Development and Validation of Performance-Based Assessment of Daily Living Tasks in Age-Related Macular Degeneration.

Purpose: To establish the reliability and validity of five performance-based activities of daily living task tests (ADLTT), to correlate structure to function, to evaluate the impact of visual impairment (VI) on age-related macular degeneration (AMD), and to develop new outcome measures. Methods: A multidisciplinary team developed five ADLTTs: (1) reading test (RT); (2) facial expression (FE) recognition; (3) item search (IS) task; (4) money counting (MC) task; and (5) making a drink (MD), tested with binocular and monocular vision. ADLTTs were tested for known-group (i.e., difference between AMD group and controls) and convergent (i.e., correlation to other measures of visual function), validity metrics, and test-retest reliability in 36 patients with VI (visual acuity (logMAR VA > 0.4) in at least one eye caused by AMD versus 36 healthy controls without VI. Results: Compared to controls, AMD patients had a slower reading speed (-77.41 words/min; P < 0.001); took longer to complete MC using monocular worse eye and binocular vision (15.13 seconds and 4.06 seconds longer compared to controls, respectively; P < 0.001); and MD using monocular worse eye vision (9.37 sec; P = 0.033), demonstrating known-group validity. Only RT and MC demonstrated convergent validity, showing correlations with VA, contrast sensitivity, and microperimetry testing. Moderate to good test-retest reliability was observed for MC and MD (interclass correlation coefficient = 0.55 and 0.77; P < 0.001) using monocular worse eye vision. Conclusions: Real-world ADL functioning associated with VI-related AMD can be assessed with our validated ADLTTs, particularly MC and MD. Translational Relevance: This study validates visual function outcome measures that are developed for use in future clinical practice and clinical trials.

Efficacy of a novel personalised aflibercept monotherapy regimen based on polypoidal lesion closure in participants with polypoidal choroidal vasculopathy.

PURPOSE: To compare the efficacy of aflibercept using a personalised versus fixed regimen in treatment-naïve participants with polypoidal choroidal vasculopathy (PCV). DESIGN: A 52-week, randomised, open-label, non-inferiority, single-centre study that included participants with symptomatic PCV. Participants were randomised (3:1 ratio) to receive either personalised (n=40) or fixed 8-weekly treatment regimen (n=13). The personalised regimen allowed for either early treat and extend (T&E) after week 12 or late T&E with 3 additional 4-weekly aflibercept injections until week 24 in participants with residual polypoidal lesions (PL) on indocyanine green angiography (ICGA) at week 12. MAIN OUTCOMES AND MEASURES: Non-inferiority of personalised to fixed regimen for mean change in best-corrected visual acuity (BCVA) from baseline to week 52 (non-inferiority margin: -5 letters). The key secondary outcomes include reduction in central subfield thickness (CSFT) on optical coherence tomography and the anatomical closure of PL on ICGA. RESULTS: Of the 53 participants, the mean (SD) age was 69.2 (8.1) years, 19 (35.8 %) were male. Personalised group was non-inferior to fixed for the primary end point (+8.1 vs +7.9 letters at week 52, respectively; difference 0.16, 95% CI -2.8 to 2.4, p=0.79). There was greater reduction in mean CSFT (SD) in the personalised versus fixed group (-248.8 (169.9) vs -164.8 (148.9) µm, p=0.03). Closure of PL occurred in 21 (55.2%) and 5 (41.6%) of study eyes in personalised and fixed groups, respectively at week 52 (p=0.41). CONCLUSIONS: Personalised regimen achieved non-inferior BCVA gain and numerically higher PL closure compared with fixed regimen. TRIAL REGISTRATION NUMBER: NCT03117634.

25-years Trends and Risk factors related to Surgical Outcomes of Giant Retinal Tear-Rhegmatogenous Retinal Detachments.

To describe the 25-year surgical trends, long-term outcomes and risk factors affecting the outcomes of giant retinal tear-related rhegmatogenous retinal detachments (GRT-RRD). Patients' demographics, pre-operative characteristics, risk factors, operative procedures and post-operative outcomes were collected and divided into three groups - Group A: 1991 to 2015 (overall); Group B: 1991 to 2005, and Group C: 2006 to 2015. Functional and anatomical successes were monitored over a 5-year period. Multivariate logistic regression analysis was performed to identify the risk factors related to functional and anatomical success.127 eyes of 127 patients were included in the study. At 5th year, 69.4% patients had visual acuity (VA) < logMAR 1.0 with 87.5% primary anatomical success rate. While the functional outcome remained the same between group B and C, there was an increase in the anatomical success from 89.7% to 100%, albeit not statistically significant. Patients with worse presenting VA, 150 degrees or more of giant retina tear, macula-detached status and presence of PVR were associated with VA of> logMAR 1.0 (all p < 0.05). The types of surgery (TPPV vs combined SB/TPPV), number of breaks, lens extraction and additional cryotherapy were not associated with the functional or anatomical success. In conclusion, the GRT-RRD functional and structural outcomes were comparable between 1991-2005 and 2006-2015, albeit a statistically insignificant improvement of anatomical outcome over the past 25 years. Worse presenting VA, 150 degrees or more of giant retinal tear, detached macula and presence of PVR were associated with poorer visual outcome.

Real-World Treatment Outcomes of Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy in Asians.

