Ichhpujani P, Thakur S, Kumar S, Singh RB. Juvenile Open Angle Glaucoma With Nonbullous Congenital Ichthyosiform Erythroderma. J Glaucoma 2018;27(11):e180-e182.Abstract
INTRODUCTION: Glaucoma in patients with nonbullous congenital ichthyosiform erythroderma (NBCIE) is a rare entity that has not been described in a histologically confirmed case. We present a unique case of coexisting glaucoma, ichthyosis, and dwarfism that has not been previously described. METHODS: We present a case of NBCIE with glaucoma and dwarfism that presented to our outpatient department. The patient was referred for watering and photophobia that were due to an epithelial defect that was subsequently managed conservatively. Investigations revealed the existence of a constellation of findings that are presented here. RESULTS: NBCIE, glaucoma, and dwarfism represent a spectrum of diseases that seem to have a syndromic association. More gene linkage-based analysis are, however, needed to further confirm our observations. CONCLUSIONS: NBCIE, glaucoma, and dwarfism can often occur together and need to be assessed and managed individually. Early diagnosis of this spectrum can help improve patient management and quality of life. Dermatologists must get an ocular examination conducted for icthyoses patients.
Khawaja AP, Cooke Bailey JN, Wareham NJ, Scott RA, Simcoe M, Igo RP, Song YE, Wojciechowski R, Cheng C-Y, Khaw PT, Pasquale LR, Haines JL, Foster PJ, Wiggs JL, Hammond CJ, Hysi PG, and Consortium UKBEV, and Consortium UKBEV. Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma. Nat Genet 2018;50(6):778-782.Abstract
Glaucoma is the leading cause of irreversible blindness globally . Despite its gravity, the disease is frequently undiagnosed in the community . Raised intraocular pressure (IOP) is the most important risk factor for primary open-angle glaucoma (POAG). Here we present a meta-analysis of 139,555 European participants, which identified 112 genomic loci associated with IOP, 68 of which are novel. These loci suggest a strong role for angiopoietin-receptor tyrosine kinase signaling, lipid metabolism, mitochondrial function and developmental processes underlying risk for elevated IOP. In addition, 48 of these loci were nominally associated with glaucoma in an independent cohort, 14 of which were significant at a Bonferroni-corrected threshold. Regression-based glaucoma-prediction models had an area under the receiver operating characteristic curve (AUROC) of 0.76 in US NEIGHBORHOOD study participants and 0.74 in independent glaucoma cases from the UK Biobank. Genetic-prediction models for POAG offer an opportunity to target screening and timely therapy to individuals most at risk.
Kang JH, Rosner BA, Wiggs JL, Pasquale LR. Sex hormone levels and risk of primary open-angle glaucoma in postmenopausal women. Menopause 2018;25(10):1116-1123.Abstract
OBJECTIVE: We evaluated the relation of prediagnostic sex hormone levels in postmenopausal women with primary open-angle glaucoma (POAG) and intraocular pressure (IOP). METHODS: Among postmenopausal participants of the Nurses' Health Study, POAG cases (n = 189; diagnosed 1990-2008) and controls (n = 189) were matched on age, fasting status, and postmenopausal hormone use at blood draw (1989-1990). Plasma concentrations of estrone sulfate, estradiol, testosterone, sex hormone binding globulin, and dehydroepiandrosterone sulfate were assessed. The primary outcome was POAG; in secondary analyses, among cases only, we evaluated maximum untreated IOP at diagnosis. Multivariable-adjusted logistic/multiple linear regression models were used to evaluate tertiles (Ts) of biomarker levels and the two outcomes, adjusting for various potential confounders. RESULTS: We observed no significant associations of estrone, estradiol, sex hormone binding globulin, or dehydroepiandrosterone sulfate with POAG risk or with maximum IOP at glaucoma diagnosis among cases. Suggestive significant associations were observed with highest testosterone and POAG risk (T3 vs T1 multivariable-adjusted odds ratio 1.84; 95% confidence interval 1.02, 3.33; P trend 0.10). Similarly, for maximum IOP at diagnosis among cases only (mean 8 years after blood draw), higher testosterone was significantly associated with higher IOP (multivariable-adjusted difference in IOP T3 vs T1 2.17 mm Hg; 95% confidence interval 0.34, 3.99; P trend 0.02). CONCLUSIONS: Overall, plasma sex hormone levels in postmenopausal women were not associated with POAG risk; however, a trend of higher testosterone levels being associated with higher POAG risk and higher IOP at diagnosis was observed and needs confirmation.
