Genetic variation at the 9p21 locus encompassing the CDKN2B-AS1, CDKN2A, and CDKN2B genes has been associated with primary open-angle glaucoma (POAG) in several independent studies. This study aimed ...to dissect the association further and to determine genotype-phenotype correlations between genetic variation at this locus and a range of glaucoma-related traits in a large cohort of POAG patients.
Comparative case series and case-control study.
One thousand four hundred thirty-two POAG patients and 595 unaffected controls recruited from 2 population-based and 2 cross-sectional studies.
Each patient was genotyped at 9 single nucleotide polymorphisms (SNPs) previously associated with POAG at the 9p21 locus. Each SNP was assessed for association with each outcome measure using linear regression under an additive genetic model. Associated traits were explored further including adjustment for relevant covariates. Highest recorded intraocular pressure (IOP) also was analyzed both with and without correction for central corneal thickness (CCT) and was dichotomized into high-tension glaucoma and normal-tension glaucoma (NTG).
Intraocular pressure and vertical cup-to-disc ratio (VCDR).
Glaucoma risk alleles at 9p21, particularly, rs7049105 and rs10120688, were associated with the presence of both NTG and advanced POAG. The SNP rs10120688 was associated with greater VCDR after adjustment for covariates (P = 0.003; β = 0.016; standard error, 0.006). In addition, multiple SNPs in the region were associated with reduced IOP, before and after adjustment for CCT. The SNP most significantly associated with IOP was also rs10120688 (P = 0.001; β = -2.135; standard error, 0.634) after adjustment for covariates under an additive model. In a comparison of high-tension versus low-tension glaucoma, this SNP was also the most significantly associated, particularly when IOP was corrected for CCT before classification of the type of glaucoma (P = 0.0009; odds ratio, 0.63; 95% confidence interval, 0.48-0.83).
Patients with POAG carrying the glaucoma risk alleles at the 9p21 locus have larger VCDR and lower IOP than POAG patients without these alleles. Carriers of these alleles seem to be predisposed to POAG developing at lower IOP levels and exhibit stronger associations with NTG and advanced glaucoma phenotypes. This may be of relevance when setting target pressures in patients carrying these risk alleles.
To assess the difference in severity of disease in primary open-angle glaucoma (POAG) patients with a Myocilin (MYOC) disease-causing variant who presented through normal clinical pathways (Clinical ...cases) versus those who were examined following genetic testing (Genetic cases).
Retrospective clinical and molecular study.
Seventy-three MYOC mutation carriers identified through the Australian and New Zealand Registry of Advanced Glaucoma.
Individuals were classified based on how they first presented to an ophthalmologist: Clinical cases were referred by their general practitioner or optometrist, and Genetic cases were referred following positive results from genetic testing for the previously identified familial MYOC variant (cascade genetic testing). All cases were then sub-classified into 4 groups (unaffected, glaucoma suspect, glaucoma, advanced glaucoma) according to the severity of disease at the time of their first examination by an ophthalmologist.
Glaucoma clinical parameters and age at presentation.
At their first examination, 83% of Genetic cases were unaffected and 17% were glaucoma suspect, whereas among Clinical cases 44% were glaucoma suspect, 28% had glaucoma, and 28% had advanced glaucoma. Genetic cases were significantly younger at presentation than Clinical cases (40.6±12.5 vs. 47.5±16.7 years; P = 0.018). The mean highest intraocular pressure (32.2±9.7 vs. 17.6±3.6 mmHg; P < 0.001), cup-to-disc ratio (0.65±0.27 vs. 0.48±0.13; P = 0.006), and mean deviation on visual field testing (-10.0±10.3 vs. -1.2±1.2; P < 0.001) were all significantly worse in Clinical cases compared with Genetic cases. Individuals with common MYOC p.Gln368Ter variant were further analyzed separately to account for the phenotypic variability of different disease-causing variants. All findings remained significant after adjusting for the common MYOC p.Gln368Ter variant.
Our findings demonstrated that MYOC cascade genetic testing for POAG allows identification of at-risk individuals at an early stage or even before signs of glaucoma are present. To our knowledge, this is the first study to demonstrate the clinical utility of predictive genetic testing for MYOC glaucoma.
To evaluate the relationship between body mass index (BMI) and glaucoma progression.
Multicohort observational study.
