Ananth C. Viswanathan

Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes

Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 × 10−9, odds ratio = 1.35, 95% CI 1.22–1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.

Practical recommendations for measuring rates of visual field change in glaucoma.

To date, there has been a lack of evidence-based guidance on the frequency of visual field examinations required to identify clinically meaningful rates of change in glaucoma. The objective of this perspective is to provide practical recommendations for this purpose. The primary emphasis is on the period of time and number of examinations required to measure various rates of change in mean deviation (MD) with adequate statistical power. Empirical data were used to obtain variability estimates of MD while statistical modelling techniques derived the required time periods to detect change with various degrees of visual field variability. We provide the frequency of examinations per year required to detect different amounts of change in 2, 3 and 5 years. For instance, three examinations per year are required to identify an overall change in MD of 4 dB over 2 years in a patient with average visual field variability. Recommendations on other issues such as examination type, strategy and quality are also made.

Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus

Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10−8). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4–1.88, P = 2.7 × 10−10, and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29–1.68, P = 4.9 × 10−9). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10−4; tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.

Detection of optic disc change with the Heidelberg retina tomograph before confirmed visual field change in ocular hypertensives converting to early glaucoma

AIM To determine whether analysis of sequential optic disc images obtained with the Heidelberg retina tomograph (HRT) is able to demonstrate optic disc change before the development of reproducible field defects in a group of ocular hypertensive (OHT) patients converting to early glaucoma. METHODS Two groups were analysed: (1) 13 eyes of 13 OHT patients who subsequently developed reproducible field defects (converters); and (2) 13 eyes of 11 normal control subjects. Two sequential optic disc images were obtained using the HRT (median separation between images was 12 months for the converters and 13 months for the normals). The second image in the converter group was obtained before confirmed visual field loss. The optic disc variables were analysed both globally and segmentally using HRT software version 1.11. The Wilcoxon signed rank test was used to determine if there were any significant differences between the variables of the two image sets. RESULTS Significant optic disc change was demonstrated in the group of converters: (1) global variables: the cup area increased by 9.7%, the C/D area ratio increased by 10.5%, and the rim area decreased by 6.9%; (2) segmental variables: the superonasal cup area increased by 11.0%, the superonasal C/D area ratio increased 11.7%, and the inferonasal cup volume increased by 28.4%.The temporal rim volume decreased by 15.6%, the inferotemporal rim volume decreased by 23.6%, and the rim area in the superonasal and superotemporal segments decreased by 6.6% and 6.9% respectively. CONCLUSION Analysis of sequential optic disc images on the HRT allowed the detection of glaucomatous change before confirmed visual field change in a group of OHT patients converting to early glaucoma.

Early detection of visual field progression in glaucoma: a comparison of PROGRESSOR and STATPAC 2.

AIM To compare the performance ofprogressor (pointwise linear regression) and statpac2 (comparison with baseline values) in detecting early deterioration in the visual fields of glaucoma patients. METHODS Visual field series from 19 untreated normal tension glaucoma eyes which were deteriorating on clinical grounds were analysed by progressor and statpac2. Progression criteria forprogressor were (1) inner points: slope < −1 dB/year, p < 0.05 and (2) edge points: slope < −2 dB/year, p < 0.05. Criteria for statpac 2 were p < 0.05 change probability for any point on three consecutive fields. Detection time was defined as the time interval between the initial field and the first field in which at least one progressing point was identified. Detection times produced by the two techniques were compared. RESULTS progressor and statpac2 agreed on progression in all 19 eyes. Mean detection time for progressor was 1.077 (SD 0.985) years and for statpac 2 was 2.161 (1.357) years. progressor detected progression sooner thanstatpac 2 in 18 eyes (p < 0.01, Wilcoxon matched pairs signed rank test). progressordetected progression earlier by a mean of 1.085 (0.936) years. CONCLUSIONS progressor consistently detected progression earlier than statpac2. The progressor software is a useful tool for the early detection of visual field deterioration in glaucoma.

Inter- and intraobserver variation in the analysis of optic disc images: comparison of the Heidelberg retina tomograph and computer assisted planimetry.

AIMS The development of imaging and measurement techniques has brought the prospect of greater objectivity in the measurement of optic disc features, and therefore better agreement between observers. The purpose of this study was to quantify and compare the variation between observers using two measurement devices. METHODS Optic disc photographs and images from the Heidelberg retina tomograph (HRT) of 30 eyes of 30 subjects were presented to six observers for analysis, and to one observer on five separate occasions. Agreement between observers was studied by comparing the analysis of each observer with the median result of the other five, and expressed as the mean difference and standard deviation of differences between the observer and the median. Inter- and intraobserver variation was calculated as a coefficient of variation (mean SD/mean × 100). RESULTS For planimetry, agreement between observers was dependent on observer experience, for the HRT it was independent. Agreement between observers (SD of differences as a percentage of the median) for optic disc area was 4.0% to 7.2% (planimetry) and 3.3% to 6.0% (HRT), for neuroretinal rim area it was 10.8% to 21.0% (planimetry) and 5.2% to 9.6% (HRT). The mean interobserver coefficient of variation for optic disc area was 8.1% (planimetry) and 4.4% (HRT), for neuroretinal rim area it was 16.3% (planimetry) and 8.1% (HRT), and (HRT only) for rim volume was 16.3%, and reference height 9.1%. HRT variability was greater for the software version 1.11 reference plane than for version 1.10. The intraobserver coefficient of variation for optic disc area was 1.5% (planimetry) and 2.4% (HRT), for neuroretinal rim area it was 4.0% (planimetry) and 4.5% (HRT). CONCLUSIONS Variation between observers is greatly reduced by the HRT when compared with planimetry. However, levels of variation, which may be clinically significant, remain for variables that depend on the subjective drawing of the disc margin.