Guo C, Wu N, Niu X, Wu Y, Chen DF, Guo W. Comparison of T Helper Cell Patterns in Primary Open-Angle Glaucoma and Normal-Pressure Glaucoma. Med Sci Monit 2018;24:1988-1996.Abstract
BACKGROUND HSP60-related immunological activities are found in normal-pressure glaucoma (NPG) patients, in whom an elevated intraocular pressure (IOP) found in primary open-angle glaucoma (POAG) is not observed. HSP60 was found in POAG and NPG patients, while anti-HSP60 level was mainly found to be higher in NPG patients. The purpose of this study was to compare the percentages of Th cells and levels of related cytokines, attempting to provide evidence to explain this discrepancy. MATERIAL AND METHODS Blood samples from POAG, NPG, and normal control (NC) groups were collected and peripheral blood monocytes were isolated and cultured with or without the stimulation of HSP60. Flow cytometry and enzyme-linked immunosorbent assay were used to assess the percentages of Th1, Th2, Th17, and Treg cells, as well as HSP60 antibody levels and related cytokine levels, before and after culture. RESULTS Significantly higher titers of anti-HSP60 were observed only in NPG patients. Comparable Th1 and Th2 cell frequencies, IL-4 level, and IFN-γ level were found in POAG and NPG patients, while higher Treg cell frequency was only found in POAG patients. After culturing with HSP60, increased Th2 frequencies and decreased Th1 frequencies were observed in the POAG, NPG, and NC groups, while increased Treg frequency was only identified in the POAG and NC groups. CONCLUSIONS Different Th cell patterns were observed among POAG, NPG, and NC groups. Lack of induction of Treg cells and imbalance of the pro-inflammatory and anti-inflammatory response patterns of Th cells exist in some NPG patients.
Guhan S, Peng S-L, Janbatian H, Saadeh S, Greenstein S, Al Bahrani F, Fadlallah A, Yeh T-C, Melki SA. Surgical adhesives in ophthalmology: history and current trends. Br J Ophthalmol 2018;Abstract
Tissue adhesives are gaining popularity in ophthalmology, as they could potentially reduce the complications associated with current surgical methods. An ideal tissue adhesive should have superior tensile strength, be non-toxic and anti-inflammatory, improve efficiency and be cost-effective. Both synthetic and biological glues are available. The primary synthetic glues include cyanoacrylate and the recently introduced polyethylene glycol (PEG) derivatives, while most biological glues are composed of fibrin. Cyanoacrylate has a high tensile strength, but rapidly polymerises upon contact with any fluid and has been associated with histotoxicity. Fibrin induces less toxic and inflammatory reactions, and its polymerisation time can be controlled. Tensile strength studies have shown that fibrin is not as strong as cyanoacrylate. While more research is needed, PEG variants currently appear to have the most promise. These glues are non-toxic, strong and time-effective. Through MEDLINE and internet searches, this paper presents a systematic review of the current applications of surgical adhesives to corneal, glaucoma, retinal, cataract and strabismus surgeries. Our review suggests that surgical adhesives have promise to reduce problems in current ophthalmic surgical procedures.