This study combined a retrospective longitudinal analysis of suspect and early ...manifest primary open angle glaucoma cases from the Progression Risk of Glaucoma: RElevant SNPs with Significant Association (PROGRESSA) study with 2 replication cohorts from the UK Biobank and the Canadian Longitudinal Study of Ageing (CLSA). In the PROGRESSA study, multivariate analysis correlated BMI with longitudinal visual field progression in 471 participants. The BMI was then associated with glaucoma diagnosis and cross-sectional vertical cup-disc ratio (VCDR) measurements in the UK Biobank, and finally prospectively associated with longitudinal change in VCDR in the CLSA study.
In the PROGRESSA study, a lower BMI conferred a faster rate of visual field progression (mean duration of monitoring (5.28 ± 1.80 years (10.6 ± 3.59 visits) (β 0.04 dB/year/SD95% CI 0.005, 0.069; P = .013). In the UK Biobank, a 1 standard deviation lower BMI was associated with a worse cross-sectional VCDR (β –0.048/SD 95% CI –0.056, 0.96; P < .001) and a 10% greater likelihood of glaucoma diagnosis, as per specialist grading of retinal fundus imaging (OR 0.90 95% CI 0.84, 0.98; P = .011). Similarly, a lower BMI was associated with a greater risk of glaucoma diagnosis as per International Classification of Disease data (OR 0.94/SD; 95% CI 0.91, 0.98; P = .002). Body mass index was also positively correlated with intraocular pressure (β 0.11/SD; 95% CI 0.06, 0.15; P < .001). Finally, a lower BMI was then associated with greater VCDR change in the CLSA (β –0.007/SD; 95% CI –0.01, –0.001; P = .023).
Body mass index correlated with longitudinal and cross-sectional glaucomatous outcomes. This supports previous work illustrating a correlation between BMI and glaucoma.
To identify biological processes associated with POAG and its subtypes, high-tension (HTG) and normal-tension glaucoma (NTG), by analyzing rare potentially damaging genetic variants.
A total of 122 ...and 65 unrelated HTG and NTG participants, respectively, with early onset advanced POAG, 103 non-glaucoma controls and 993 unscreened ethnicity-matched controls were included in this study. Study participants without myocilin disease-causing variants and non-glaucoma controls were subjected to whole exome sequencing on an Illumina HiSeq2000. Exomes of participants were sequenced on an Illumina HiSeq2000. Qualifying variants were rare in the general population (MAF < 0.001) and potentially functionally damaging (nonsense, frameshift, splice or predicted pathogenic using SIFT or Polyphen2 software). Genes showing enrichment of qualifying variants in cases were selected for pathway and network analysis using InnateDB.
POAG cases showed enrichment of rare variants in camera-type eye development genes (p = 1.40×10-7, corrected p = 3.28×10-4). Implicated eye development genes were related to neuronal or retinal development. HTG cases were significantly enriched for key regulators in the unfolded protein response (UPR) (p = 7.72×10-5, corrected p = 0.013). The UPR is known to be involved in myocilin-related glaucoma; our results suggest the UPR has a role in non-myocilin causes of HTG. NTG cases showed enrichment in ion channel transport processes (p = 1.05×10-4, corrected p = 0.027) including calcium, chloride and phospholipid transporters involved in plasma membrane homeostasis. Network analysis also revealed enrichment of the MHC Class I antigen presentation pathway in HTG, and the EGFR1 and cell-cycle pathways in both HTG and NTG.
This study suggests that mutations in eye development genes are enriched in POAG. HTG can result from aberrant responses to protein misfolding which may be amenable to molecular chaperone therapy. NTG is associated with impaired plasma membrane homeostasis increasing susceptibility to apoptosis.
To investigate which clinical measures influence whether an individual demonstrates earliest glaucomatous structural progression on peripapillary retinal nerve fiber layer (pRNFL) or macular ganglion ...cell-inner plexiform layer (mGCIPL).
Prospective, longitudinal cohort study.
Two hundred seventy-one eyes from 207 individuals with statistically significant evidence of glaucomatous progression on OCT Guided Progression Analysis (GPA) software were drawn from a total of 1271 eyes from 686 individuals categorized as glaucoma suspect or having early manifest glaucoma undergoing glaucoma surveillance.
Individuals demonstrating earliest evidence of longitudinal progression on mGCIPL GPA event analysis were compared with individuals demonstrating evidence of earliest longitudinal progression on pRNFL GPA event analysis.
