG18.1 repeat expansion in the TCF4 gene and FECD suggests it a common, causal variant shared in Eurasian populations conferring significant risk for the development of FECD. Our data suggests that the expanded CTG18.1 allele is the main, if not sole, causal variant at this gene locus in Chinese.
[Show abstract][Hide abstract] ABSTRACT: Purpose To compare anterior segment parameters in Chinese and Japanese subjects using anterior segment optical coherence tomography (ASOCT) and to determine if the associations between these parameters and angle closure vary between the two ethnic groups.Methods We conducted a case-control study among 117 Japanese and 102 Chinese patients with primary angle closure (PAC) or primary angle closure glaucoma (PACG); and 117 Japanese and 176 Chinese controls. All participants underwent A-scan biometry and ASOCT imaging (Visante, Carl Zeiss Meditec, Dublin, Ca). ASOCT-derived biometric parameters were compared between groups. Multivariate analysis was performed to determine predictors of angle opening distance at 750µm from the scleral spur (AOD750).Results Japanese were older (p<0.001) and consisted of more females (p<0.001). Age and gender adjusted analysis of covariance showed that Japanese eyes with angle closure had a significantly shallower anterior chamber depth (p=0.015), shorter axial length (p<0.001), greater lens thickness (p<0.001), lens vault (LV) (p=0.001) and iris curvature (I-Curv) (p<0.001), and a smaller anterior chamber area (p=0.044) and volume (p=0.028); but no significant difference was noted for anterior chamber width (ACW). In Japanese, the predictors of AOD750 were LV (p=0.004), ACW (p=0.049) and ICurv (p=0.017); in Chinese, only the LV (p<0.001) was a determinant factor.Conclusion Japanese eyes with angle closure were smaller, with thicker lenses. LV is an important factor for angle closure in both races. These results suggest differing mechanisms of angle closure pathogenesis between the two ethnic groups.
[Show abstract][Hide abstract] ABSTRACT: We performed a genome-wide association study for primary open-angle glaucoma (POAG) in 1,007 cases with high-pressure glaucoma (HPG) and 1,009 controls from southern China. We observed genome-wide significant association at multiple SNPs near ABCA1 at 9q31.1 (rs2487032; P = 1.66 × 10(-8)) and suggestive evidence of association in PMM2 at 16p13.2 (rs3785176; P = 3.18 × 10(-6)). We replicated these findings in a set of 525 HPG cases and 912 controls from Singapore and a further set of 1,374 POAG cases and 4,053 controls from China. We observed genome-wide significant association with more than one SNP at the two loci (P = 2.79 × 10(-19) for rs2487032 representing ABCA1 and P = 5.77 × 10(-10) for rs3785176 representing PMM2). Both ABCA1 and PMM2 are expressed in the trabecular meshwork, optic nerve and other ocular tissues. In addition, ABCA1 is highly expressed in the ganglion cell layer of the retina, a finding consistent with it having a role in the development of glaucoma.
[Show abstract][Hide abstract] ABSTRACT: Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 × 10(-8) for rs6445055), two on chromosome 9 (P = 2.80 × 10(-11) for rs2472493 near ABCA1 and P = 6.39 × 10(-11) for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 × 10(-11) for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.
[Show abstract][Hide abstract] ABSTRACT: To compare the intraocular pressure (IOP)-lowering efficacy and safety of brinzolamide 1% and brimonidine 0.2% fixed combination (BBFC) with that of brinzolamide 1% or brimonidine 0.2% monotherapy, all dosed 2 times per day (BID).
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to investigate the association of a novel biometric parameter, relative lens vault (LV), with primary angle-closure (PAC) and primary angle-closure glaucoma (PACG).
[Show abstract][Hide abstract] ABSTRACT: Glaucoma is the leading cause of global irreversible blindness. Present estimates of global glaucoma prevalence are not up-to-date and focused mainly on European ancestry populations. We systematically examined the global prevalence of primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG), and projected the number of affected people in 2020 and 2040.