Wang M, Pasquale LR, Shen LQ, Boland MV, Wellik SR, De Moraes CG, Myers JS, Wang H, Baniasadi N, Li D, Silva RNE, Bex PJ, Elze T. Reversal of Glaucoma Hemifield Test Results and Visual Field Features in Glaucoma. Ophthalmology 2018;125(3):352-360.Abstract
PURPOSE: To develop a visual field (VF) feature model to predict the reversal of glaucoma hemifield test (GHT) results to within normal limits (WNL) after 2 consecutive outside normal limits (ONL) results. DESIGN: Retrospective cohort study. PARTICIPANTS: Visual fields of 44 503 eyes from 26 130 participants. METHODS: Eyes with 3 or more consecutive reliable VFs measured with the Humphrey Field Analyzer (Swedish interactive threshold algorithm standard 24-2) were included. Eyes with ONL GHT results for the 2 baseline VFs were selected. We extracted 3 categories of VF features from the baseline tests: (1) VF global indices (mean deviation [MD] and pattern standard deviation), (2) mismatch between baseline VFs, and (3) VF loss patterns (archetypes). Logistic regression was applied to predict the GHT results reversal. Cross-validation was applied to evaluate the model on testing data by the area under the receiver operating characteristic curve (AUC). We ascertained clinical glaucoma status on a patient subset (n = 97) to determine the usefulness of our model. MAIN OUTCOME MEASURES: Predictive models for GHT results reversal using VF features. RESULTS: For the 16 604 eyes with 2 initial ONL results, the prevalence of a subsequent WNL result increased from 0.1% for MD < -12 dB to 13.8% for MD ≥-3 dB. Compared with models with VF global indices, the AUC of predictive models increased from 0.669 (MD ≥-3 dB) and 0.697 (-6 dB ≤ MD < -3 dB) to 0.770 and 0.820, respectively, by adding VF mismatch features and computationally derived VF archetypes (P < 0.001 for both). The GHT results reversal was associated with a large mismatch between baseline VFs. Moreover, the GHT results reversal was associated more with VF archetypes of nonglaucomatous loss, severe widespread loss, and lens rim artifacts. For a subset of 97 eyes, using our model to predict absence of glaucoma based on clinical evidence after 2 ONL results yielded significantly better prediction accuracy (87.7%; P < 0.001) than predicting GHT results reversal (68.8%) with a prescribed specificity 67.7%. CONCLUSIONS: Using VF features may predict the GHT results reversal to WNL after 2 consecutive ONL results.
Struebing FL, King R, Li Y, Cooke Bailey JN, Wiggs JL, Geisert EE. Genomic loci modulating retinal ganglion cell death following elevated IOP in the mouse. Exp Eye Res 2018;169:61-67.Abstract
The present study was designed to identify genomic loci modulating the susceptibility of retinal ganglion cells (RGC) to elevated intraocular pressure (IOP) in the BXD recombinant inbred mouse strain set. IOP was elevated by injecting magnetic microspheres into the anterior chamber and blocking the trabecular meshwork using a handheld magnet to impede drainage. The IOP was then measured over the next 21 days. Only animals with IOP greater than 25 mmHg for two consecutive days or an IOP above 30 mmHg on a single day after microsphere-injection were used in this study. On day 21, mice were sacrificed and the optic nerve was processed for histology. Axons were counted for both the injected and the control eye in 49 BXD strains, totaling 181 normal counts and 191 counts associated with elevated IOP. The axon loss for each strain was calculated and the data were entered into The average number of normal axons in the optic nerve across all strains was 54,788 ± 16% (SD), which dropped to 49,545 ± 20% in animals with artificially elevated IOP. Interval mapping demonstrated a relatively similar genome-wide map for both conditions with a suggestive Quantitative Trait Locus (QTL) on proximal Chromosome 3. When the relative axon loss was used to generate a genome-wide interval map, we identified one significant QTL (p < 0.05) on Chromosome 18 between 53.6 and 57 Mb. Within this region, the best candidate gene for modulating axon loss was Aldh7a1. Immunohistochemistry demonstrated ALDH7A1 expression in mouse RGCs. ALDH7A1 variants were not significantly associated with glaucoma in the NEIGHBORHOOD GWAS dataset, but this enzyme was identified as part of the butanoate pathway previously associated with glaucoma risk. Our results suggest that genomic background influences susceptibility to RGC degeneration and death in an inducible glaucoma model.