Correlation of OCT event change analysis with intraocular pressure (IOP), clinical variables, and baseline thickness of the pRNFL and mGCIPL.
Intraocular pressure, baseline pRNFL thickness, baseline mGCIPL thickness, and systemic hypertension were associated with location of first progression. Eyes demonstrating earliest longitudinal progression on mGCIPL had significantly lower maximum-recorded pretreatment IOP (mean difference, 3.90 mmHg; 95% confidence interval CI, 2.37-5.43 mmHg; P < 0.001). The interval between progression on pRNFL and progression on mGCIPL increased by 12.4 months for every 5-mmHg increase in IOP (95% CI, 10.32-15.72 months). Eyes demonstrating earliest longitudinal progression on mGCIPL showed significantly lower baseline average pRNFL thickness than eyes progressing on pRNFL first (mean difference, 7.07 μm; 95% CI, 4.38-9.77 μm; P < 0.001). Eyes progressing first on mGCIPL parameters were 3.03 times more likely to demonstrate a new paracentral field defect than eyes progressing first on pRNFL parameters (odds ratio, 3.03; 95% CI, 1.26-7.28; P = 0.01).
Clinical features, particularly pretreatment IOP, influence whether structural glaucoma progression is detected earlier with mGCIPL or pRNFL imaging. These data support the usefulness of mGCIPL imaging in addition to pRNFL analysis for detection of glaucoma progression, particularly in patients with normal IOP.
Background
To investigate the effects of current intraocular pressure‐lowering medications on the efficacy of selective laser trabeculoplasty.
Design
Retrospective chart review of records from an ...urban glaucoma clinic in Sydney, Australia.
Participants
Patients who received their first selective laser trabeculoplasty between 2002 and 2005 were studied (grouped from 0 to 3 according to the number of pre‐selective laser trabeculoplasty medications, and followed for 5 years). Those with previous argon laser therapy, trabeculectomy or angle‐closure were excluded.
Methods
Selective laser trabeculoplasty (Ellex) used to deliver 180 or 360 degree of treatment, under the same protocol.
Main Outcome Measures
Responders were defined by ≥20% reduction from baseline intraocular pressure. Data were censored when pressure‐lowering intervention was required. The mean intraocular pressure, survivor, response rate, number and type of medications were compared.
Results
There were 206 patients with ocular hypertension, primary, pseudo‐exfoliation, or pigmentary glaucoma who used none (n = 20), one (n = 33), two (n = 61) or three or more (n = 92) pre‐selective laser trabeculoplasty topical anti‐glaucoma medications. The mean baseline intraocular pressures for each group was 23.7, 22.2, 20.7 and 20.4 mmHg, respectively (P = 0.061). Post‐treatment mean intraocular pressure was 17.9, 17.7, 15.5, and 15.7 mmHg; percentage reduction was similar between groups (23.6–25.6%, P = 0.20). Kaplan–Meier survival analysis showed comparable survival rates across groups (P = 0.445). At 60 months, 11.1, 17.1, 30.5 and 11.5% of responders remained in each group. Higher proportions of patients in groups 2 and 3 required further laser or surgery.
Conclusion
The number of pre‐selective laser trabeculoplasty medications did not affect the intraocular pressure‐lowering effectiveness of selective laser trabeculoplasty; however, groups on more medications required more pressure‐lowering interventions.
Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank ...participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 × 10
). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.
To determine if selective laser trabeculoplasty (SLT) is superior to topical medication as a first-line treatment for glaucoma on quality of life (QoL) and clinical outcomes.
In this international, ...longitudinal, multisite randomised controlled trial, treatment naïve mild-to-moderate primary open angle or exfoliation glaucoma patients were randomised 1:1 to SLT or topical medication. Glaucoma-specific QoL (primary outcome) was measured using the Glaucoma Outcomes Assessment Tool (GOAT; 342 items, 12 domains). Secondary outcomes included rate of successful intraocular pressure (IOP) reduction (>25% reduction from baseline) and presence of ocular surface disease including conjunctival hyperaemia and eyelid erythema. Our intention-to-treat analysis was performed at months 12 and 24.
