A Common Glaucoma-risk Variant of SIX6 Alters Retinal Nerve Fiber Layer and Optic Disc Measures in a European Population: The EPIC-Norfolk Eye Study

PURPOSE: A common missense variant in the SIX6 gene (rs33912345) is strongly associated with primary open-angle glaucoma (POAG). We aimed to examine the association of rs33912345 with optic disc and retinal nerve fiber layer (RNFL) measures in a European population. METHODS: We examined participants of the population-based EPIC-Norfolk Eye Study. Participants underwent confocal laser scanning tomography (Heidelberg Retina Tomograph II, HRT) to estimate optic disc rim area and vertical cup-disc ratio (VCDR). Scanning laser polarimetry (GDxVCC) was used to estimate average RNFL thickness. The mean of right and left eye values was considered for each participant. Genotyping was performed using the Affymetrix UK Biobank Axiom Array. Multivariable linear regression with the optic nerve head parameter as outcome variable and dosage of rs33912345 genotype as primary explanatory variable was used, adjusted for age, sex, disc area, axial length and intraocular pressure. We further repeated analyses stratified into age tertiles. RESULTS: In total, 5433 participants with HRT data and 3699 participants with GDxVCC data were included. Each "C" allele of rs33912345 was associated with a smaller rim area (-0.030▒mm [95% CI -0.040, -0.020], P=5.4×10), a larger VCDR (0.025 [95% CI 0.017, 0.033], P=3.3×10) and a thinner RNFL (-0.39▒μm [95% CI -0.62, -0.15], P=0.001). The RNFL association was strongest in the oldest age tertile, whereas rim area and VCDR associations were strongest in the youngest and oldest age tertiles. CONCLUSIONS: The protein coding SIX6 variant rs33912345, previously associated with POAG, has a functional effect on glaucoma-associated optic nerve head traits in Europeans

Retinal Nerve Fiber Layer Measures and Cognitive Function in the EPIC-Norfolk Cohort Study

PURPOSE: We examined the relationship between retinal nerve fiber layer (RNFL) thickness and cognitive function in a population of older British adults. METHODS: Participants of the European Prospective Investigation of Cancer (EPIC) Norfolk cohort study underwent ophthalmic and cognitive assessment. Measurements of RNFL thickness were made using the Heidelberg Retina Tomograph (HRT). Cognitive testing included a short form of the Mini-Mental State Examination (SF-MMSE), an animal naming task, a letter cancellation task, the Hopkins Verbal Learning Test (HVLT), the National Adult Reading Test (NART), and the Paired Associates Learning Test. Multivariable linear regression models were used to assess associations of RNFL thickness with cognitive test scores, adjusted for age, sex, education level, social class, visual acuity, axial length, and history of cataract surgery. RESULTS: Data were available from 5563 participants with a mean age of 67 years. A thicker HRT-derived RNFL thickness was associated with better scores for the SF-MMSE (0.06; 95% confidence interval [CI], [0.02, 0.10], P = 0.005), HVLT (0.16, 95% CI [0.03, 0.29]; P = 0.014), and NART (−0.24, 95% CI [−0.46, −0.02], P = 0.035). The associations of RNFL thickness with SF-MMSE and HVLT remained significant following further adjustment for NART. CONCLUSIONS: We found a significant association between HRT-derived RNFL thickness and scores from cognitive tests assessing global function, recognition, learning, episodic memory, and premorbid intelligence. However, the associations were weak and not currently of predictive value. Further research is required to confirm and clarify the nature of these associations, and identify biological mechanisms

Retinal Nerve Fiber Layer Measures and Cognitive Function in the EPIC-Norfolk Cohort Study.

PURPOSE: We examined the relationship between retinal nerve fiber layer (RNFL) thickness and cognitive function in a population of older British adults. METHODS: Participants of the European Prospective Investigation of Cancer (EPIC) Norfolk cohort study underwent ophthalmic and cognitive assessment. Measurements of RNFL thickness were made using the Heidelberg Retina Tomograph (HRT). Cognitive testing included a short form of the Mini-Mental State Examination (SF-MMSE), an animal naming task, a letter cancellation task, the Hopkins Verbal Learning Test (HVLT), the National Adult Reading Test (NART), and the Paired Associates Learning Test. Multivariable linear regression models were used to assess associations of RNFL thickness with cognitive test scores, adjusted for age, sex, education level, social class, visual acuity, axial length, and history of cataract surgery. RESULTS: Data were available from 5563 participants with a mean age of 67 years. A thicker HRT-derived RNFL thickness was associated with better scores for the SF-MMSE (0.06; 95% confidence interval [CI], [0.02, 0.10], P = 0.005), HVLT (0.16, 95% CI [0.03, 0.29]; P = 0.014), and NART (-0.24, 95% CI [-0.46, -0.02], P = 0.035). The associations of RNFL thickness with SF-MMSE and HVLT remained significant following further adjustment for NART. CONCLUSIONS: We found a significant association between HRT-derived RNFL thickness and scores from cognitive tests assessing global function, recognition, learning, episodic memory, and premorbid intelligence. However, the associations were weak and not currently of predictive value. Further research is required to confirm and clarify the nature of these associations, and identify biological mechanisms.Supported by grants from the Medical Research Council (G1000143) and Cancer Research UK (C864/A14136; EPIC-Norfolk infrastructure and core functions), The clinic for the third health examination was funded by Research into Ageing (262; the clinic for the third health examination), a Wellcome Trust Clinical Research Fellowship (APK), and the Richard Desmond Charitable Trust (via Fight for Sight) and the Department for Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital and the UCL Institute of Ophthalmology for a specialist Biomedical Research Centre for Ophthalmology (PJF

Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma.