McLaurin E, Cavet ME, Gomes PJ, Ciolino JB. Brimonidine Ophthalmic Solution 0.025% for Reduction of Ocular Redness: A Randomized Clinical Trial. Optom Vis Sci 2018;95(3):264-271.Abstract
SIGNIFICANCE: The α2-adrenergic receptor agonist brimonidine has been reported to induce conjunctival blanching in cataract, strabismus, laser refractive, and filtration procedures. Clinicians are often faced with red eyes with no apparent underlying pathology. Low-dose brimonidine reduced ocular redness in such subjects with efficacy maintained over 1 month and negligible rebound redness. PURPOSE: The aim of this study was to evaluate the safety and efficacy of brimonidine tartrate ophthalmic solution 0.025% for the treatment of ocular redness. METHODS: In this single-center, double-masked, phase 3 clinical trial, adult subjects with baseline redness of more than 1 unit in both eyes (0- to 4-unit scale) were randomized 2:1 to brimonidine 0.025% or vehicle. A single dose was administered in-office (day 1); thereafter subjects instilled treatment four times a day for 4 weeks, with clinic visits on days 15, 29, and 36 (7 days post-treatment). Efficacy end points included investigator-evaluated redness 5 to 240 minutes post-instillation on day 1 (primary); investigator-evaluated change from baseline 1, 360, and 480 minutes post-instillation on day 1, and 1 and 5 minutes post-instillation on days 15 and 29; total clearance of redness, and subject-assessed redness. Safety/tolerability measures included adverse events, rebound redness, and drop comfort. RESULTS: Sixty subjects were randomized (n = 40 brimonidine, n = 20 vehicle). Investigator-assessed redness was lower with brimonidine versus vehicle over the 5- to 240-minute post-instillation period (mean [SE], 0.62 [0.076] vs. 1.49 [0.108]; P < .0001) and at each time point within that period (P < .0001). At 1, 360, and 480 minutes post-instillation, respectively, the mean differences (95% confidence interval) between treatments were -0.73 (-1.05 to -0.41), -0.57 (-0.84 to -0.29), and -0.39 (-0.67 to -0.10), respectively. No tachyphylaxis was evident with brimonidine on days 15 and 29, and minimal rebound redness was observed following discontinuation. Adverse events were infrequent, and brimonidine was rated as very comfortable. CONCLUSIONS: Brimonidine 0.025% appeared safe and effective for reduction of ocular redness, with an 8-hour duration of action, no evidence of tachyphylaxis, and negligible rebound redness.