Vertical cup/disc ratio in relation to optic disc size: its value in the assessment of the glaucoma suspect

AIMS The vertical cup/disc ratio (CDR) has long been used in the assessment of the glaucoma suspect, though the wide range of CDR values in the normal population limits its use. Cup size is related physiologically to disc size and pathologically to glaucomatous damage. Disc size can be measured at the slit lamp as the vertical disc diameter (DD). The ability of the CDR, in relation to DD, to identify glaucomatous optic discs was investigated. METHODS 88 normal, 53 early glaucoma, and 59 ocular hypertensive subjects underwent stereoscopic optic disc photography and clinical biometry. Photographs were analysed in a masked fashion by computer assisted planimetry. The relation between vertical cup diameter and DD was explored by linear regression, and expressed in terms of CDR. The upper limit of normal was defined by the 95% prediction intervals of this regression (method 1) and by the upper 97.5 percentile for CDR (method 2). The sensitivity and specificity of CDR to identify an optic disc as glaucomatous was tested with these disc size dependent and disc size independent cut offs in small, medium, and large discs. RESULTS The CDR was related to DD by the equation CDR = (−1.31 + (1.194 × DD))/DD. The sensitivity in small, medium, and large discs was 80%, 60%, and 38% respectively for method 1 and 33%, 67%, and 63% respectively for method 2. Specificity was 98.9% (method 1) and 97.7% (method 2). CONCLUSIONS The CDR, relative to disc size, is useful clinically, especially to assist in identifying small glaucomatous discs.

Risk factors for elevated intraocular pressure in uveitis.

Purpose: To determine the prevalence of raised intraocular pressure (TOP) in patients with uveitis and to identify risk factors for raised TOP in patients with uveitis.Patients and Methods: Consecutive case notes of 257 patients (402 eyes) attending a specialist uveitis clinic during a three-month period were reviewed. Patients with raised TOP were identified and further evaluated. Risk factors for raised TOP were determined.Results: The prevalence of raised TOP in the study eyes was 41.8%. The prevalence of raised TOP requiring treatment was 29.8%. Raised TOP was found in 26.0% of eyes with acute uveitis and 46.1% of eyes with chronic uveitis. This difference was significant (P = 0.002). Similarly the prevalence of raised TOP requiring treatment in acute and chronic uveitis was 15.1% and 33.8%, respectively. This difference was also significant (P = 0.002). Active inflammation was significantly associated with raised TOP (P = 0.031). Steroid usage, increasing age, and number of years since diagnosis were significantly correlated with raised TOP (P = 0.008, P = 0.022, and P = 0.006, respectively); 9.6% of the study eyes developed glaucoma. The majority of these eyes (69.7%) were treated medically. The remainder (30.3%) required both medical and surgical management.Conclusion: Raised TOP is significantly more common in patients with chronic intraocular inflammation than those with acute uveitis. Risk factors for elevated TOP that should enable closer monitoring of at-risk eyes have been identified.

Common variants in the HLA-DRB1-HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis

To identify susceptibility loci for visceral leishmaniasis, we undertook genome-wide association studies in two populations: 989 cases and 1,089 controls from India and 357 cases in 308 Brazilian families (1,970 individuals). The HLA-DRB1–HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, and combined analysis across the three cohorts for rs9271858 at this locus showed Pcombined = 2.76 × 10−17 and odds ratio (OR) = 1.41, 95% confidence interval (CI) = 1.30–1.52. A conditional analysis provided evidence for multiple associations within the HLA-DRB1–HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion, the HLA-DRB1–HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species.

Simulating binocular visual field status in glaucoma

AIMS To simulate the central binocular visual field using results from merged left and right monocular Humphrey fields. To assess the agreement between the simulation and the binocular Humphrey Esterman visual field test (EVFT). METHOD 59 consecutive patients with bilateral glaucoma each recorded Humphrey 24-2 fields for both eyes and binocular EVFT on the same visit. EVFT results were used to identify patients exhibiting at least one defect (<10 dB) within the central 20° of the binocular field. This criterion is relevant to a patient’s legal fitness to drive in the UK. Individual sensitivity values from monocular fields are merged to generate a simulated central binocular field. Results are displayed as a grey scale and as symbols representing defects at the <10 dB level. Agreement between patients failing the criterion using the simulation and the EVFT was evaluated. RESULTS Substantial agreement was observed between the methods in classifying patients with at least one defect (<10 dB) within the central binocular field (kappa 0.81; SE 0.09). Patients failing this criterion using the EVFT results were identified by the binocular simulation with high levels of sensitivity (100%) and specificity (86%). CONCLUSIONS Excellent agreement exists between the simulated binocular results and EVFT in classifying glaucomatous patients with central binocular defects. A rapid estimate of a patient’s central binocular field and visual functional capacity can be ascertained without extra perimetric examination.