[Show abstract][Hide abstract] ABSTRACT: Corneal curvature measures the steepness of the cornea and is an important parameter for clinically diseases such as astigmatism and myopia. Despite the high heritability of corneal curvature, only two associated genes have been discovered to date. We performed a three-stage genome-wide association study meta-analysis in 12,660 Asian individuals. Our Stage 1 was done in multi-ethnic cohorts comprising 7,440 individuals, followed by a Stage 2 replication in 2,473 Chinese and Stage 3 in 2,747 Japanese. The SNP array genotype data were imputed up to the 1000 Genomes Project Phase 1 cosmopolitan panel. The SNP association with the radii of corneal curvature was investigated in the linear regression model with the adjustment of age, gender, and principal components. In addition to the known genes, MTOR (also known as FRAP1) and PDGFRA, we discovered two novel genes associated with corneal curvature: CMPK1 (rs17103186, P=3.3 x 10(-12)) and RBP3 (rs11204213 [Val884Met], P=1.1 x 10(-13)). The missense RBP3 SNP, rs11204213, was also associated with axial length (P=4.2 x 10(-6)) and had larger effects on both corneal curvature and axial length compared to other SNPs. The index SNPs at the four indicated loci explained 1.9% of corneal curvature variance across the Stages 1 and 2 cohorts, while 33.8% of corneal curvature variance was explained by the genome-wide imputation data. We identified two novel genes influencing corneal curvature, which are related to either corneal shape or eye size. This study provides additional insights into genetic architecture of corneal shape.
Human Molecular Genetics 06/2014; · 7.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Age-related cataract is a leading cause of blindness worldwide, especially in developing countries where access to cataract surgery remains limited. Previous linkage and candidate gene studies suggested genetic influences on age-related nuclear cataract but few genetic markers have been identified thus far. We conducted genome-wide association studies on 4,569 Asians (including 2,369 Malays and 2,200 Indians), and replicated our analysis in 2,481 Chinese from two independent cohorts (1,768 Chinese in Singapore and 803 Chinese in Beijing). We confirmed two genome-wide significant loci for nuclear cataract in the combined meta-analysis of four cohorts (n=7,140). The first locus was at chromosome 3q25.31 in KCNAB1 (rs7615568, fixed-effect Pmeta=2.30 x 10(-8); random-effect Pmeta=1.08 x 10(-8)). The second locus was at chromosome 21 in the proximity of CRYAA (rs11911275, fixed-effect Pmeta=2.77×10(-8); random-effect Pmeta=1.98 x 10(-9)), a major protein component of eye lens. The findings were further supported by up-regulation and down-regulation of KCNAB1 and CRYAA in human lens capsule, respectively, as the severity of nuclear cataract increases. The results offer additional insights into the pathogenesis of nuclear cataract in Asians.
Human Molecular Genetics 06/2014; · 7.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p ≤ 5 × 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 × 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.
The American Journal of Human Genetics 06/2014; · 11.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the ethnic differences in the distribution of intraocular pressure (IOP) and central corneal thickness (CCT) in a multi-ethnic Asian population by self-reported ethnicity and genetic ancestry.
[Show abstract][Hide abstract] ABSTRACT: Noninvasive medical imaging techniques have high potential in the field of ocular imaging research. Angle closure glaucoma is a major disease causing blindness and a possible way of detection is the examination of the anterior chamber angle in eyes. Here, a simple optical method for the evaluation of angle-closure glaucoma is proposed and illustrated. The light propagation from the region associated with the iridocorneal angle to the exterior of eye is considered analytically. The design of the gel assisted probe prototype is carried out and the imaging of iridocorneal angle is performed on an eye model.
Review of Scientific Instruments 06/2014; 85(6):066105-066105-3. · 1.60 Impact Factor