Shiga Y, Akiyama M, Nishiguchi KM, Sato K, Shimozawa N, Takahashi A, Momozawa Y, Hirata M, Matsuda K, Yamaji T, Iwasaki M, Tsugane S, Oze I, Mikami H, Naito M, Wakai K, Yoshikawa M, Miyake M, Yamashiro K, Kashiwagi K, Iwata T, Mabuchi F, Takamoto M, Ozaki M, Kawase K, Aihara M, Araie M, Yamamoto T, Kiuchi Y, Nakamura M, Ikeda Y, Sonoda K-H, Ishibashi T, Nitta K, Iwase A, Shirato S, Oka Y, Satoh M, Sasaki M, Fuse N, Suzuki Y, Cheng C-Y, Khor CC, Baskaran M, Perera S, Aung T, Vithana EN, Cooke Bailey JN, Kang JH, Pasquale LR, Haines JL, Wiggs JL, Burdon KP, Gharahkhani P, Hewitt AW, Mackey DA, Macgregor S, Craig JE, Allingham RR, Hauser M, Ashaye A, Budenz DL, Akafo S, Williams SEI, Kamatani Y, Nakazawa T, Kubo M. Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma. Hum Mol Genet 2018;27(8):1486-1496.Abstract
Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide for which 15 disease-associated loci had been discovered. Among them, only 5 loci have been associated with POAG in Asians. We carried out a genome-wide association study and a replication study that included a total of 7378 POAG cases and 36 385 controls from a Japanese population. After combining the genome-wide association study and the two replication sets, we identified 11 POAG-associated loci, including 4 known (CDKN2B-AS1, ABCA1, SIX6 and AFAP1) and 7 novel loci (FNDC3B, ANKRD55-MAP3K1, LMX1B, LHPP, HMGA2, MEIS2 and LOXL1) at a genome-wide significance level (P < 5.0×10-8), bringing the total number of POAG-susceptibility loci to 22. The 7 novel variants were subsequently evaluated in a multiethnic population comprising non-Japanese East Asians (1008 cases, 591 controls), Europeans (5008 cases, 35 472 controls) and Africans (2341 cases, 2037 controls). The candidate genes located within the new loci were related to ocular development (LMX1B, HMGA2 and MAP3K1) and glaucoma-related phenotypes (FNDC3B, LMX1B and LOXL1). Pathway analysis suggested epidermal growth factor receptor signaling might be involved in POAG pathogenesis. Genetic correlation analysis revealed the relationships between POAG and systemic diseases, including type 2 diabetes and cardiovascular diseases. These results improve our understanding of the genetic factors that affect the risk of developing POAG and provide new insight into the genetic architecture of POAG in Asians.
Gharahkhani P, Burdon KP, Cooke Bailey JN, Hewitt AW, Law MH, Pasquale LR, Kang JH, Haines JL, Souzeau E, Zhou T, Siggs OM, Landers J, Awadalla M, Sharma S, Mills RA, Ridge B, Lynn D, Casson R, Graham SL, Goldberg I, White A, Healey PR, Grigg J, Lawlor M, Mitchell P, Ruddle J, Coote M, Walland M, Best S, Vincent A, Gale J, RadfordSmith G, Whiteman DC, Montgomery GW, Martin NG, Mackey DA, Wiggs JL, Macgregor S, Craig JE, Craig JE. Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma. Sci Rep 2018;8(1):3124.Abstract
Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1, LINC02052 and CRYGS, LMX1B, and LMO7 using single variant tests, one additional locus (C9) using gene-based tests, and two genetic pathways - "response to fluid shear stress" and "abnormal retina morphology" - in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping.
Radhakrishnan S, Chen PP, Junk AK, Nouri-Mahdavi K, Chen TC. Laser Peripheral Iridotomy in Primary Angle Closure: A Report by the American Academy of Ophthalmology. Ophthalmology 2018;125(7):1110-1120.Abstract
PURPOSE: To examine the efficacy and complications of laser peripheral iridotomy (LPI) in subjects with primary angle closure (PAC). METHODS: Literature searches in the PubMed and Cochrane databases were last conducted in August 2017 and yielded 300 unique citations. Of these, 36 met the inclusion criteria and were rated according to the strength of evidence; 6 articles were rated level I, 11 articles were rated level II, and 19 articles were rated level III. RESULTS: Reported outcomes were change in angle width, effect on intraocular pressure (IOP) control, disease progression, and complications. Most of the studies (29/36, 81%) included only Asian subjects. Angle width (measured by gonioscopy, ultrasound biomicroscopy, and anterior segment OCT) increased after LPI in all stages of angle closure. Gonioscopically defined persistent angle closure after LPI was reported in 2% to 57% of eyes across the disease spectrum. Baseline factors associated with persistent angle closure included narrower angle and parameters representing nonpupillary block mechanisms of angle closure, such as a thick iris, an anteriorly positioned ciliary body, or a greater lens vault. After LPI, further treatment to control IOP was reported in 0%-8% of PAC suspect (PACS), 42% to 67% of PAC, 21% to 47% of acute PAC (APAC), and 83%-100% of PAC glaucoma (PACG) eyes. Progression to PACG ranged from 0% to 0.3% per year in PACS and 0% to 4% per year in PAC. Complications after LPI included IOP spike (8-17 mmHg increase from baseline in 6%-10%), dysphotopsia (2%-11%), anterior chamber bleeding (30%-41%), and cataract progression (23%-39%). CONCLUSIONS: Laser peripheral iridotomy increases angle width in all stages of primary angle closure and has a good safety profile. Most PACS eyes do not receive further intervention, whereas many PAC and APAC eyes, and most PACG eyes, receive further treatment. Progression to PACG is uncommon in PACS and PAC. There are limited data on the comparative efficacy of LPI versus other treatments for the various stages of angle closure; 1 randomized controlled trial each demonstrated superiority of cataract surgery over LPI in APAC and of clear lens extraction over LPI in PACG or PAC with IOP above 30 mmHg.