Of 167 enrolled patients, 83 and 84 were randomised to SLT and topical medication, respectively; and 145 (n=75 SLT, n=70 medication) completed 24-month follow-up. While both treatment arms achieved significant within-group gains in GOAT outcomes at both endpoints, SLT patients reported a greater between-group improvement in 'social well-being' compared with medication patients (mean±SE=0.28±0.13; p=0.034) at 24 months. At month 24, the rate of successful IOP reduction was 18.6% (95% CI 3.0% to 34.3%, p=0.022) higher (absolute difference) in the medication compared with SLT group. More individuals in the medication group had conjunctival hyperaemia and eyelid erythema compared with SLT at 24 months.
Overall, we did not find evidence that SLT was superior to medication in improving glaucoma-specific QoL. While we found superior IOP reduction in the medication arm, eyelid erythema and conjunctival hyperaemia were more prevalent in these patients compared with the SLT group.
ACTRN12611000720910.
To assess the prevalence and associations of a notch in the optic disc neural rim.
Stereo-photographs from the Blue Mountains Eye Study were graded for the presence of a notch (defined as focal ...reduction in neural rim width associated with a change in the curvature of the rim for no greater than 4 clock hours).
A notch was found in at least 1 eye of 205 participants (5.7%), and was bilateral in 51 (1.4%). Notch prevalence increased with age from 2.48% in participants aged <60 years, to 4.1% for ages 60 to 69 years, 7.98% for ages 70 to 79 years and 15.3% for ages 80 years or older. No sex differences were found. Notches were more frequent in eyes with myopia (odds ratio, OR, 1.98, 95% confidence interval, CI, 1.31-2.98) or beta-peripapillary atrophy (OR 2.20, CI 1.52-3.22). No associations were found with intraocular pressure, optic disc hemorrhage, or migraine history. After adjusting for other risk factors, a neural rim notch was strongly associated with glaucoma diagnosis (OR 21.2, CI 8.8-50.8). The sensitivity and specificity for glaucoma with visual field loss of finding a notch in either eye was 90.3% and 96.8%, respectively. The positive predictive value of a notch was 45.4% and negative predictive value 99.7%.
A notch in the neural rim is a relatively infrequent sign in normal eyes but is very frequent in glaucoma. This sign has both good sensitivity and a positive predictive value for glaucoma.
To assess the association between a glaucoma polygenic risk score (PRS) and treatment outcomes in primary open-angle glaucoma.
Prospective, observational cohort study.
Participants from the ...Progression Risk of Glaucoma: Relevant SNPs with Significant Association Study were divided into a cohort with suspect glaucoma who were treatment naive at enrollment and one with early manifest and suspect glaucoma receiving treatment at enrollment.
A per-allele weighted glaucoma PRS was calculated for 1107 participants. Multivariable mixed-effects Cox proportional regression analysis assessed the association between PRS and time to commencement of intraocular pressure (IOP)-lowering therapy in 416 patients with suspect glaucoma who were treatment naive at study enrollment. Secondary analysis evaluated the association between PRS and escalation of IOP-lowering therapy among 691 patients with suspect and early manifest glaucoma who were receiving IOP-lowering therapy at enrollment.
Commencement or escalation of IOP-lowering therapy.
A higher PRS was associated with a greater risk of commencing IOP-lowering therapy within 5 years (hazard ratio HR, 1.45 per 1 standard deviation /SD; 95% confidence interval CI, 1.27-1.62; P < 0.001). Participants in the upper population-based quintile showed a 3.3 times greater risk of commencing therapy by 5 years than those in the lowest quintile (HR, 3.30; 95% CI, 1.63-6,70; P < 0.001) and a 5.4 times greater risk of commencing IOP-lowering therapy by 2 years than the those in the lowest quintile (HR, 5.45; 95% CI, 2.08-14.25; P < 0.001). A higher PRS was associated with a greater risk of treatment escalation among patients receiving treatment at enrollment (HR, 1.19/SD; 95% CI, 1.09-1.31; P < 0.001). In combined analysis of all participants, participants in the top population-based quintile were at 2.3 times greater risk of requiring initiation or escalation of IOP-lowering therapy than those in the lowest quintile (HR, 2.33; 95% CI, 1.75-3.01; P < 0.001).
This study demonstrated novel associations between glaucoma polygenic risk and risk of commencement or escalation of IOP-lowering therapy, building on previous work highlighting the potential clinical usefulness of genetic risk stratification in glaucoma.
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