Samantha Mann

Genome-wide association study of age-related macular degeneration identifies associated variants in the TNXB–FKBPL–NOTCH4 region of chromosome 6p21.3

Age-related macular degeneration (AMD) is a leading cause of visual loss in Western populations. Susceptibility is influenced by age, environmental and genetic factors. Known genetic risk loci do not account for all the heritability. We therefore carried out a genome-wide association study of AMD in the UK population with 893 cases of advanced AMD and 2199 controls. This showed an association with the well-established AMD risk loci ARMS2 (age-related maculopathy susceptibility 2)-HTRA1 (HtrA serine peptidase 1) (P =2.7 × 10(-72)), CFH (complement factor H) (P =2.3 × 10(-47)), C2 (complement component 2)-CFB (complement factor B) (P =5.2 × 10(-9)), C3 (complement component 3) (P =2.2 × 10(-3)) and CFI (P =3.6 × 10(-3)) and with more recently reported risk loci at VEGFA (P =1.2 × 10(-3)) and LIPC (hepatic lipase) (P =0.04). Using a replication sample of 1411 advanced AMD cases and 1431 examined controls, we confirmed a novel association between AMD and single-nucleotide polymorphisms on chromosome 6p21.3 at TNXB (tenascin XB)-FKBPL (FK506 binding protein like) [rs12153855/rs9391734; discovery P =4.3 × 10(-7), replication P =3.0 × 10(-4), combined P =1.3 × 10(-9), odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.3-1.6] and the neighbouring gene NOTCH4 (Notch 4) (rs2071277; discovery P =3.2 × 10(-8), replication P =3.8 × 10(-5), combined P =2.0 × 10(-11), OR = 1.3, 95% CI = 1.2-1.4). These associations remained significant in conditional analyses which included the adjacent C2-CFB locus. TNXB, FKBPL and NOTCH4 are all plausible AMD susceptibility genes, but further research will be needed to identify the causal variants and determine whether any of these genes are involved in the pathogenesis of AMD.

Ethnic variation in the prevalence of visual impairment in people attending diabetic retinopathy screening in the United Kingdom (DRIVE UK).

Purpose To provide estimates of visual impairment in people with diabetes attending screening in a multi-ethnic population in England (United Kingdom). Methods The Diabetic Retinopathy In Various Ethnic groups in UK (DRIVE UK) Study is a cross-sectional study on the ethnic variations of the prevalence of DR and visual impairment in two multi-racial cohorts in the UK. People on the diabetes register in West Yorkshire and South East London who were screened, treated or monitored between April 2008 to July 2009 (London) or August 2009 (West Yorkshire) were included in the study. Data on age, gender, ethnic group, visual acuity and diabetic retinopathy were collected. Ethnic group was defined according to the 2011 census classification. The two main ethnic minority groups represented here are Blacks (“Black/African/Caribbean/Black British”) and South Asians (“Asians originating from the Indian subcontinent”). We examined the prevalence of visual impairment in the better eye using three cut-off points (a) loss of vision sufficient for driving (approximately <6/9) (b) visual impairment (<6/12) and (c) severe visual impairment (<6/60), standardising the prevalence of visual impairment in the minority ethnic groups to the age-structure of the white population. Results Data on visual acuity and were available on 50,331individuals 3.4% of people diagnosed with diabetes and attending screening were visually impaired (95% confidence intervals (CI) 3.2% to 3.5%) and 0.39% severely visually impaired (0.33% to 0.44%). Blacks and South Asians had a higher prevalence of visual impairment (directly age standardised prevalence 4.6%, 95% CI 4.0% to 5.1% and 6.9%, 95% CI 5.8% to 8.0% respectively) compared to white people (3.3%, 95% CI 3.1% to 3.5%). Visual loss was also more prevalent with increasing age, type 1 diabetes and in people living in Yorkshire. Conclusions Visual impairment remains an important public health problem in people with diabetes, and is more prevalent in the minority ethnic groups in the UK.

Non-attendance at diabetic eye screening and risk of sight-threatening diabetic retinopathy: a population-based cohort study.

Aims/hypothesisThis study evaluated whether repeated non-attendance for diabetic eye screening is associated with the risk of sight-threatening diabetic retinopathy (STDR).MethodsThis was a cohort study of 6,556 residents with diabetes who were invited for screening between 2008 and 2011 in a population-based eye screening programme in inner London and who attended for their first-ever screen in 2008. The proportion of participants with STDR was evaluated in relation to the number of years in which screening was missed.ResultsThe proportion of participants who did not attend screening decreased between 2009 and 2011 (annual reduction 1.6% [95% CI 0.9%, 2.3%]). The adjusted relative odds of STDR for 210 participants who did not attend two consecutive years of screening were 3.76 (95% CI 2.14, 6.61; p < 0.001), compared with participants who were screened annually. In 605 participants with mild non-proliferative retinopathy at the first screen, the adjusted relative odds of developing proliferative or moderate to severe non-proliferative retinopathy were 5.72 (95% CI 7.43, 22.83; p = 0.013) for 53 participants who missed two screens.Conclusions/interpretationPatients who do not attend diabetic eye screening are at increased risk of developing STDR. Tracing of non-attenders with evidence of established retinopathy should be an important fail-safe procedure.