Han X, Liu Y, Kam WR, Sullivan DA. Effect of brimonidine, an α2 adrenergic agonist, on human meibomian gland epithelial cells. Exp Eye Res 2018;170:20-28.Abstract
We recently discovered that the anti-glaucoma pharmaceuticals timolol, a β adrenergic antagonist, and pilocarpine, a cholinergic compound, negatively influence the morphology, proliferative capacity and survival of human meibomian gland epithelial cells (HMGECs). We hypothesize that another class of anti-glaucoma drugs, the α2 adrenergic agonists, also acts directly on HMGECs to affect their structure and function. We tested this hypothesis. Immortalized (i) HMGECs were cultured with brimonidine, as well as clonidine (α2 agonist), phenylephrine (α1 agonist), RX821002 (inverse α2 agonist) and MK912 (neutral α2 agonist) for up to 7 days. Cells were counted with a hemocytometer, and evaluated for morphology, signaling pathway activity, protein biomarker expression, and the accumulation of neutral lipids, phospholipids and lysosomes. Our findings demonstrate that brimondine treatment induces a dose-dependent decrease in Akt signaling and proliferation of iHMGECs. In contrast, brimonidine also promotes a dose-dependent differentiation of iHMGECs, including an increase in neutral lipid, phospholipid and lysosome levels. These effects were paralleled by an inhibition of p38 signaling, and duplicated by cellular exposure to clonidine, but not phenylephrine. Brimonidine also enhanced the cellular content of sterol regulatory binding protein-1, a master regulator of lipid synthesis. Of particular interest, the putative α2 antagonists, RX821002 and MK912, did not interfere with brimonidine action, but rather stimulated IHMGEC differentiation. Our results support our hypothesis and demonstrate that α2 adrenergic agonists act directly on iHMGECs. However, these compounds do not elicit an overall negative effect. Rather, the α2 agonists promote the differentiation of iHMGECs.
Bailey JCN, Gharahkhani P, Kang JH, Butkiewicz M, Sullivan DA, Weinreb RN, Aschard H, Allingham RR, Ashley-Koch A, Lee RK, Moroi SE, Brilliant MH, Wollstein G, Schuman JS, Fingert JH, Budenz DL, Realini T, Gaasterland T, Scott WK, Singh K, Sit AJ, Igo RP, Song YE, Hark L, Ritch R, Rhee DJ, Vollrath D, Zack DJ, Medeiros F, Vajaranant TS, Chasman DI, Christen WG, Pericak-Vance MA, Liu Y, Kraft P, Richards JE, Rosner BA, Hauser MA, Craig JE, Burdon KP, Hewitt AW, Mackey DA, Haines JL, Macgregor S, Wiggs JL, Pasquale LR, and of Consortium ANZRAG (ANZRAG). Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets. Invest Ophthalmol Vis Sci 2018;59(2):629-636.Abstract
Purpose: Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods: We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results: In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.