Glaucoma is the leading cause of irreversible blindness globally 1 . Despite its gravity, the disease is frequently undiagnosed in the community 2 . Raised intraocular pressure (IOP) is the most important risk factor for primary open-angle glaucoma (POAG)3,4. 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

Combinatorial use of offline SCX and online RP-RP liquid chromatography for iTRAQ-based quantitative proteomics applications

Extensive front-end separation is usually required for complex samples in bottom-up proteomics to alleviate the problem of peptide undersampling. Isobaric Tags for Relative and Absolute Quantification (iTRAQ)-based experiments have particularly higher demands, in terms of the number of duty cycles and the sensitivity, to confidently quantify protein abundance. Strong cation exchange (SCX)/reverse phase (RP) liquid chromatography (LC) is currently used routinely to separate iTRAQ-labeled peptides because of its ability to simultaneously clean up the iTRAQ reagents and byproducts and provide first-dimension separation; nevertheless, the low resolution of SCX means that peptides can be redundantly sampled across fractions, leading to loss of usable duty cycles. In this study, we explored the combinatorial application of offline SCX fractionation with online RP-RP applied to iTRAQ-labeled chloroplast proteins to evaluate the effect of three-dimensional LC separation on the overall performance of the quantitative proteomics experiment. We found that the higher resolution of RP-RP can be harnessed to complement SCX-RP and increase the quality of protein identification and quantification, without significantly impacting instrument time and reproducibility. © The Royal Society of Chemistry 2011.link_to_subscribed_fulltex

Eye advance online publication

Abstract Purpose To determine ocular, demographic, and socioeconomic associations with selfreported glaucoma in the UK Biobank. Methods Biobank is a study of UK residents aged 40-69 years registered with the National Health Service. Data were collected on visual acuity, intraocular pressure (IOP), corneal biomechanics, and questionnaire from 112 690 participants. Relationships between ocular, demographic, and socioeconomic variables with reported diagnosis of glaucoma were examined. Results In all, 1916 (1.7%) people in UK Biobank reported glaucoma diagnosis. Participants reporting glaucoma were more likely to be older (mean 61.4 vs 56.7 years, Po0.001) and male (2.1% vs 1.4%, P = 0.001). The rate of reported glaucoma was significantly higher in Black (3.28%, Po0.001) and Asian (2.14%, P = 0.009) participants compared with White participants (1.62%, reference). Cases of reported glaucoma had a higher mean IOP (18 mm Hg both eyes, Po0.001), lower corneal hysteresis (9.96 right eye, 9.89 left eye, Po0.001), and lower visual acuity (0.09 logMAR right eye, 0.08 logMAR left eye, Po0.001) compared with those without (16 mm Hg both eyes, hysteresis 10.67 right eye, 10.63 left eye, 0.03 logMAR right eye, 0.02 logMAR left eye). The mean Townsend deprivation index was − 0.72 for those reporting glaucoma and − 0.95 for those without (Po0.001), indicating greater relative deprivation in those reporting glaucoma. Multivariable logistic regression showed that people in the lowest income group (o£18 000/ year) were significantly more likely to report a diagnosis of glaucoma compared with any other income level (Po0.01). We observed increasing glaucoma risk across the full range of income categories, with highest risk among those of lowest income, and no evidence of a threshold effect. Conclusions In a large UK cohort, individuals reporting glaucoma had more adverse socioeconomic characteristics. Study of the mechanisms explaining these effects may aid our understanding of health inequality and will help inform public health interventions

Inter-optometrist variability of IOP measurement for modern tonometers and their agreement with Goldmann Applanation Tonometry

Background: This study investigates: agreement in intraocular pressure measurements between three tonometers and Goldmann applanation tonometry (GAT); inter-optometrist agreement for each tonometer; intra-optometrist agreement for GAT; association between central corneal thickness (CCT) and IOP measurements with each tonometer. Methods: IOP was measured using: CT-1P Non-Contact Tonometer (NCT) (Topcon Corporation, Tokyo, Japan), Pulsair IntelliPuff (Keeler Ltd., Windsor, UK) and Icare rebound tonometer (Icare, Helsinki, Finland) by two optometrists in a random order. Two GAT readings were obtained by each optometrist in a randomised masked manner. Mean differences, and 95% limits of agreement (LoA) for each measurement were calculated. CCT was measured by CT-1P pachymeter. Results: Forty-one participants’ IOPs were measured. Mean differences (95% LoA) between NCT, Pulsair, Icare compared to GAT for one optometrist were: 0.8 (−5.4 to 6.9) mmHg, −1.7 (−8.2 to 4.8) mmHg, −1.6 (−9.0 to 5.9) mmHg. Mean differences (95% LoA) in inter-optometrist agreement for GAT, NCT, Pulsair and Icare were: 0.3 (−6.7 to 7.3) mmHg, 0.4 (−2.1 to 2.9) mmHg, −0.9 (−3.6 to 1.9) mmHg and −0.2 (−4.9 to 4.5) mmHg, respectively. Mean differences (95% LoA) for intra-optometrist agreement for GAT were 0.2 (4.3 to −4.7) mmHg and 0.1 (3.6 to −3.9) mmHg for each optometrist, respectively. There was a weak positive association between CCT and both GAT (r2 = 0.11) and NCT (r2 = 0.12). Conclusion: Pulsair and Icare may measure IOP lower than GAT. Mean differences for inter-optometrist agreement for all tonometers were < 1 mmHg; Pulsair showed a statistically significant difference. Intra-optometrist agreement for GAT was good. IOP measurements taken by two community optometrists are comparable using tonometers used in community practice