Changes in Detection of Retinopathy in Type 2 Diabetes in the First 4 Years of a Population-Based Diabetic Eye Screening Program: Retrospective cohort study

OBJECTIVE Annual diabetic eye screening has been implemented in England since 2008. This study aimed to estimate changes in the detection of retinopathy in the first 4 years of the program. RESEARCH DESIGN AND METHODS Participants included 32,340 patients with type 2 diabetes resident in three London boroughs with one or more screening records between 2008 and 2011. Data for 87,570 digital images from 2008 to 2011 were analyzed. Frequency of sight-threatening diabetic retinopathy (STDR) was estimated by year of screen for first screens and for subsequent screens according to retinopathy status at first screen. RESULTS Among 16,621 first-ever screens, the frequency of STDR was 7.1% in 2008, declining to 6.4% in 2011 (P = 0.087). The proportion with a duration of diabetes of <1 year at first screen increased from 18.7% in 2008 to 48.6% in 2011. Second or later screens were received by 26,308 participants. In participants with mild nonproliferative retinopathy at first screen, the proportion with STDR at second or later screen declined from 21.6% in 2008 to 8.4% in 2011 (annual change −2.2% [95% CI −3.3 to −1.0], P < 0.001). In participants with no retinopathy at first screen, STDR declined from 9.2% in 2008 to 3.2% in 2011 (annual change −1.8% [−2.0 to −1.7], P < 0.001). Declining trends were similar in sociodemographic subgroups. CONCLUSIONS After the inception of population-based diabetic eye screening, patients at lower risk of STDR contribute an increasing proportion to the eligible population, and the proportion detected with STDR at second or subsequent screening rounds declines rapidly.

The symmetry of phenotype between eyes of patients with early and late bilateral age-related macular degeneration (AMD)

BackgroundMacular degeneration is known to be a bilateral disease. This study set out to determine the symmetry of phenotype between eyes of patients with bilateral early AMD (or drusen) or late-stage AMD. This may be important information when considering the likelihood of anti-VEGF treatment.MethodsThis prospective, observational, cross-sectional study graded the color fundus photographs of both eyes of 1,114 Caucasian patients with either early or late-stage AMD. Patients were recruited from a tertiary referral UK population. The main outcomes were phenotype, comparison of number, type and overall area of drusen in early AMD and symmetry of late AMD.ResultsThe overall agreement of phenotype in the entire cohort of patients was 53%, kappa statistic (κ)=0.31, (95% CI = 0.27–0.36). Within this group, a total of 271 patients were identified with bilateral soft and hard drusen (early AMD). Symmetry of phenotype within this group was high in terms of total of area of drusen (agreement = 79%, weighted κ = 0.75) and number of drusen. In those with bilateral geographic atrophy (GA), symmetry between area of GA was moderate (agreement 72%, weighted κ = 0.54), and in those with bilateral neovascular disease (choroidal neovascularization or pigment epithelial detachment), symmetry was poor (agreement 45%, weighted κ = 0.16). Out of the entire cohort, 62% (n = 688) had neovascular disease in at least one eye and 37.5% of these had bilateral disease.ConclusionsThe observed symmetry of phenotype between eyes with drusen appears to reduce in GA and neovascular forms of AMD. Overall, 53% of the cohort had symmetrical disease in terms of phenotype, 23% had neovascular disease in both eyes, 9.3% had GA in both eyes, and 39% of patients had neovascular disease in one eye and non-neovascular disease in the other. This may have implications for the potential need for anti-VEGF treatment of AMD in second eye involvement.

Prevalence of vitreomacular interface abnormalities on spectral domain optical coherence tomography of patients undergoing macular photocoagulation for centre involving diabetic macular oedema

Aim Macular traction may influence the formation and response to treatment of diabetic macular oedema (DME). The aim of this study was to determine the prevalence and associations of spectral domain optical coherence tomography (SD-OCT) evident epiretinal membrane (ERM) and/or partial vitreomacular separation (pVMS) in consecutive patients undergoing macular photocoagulation for centre involving DME. Methods A single-centre retrospective cross-sectional observational study. Results 198 eyes of 198 patients were included. Twelve per cent of eyes demonstrated pVMS and 14% ERM. All cases of pVMS had vitreoretinal adhesion located in the Early Treatment Diabetic Retinopathy Study grid central 1 mm subfield. In 2/3 of ERM cases, ERM was either found in the central subfield or the thickening associated with ERM was contiguous with the thickening in the central subfield. Patients with signs of ERM or pVMS were significantly older and had significantly worse acuity than those without (mean age 67.2 vs 62.8 years (p=0.02); 0.49 vs 0.31 logMAR, p=0.0006). Macular thickness was similar in both groups. The prevalence of pVMS and/or ERM were 31% in Caucasian, 5% in Asian and 24% in Afro-Caribbean subjects (p=0.11). Conclusions ERM or pVMS was found on SD-OCT scanning in 25% of patients undergoing laser for centre involving DME. In 20% of all patients, these potentially tractional elements were either present in the central subfield scan or the traction was contiguous with the central macular thickening, suggesting a possible role for surgical or enzymatic relief of traction in their management. This requires targeted investigation.

Cilioretinal Artery Territory Infarction Associated With Papilledema in a Patient With Neurofibromatosis Type 2.

Cilioretinal artery territory infarction can occur in isolation or in association with other vascular compromise of the retinal circulation. Our patient, an 18-year-old woman with neurofibromatosis type 2, developed a cilioretinal artery territory infarction in the setting of papilledema. Our case, together with one previous report, suggests that cilioretinal artery territory infarction in the context of papilledema, although rare, is a real entity.

Central visual disturbance associated with transient disruption of photoreceptor inner-outer segment junction

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