King R, Struebing FL, Li Y, Wang J, Koch AA, Cooke Bailey JN, Gharahkhani P, Gharahkhani P, Gharahkhani P, Macgregor S, Allingham RR, Hauser MA, Wiggs JL, Geisert EE. Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma. PLoS Genet 2018;14(1):e1007145.Abstract
Central corneal thickness (CCT) is one of the most heritable ocular traits and it is also a phenotypic risk factor for primary open angle glaucoma (POAG). The present study uses the BXD Recombinant Inbred (RI) strains to identify novel quantitative trait loci (QTLs) modulating CCT in the mouse with the potential of identifying a molecular link between CCT and risk of developing POAG. The BXD RI strain set was used to define mammalian genomic loci modulating CCT, with a total of 818 corneas measured from 61 BXD RI strains (between 60-100 days of age). The mice were anesthetized and the eyes were positioned in front of the lens of the Phoenix Micron IV Image-Guided OCT system or the Bioptigen OCT system. CCT data for each strain was averaged and used to QTLs modulating this phenotype using the bioinformatics tools on GeneNetwork ( The candidate genes and genomic loci identified in the mouse were then directly compared with the summary data from a human POAG genome wide association study (NEIGHBORHOOD) to determine if any genomic elements modulating mouse CCT are also risk factors for POAG.This analysis revealed one significant QTL on Chr 13 and a suggestive QTL on Chr 7. The significant locus on Chr 13 (13 to 19 Mb) was examined further to define candidate genes modulating this eye phenotype. For the Chr 13 QTL in the mouse, only one gene in the region (Pou6f2) contained nonsynonymous SNPs. Of these five nonsynonymous SNPs in Pou6f2, two resulted in changes in the amino acid proline which could result in altered secondary structure affecting protein function. The 7 Mb region under the mouse Chr 13 peak distributes over 2 chromosomes in the human: Chr 1 and Chr 7. These genomic loci were examined in the NEIGHBORHOOD database to determine if they are potential risk factors for human glaucoma identified using meta-data from human GWAS. The top 50 hits all resided within one gene (POU6F2), with the highest significance level of p = 10-6 for SNP rs76319873. POU6F2 is found in retinal ganglion cells and in corneal limbal stem cells. To test the effect of POU6F2 on CCT we examined the corneas of a Pou6f2-null mice and the corneas were thinner than those of wild-type littermates. In addition, these POU6F2 RGCs die early in the DBA/2J model of glaucoma than most RGCs. Using a mouse genetic reference panel, we identified a transcription factor, Pou6f2, that modulates CCT in the mouse. POU6F2 is also found in a subset of retinal ganglion cells and these RGCs are sensitive to injury.
Feinstein M, Moussa K, Han Y. Ab Interno Tube Occlusion for Postoperative Hypotony in a Patient With an Ahmed Glaucoma Drainage Device. J Glaucoma 2018;27(3):e61-e63.Abstract
PURPOSE: To report a case of Ahmed glaucoma valve-induced hypotony that was successfully managed with postoperative intraluminal stenting of the aqueous shunt tube. PATIENT AND METHODS: We describe a 68-year-old man with advanced uveitic glaucoma with an intraocular pressure (IOP) of 25 mm Hg in the left eye. The patient initially responded well to an Ahmed glaucoma valve implant, but at 10 weeks postimplantation, the patient underwent cataract surgery and developed persistent hypotony, choroidal folds, and decreased vision. RESULTS: Before partial occlusion of the aqueous shunt tube, the patient had an IOP of 3 mm Hg and a best-corrected visual acuity (BCVA) of 20/60. Following intraluminal stenting of the aqueous shunt tube with 4-0 polypropylene suture (Prolene; Ethican), IOP rose from 7 to 10 mm Hg, BCVA improved to 20/30, and the choroidal folds resolved; IOP and BCVA remained stable through 1 year of follow-up and no additional surgical or pharmacological interventions were required. CONCLUSIONS: Aqueous shunt-induced hypotony can be successfully managed with intraluminal stenting and should be considered before tubal ligation or shunt removal.