Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly with limited therapeutic options. Here, we report on a study of >12 million variants including 163,714 directly genotyped, most rare, protein-altering variant. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5×10–8) distributed across 34 loci. While wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first signal specific to wet AMD, near MMP9 (difference-P = 4.1×10–10). Very rare coding variants (frequency < 0.1%) in CFH, CFI, and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

Submacular haemorrhages seem to be a significant adverse event following intravitreal bevacizumab in large occult choroidal neovascularisation and may affect visual outcomes. Prospective studies are required to establish the optimal dose of bevacizumab for larger lesion sizes or to identify the most appropriate anti-VEGF agent in large occult CNV with fibrovascular and serous PED lesions.

Acute submacular haemorrhages appear to be a significant adverse event following intravitreal bevacizumab in occult CNV > or = 15 mm(2). Intravitreal ranibizumab appears to have a significantly lower incidence of postoperative submacular haemorrhage in occult CNV > or = 15 mm(2). Larger studies are required to identify the most appropriate agent for the treatment of large occult CNV.

No abstract

IMPORTANCE Advanced age-related macular degeneration (AMD) is a leading cause of blindness in Western countries. Causal, modifiable risk factors need to be identified to develop preventive measures for advanced AMD.OBJECTIVE To assess whether smoking, alcohol consumption, blood pressure, body mass index, and glycemic traits are associated with increased risk of advanced AMD. DESIGN, SETTING, PARTICIPANTSThis study used 2-sample mendelian randomization. Genetic instruments composed of variants associated with risk factors at genome-wide significance (P < 5 × 10 −8 ) were obtained from published genome-wide association studies. Summary-level statistics for these instruments were obtained for advanced AMD from the International AMD Genomics Consortium 2016 data set, which consisted of 16 144 individuals with AMD and 17 832 control individuals. Data were analyzed from July 2020 to September 2021.EXPOSURES Smoking initiation, smoking cessation, lifetime smoking, age at smoking initiation, alcoholic drinks per week, body mass index, systolic and diastolic blood pressure, type 2 diabetes, glycated hemoglobin, fasting glucose, and fasting insulin. MAIN OUTCOMES AND MEASURESAdvanced AMD and its subtypes, geographic atrophy (GA), and neovascular AMD.RESULTS A 1-SD increase in logodds of genetically predicted smoking initiation was associated with higher risk of advanced AMD (odds ratio [OR], 1.26; 95% CI, 1.13-1.40; P < .001), while a 1-SD increase in logodds of genetically predicted smoking cessation (former vs current smoking) was associated with lower risk of advanced AMD (OR, 0.66; 95% CI, 0.50-0.87; P = .003). Genetically predicted increased lifetime smoking was associated with increased risk of advanced AMD (OR per 1-SD increase in lifetime smoking behavior, 1.32; 95% CI, 1.09-1.59; P = .004). Genetically predicted alcohol consumption was associated with higher risk of GA (OR per 1-SD increase of log-transformed alcoholic drinks per week, 2.70; 95% CI, 1.48-4.94; P = .001). There was insufficient evidence to suggest that genetically predicted blood pressure, body mass index, and glycemic traits were associated with advanced AMD. CONCLUSIONS AND RELEVANCEThis study provides genetic evidence that increased alcohol intake may be a causal risk factor for GA. As there are currently no known treatments for GA, this finding has important public health implications. These results also support previous observational studies associating smoking behavior with risk of advanced AMD, thus reinforcing existing public health messages regarding the risk of blindness associated with smoking.

Early stages of geographic atrophy (GA) age-related macular degeneration is characterised by the demise of photoreceptors, which precedes the loss of underlying retinal pigment epithelial (RPE) cells. Sight-loss due to GA has no effective treatment; reflecting both the complexity of the disease and the lack of suitable animal models for testing potential therapies. We report the development and characterisation of a laser-induced mouse model with early GA-like pathology. Retinas were lasered at adjacent sites using a 810 nm laser (1.9 J/spot), resulting in the development of confluent, hypopigmented central lesions with well-defined borders. Optical Coherence Tomography over 2-months showed progressive obliteration of photoreceptors with hyper-reflective outer plexiform and RPE/Bruch’s membrane (BrM) layers within lesions, but an unaffected inner retina. Light/electron microscopy after 3-months revealed lesions without photoreceptors, leaving the outer plexiform layer apposed to the RPE. We observed outer segment debris, hypo/hyperpigmented RPE, abnormal apical-basal RPE surfaces and BrM thickening. Lesions had wedge-shaped margins, extended zones of damage, activated Müller cells, microglial recruitment and functional retinal deficits. mRNA studies showed complement and inflammasome activation, microglial/macrophage phagocytosis and oxidative stress providing mechanistic insights into GA. We propose this mouse model as an attractive tool for early GA studies and drug-discovery.

The HLA-Cw*0701 allele and KIR haplotype AA are associated with AMD. This genotype combination suggests that natural killer cells have a role in the pathogenesis of AMD. Replication studies are needed to confirm these novel HLA-KIR associations with AMD.

Abstract:Purpose: To evaluate the effect of vitreomacular traction (VMT) on the visual acuity outcomes and central retinal thickness measurements following intravitreal antivascular endothelial growth factor (anti-VEGF) therapy for the treatment of exudative AMD.Methods: In this retrospective series, we evaluate the clinical records and optical coherence tomography (OCT) scans of 34 eyes of 32 patients, with VMT confirmed on OCT scanning at baseline, to assess the effects of VMT on anti-VEGF therapy for newly diagnosed exudative wet AMD. Best corrected visual acuity (BCVA) at baseline, 1, 3, 6, 9 and 12 months and central retinal thickness (CRT) at baseline, 3, 6, and 12 months were assessed. Comparison was made with a control group of 29 eyes of 28 patients with wet AMD and no VMT on OCT and with key variable dosing studies for anti-VEGF in exudative AMD (CATT, HARBOR, PrONTO, SUSTAIN and Gupta et al).Results: BCVA results showed a visual acuity improvement that peaked at 3 months with 2.47 letters, well below other variable dosing studies for anti-VEGF therapy in exudative AMD. This was then followed by a steady decline with mean BCVA at 12 months ending below the baseline level (-1.00 letters) compared to a gain of 9.39 letters in the control group at 12 months. Comparison of the mean CRT in the VMT Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporationgroup between baseline and 12 months showed no significant difference (P=0.67), while the PrONTO study and control group showed a highly significant difference at 12 months compared to baseline (P< 0.001).Mean CRT values at 6 and 12 months were essentially at baseline levels (0.26 um, -0.62 um respectively).Conclusion: VMT at baseline, existing concurrently with newly diagnosed exudative AMD treated with intravitreal anti-VEGF therapy on a variable dosing regime, was associated with poorer visual outcomes and a decreased response to reduction in CRT, compared to a control group of wet AMD without VMT treated with intravitreal anti-VEGF and compared to major variable dosing studies for intravitreal anti-VEGF in exudative AMD. While change in letter score is fine, the visual acuities should be provided with their Snellen equivents. This needs to be done in Table 1. Otherwise the manuscript should be accepted. Amendments:I have added the Snellen equivalents to the ETDRS visual acuities in Table 1 as requested above. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation Key words:Age-related macular degeneration; anti-vascular endothelial growth factor; exudative; vitreomacular traction 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 Summary statement:In patients with AMD treated with anti-VEGF therapy on a variable dosing regime, concurrent vitreomacular traction was associated with a less favourable visual outcome and less ...