PURPOSE: To describe the 12-month outcomes of treatment-naïve eyes with choroidal neovascularization (CNV) resulting from age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) after initiation of intravitreal anti-vascular endothelial growth factor (VEGF) monotherapy or combination therapy with verteporfin photodynamic therapy (PDT). DESIGN: A 12-month single-center, retrospective, comparative, nonrandomized cohort study. PARTICIPANTS: Patients with AMD or PCV who initiated intravitreal anti-VEGF therapy during 2015. METHODS: Demographics, visual outcomes, OCT, and treatment data were collected at baseline and months 1, 3, 6, and 12 after treatment initiation. Multivariate analysis was performed to identify baseline features predictive of visual maintenance and improvement after 12 months of treatment. MAIN OUTCOME MEASURES: Primary end point was visual acuity (VA) change from baseline to month 12. Secondary end points were treatment exposure and change in central subfield thickness on OCT. RESULTS: A total of 364 patients (165 AMD and 199 PCV) were included. Baseline vision was 41 and 43 logarithm of the minimum angle of resolution (logMAR) letters for AMD and PCV patients, respectively. Patients with AMD and PCV received 5.5 and 5.3 injections (5.0 monotherapy vs. 5.6 combination therapy; mean, 1.2 PDT sessions), respectively. Patients with AMD gained 4.7 logMAR letters after 12 months (P = 0.002), whereas PCV patients gained 6.6 logMAR letters (P = 0.001) and 10.8 logMAR letters (P < 0.001) for monotherapy and combination therapy, respectively. Only patients with presenting VA of fewer than 35 letters (Snellen equivalent, 6/60) achieved significant visual improvement (10.4 letters for AMD, 17.1 letters for PCV with monotherapy, and 35.5 letters for PCV with combination therapy). Predictors of VA gain included number of intravitreal injections (AMD and PCV adjusted odds ratio, 12.1 [P = 0.001] and 12.5 [P = 0.004] for ≥7 injections, respectively) and baseline VA of 20 logMAR letters or fewer (adjusted odds ratio, 3.8 and 10.6 for AMD and PCV, respectively). Age, gender, race, use of PDT or focal laser therapy, and central subfield thickness were not predictive of significant visual gain at 12 months. CONCLUSIONS: In Asian patients, treatment of AMD with anti-VEGF therapy yielded 12-month visual outcomes comparable with those of other real-world studies from Western populations but poorer than those of controlled trials. In contrast, for PCV eyes, anti-VEGF monotherapy and combination therapy with PDT yielded comparable outcomes as those of controlled clinical trials.

Identification of imaging features that determine quality and repeatability of retinal capillary plexus density measurements in OCT angiography.

PURPOSE: Optical coherence tomography angiography (OCT-A) potentially allows for rapid and non-invasive quantification of retinal capillary plexus density in various disease states. This study aims to identify the key features that influenced the repeatability of OCT-A measurements. METHODS: We obtained OCT-A images on two separate visits in 44 healthy eyes from 44 subjects, each imaged with using the Topcon DRI OCT Triton imaging system. The parafoveal vessel density within a 1.5 mm radius centred over the fovea was obtained with the built-in tool for the superficial and deep retinal plexuses. Repeatability of vessel density was determined by intraclass correlation (ICC) and mean variation. We evaluated several image parameters to determine their influence on the repeatability of vessel density measurement in each of the two capillary plexuses. RESULTS: The mean age of the subjects was 70.2±9.2 years, with 64% males. Mean parafoveal vessel density measurements for the first and second visits were 53.3±11.1 and 53.3±10.3 for the superficial plexus and 27.3±8.59 and 27.0±8.78 for the deep plexus. ICC analyses demonstrated that high fine vessel visibility, the absence of motion artefact and software-derived image quality score of 60 or above were necessary to obtain a good (ICC>0.6) or excellent (ICC>0.75) repeatability. CONCLUSIONS: Our study identified the imaging parameters that determined the repeatability of quantitative retinal vessel density measurements. These findings have implications in determining if OCT-A images can be used to accurately evaluate serial changes in retinal vessel density.

Shared genetic variants for polypoidal choroidal vasculopathy and typical neovascular age-related macular degeneration in East Asians.

Polypoidal choroidal vasculopathy (PCV), a subtype of age-related macular degeneration (AMD) more frequently seen in East Asians, has both common and distinct clinical manifestations with typical neovascular AMD (tAMD). We aim to examine the extent to which common genetic variants are shared between these two subtypes. We performed the meta-analysis of association in a total of 1062 PCV patients, 1157 tAMD patients and 5275 controls of East Asian descent from the Genetics of AMD in Asians Consortium at the 34 known AMD loci. A total of eight loci were significantly associated with PCV, including age-related maculopathy susceptibility 2 (ARMS2)-HtrA serine peptidase 1 (HTRA1), complement factor H (CFH), C2-CFB-SKIV2L, CETP, VEGFA, ADAMTS9-AS2 and TGFBR1 (P<5 × 10-4) from the single-nucleotide polymorphism-based test and COL4A3 from the gene-based tests (Pgene=2.02 × 10-4). PCV and tAMD are genetically highly correlated (rg=0.69, P=4.68 × 10-3), with AMD known loci accounting for up to 36% variation. Weaker association for PCV was observed at ARMS2-HTRA1 (Pdif=4.39 × 10-4) and KMT2E-SRPK2(Pdif=4.43 × 10-3), compared with tAMD. Variants at CFH, CETP and VEGFA exhibited different association signals in East Asians, in contrast to those in European individuals. Our data suggest a substantially shared genetic susceptibility for PCV and tAMD, while also highlight the unique associations for PCV, which is useful in understanding the pathogenesis of PCV.

A missense variant in FGD6 confers increased risk of polypoidal choroidal vasculopathy.

Polypoidal choroidal vasculopathy (PCV), a subtype of 'wet' age-related macular degeneration (AMD), constitutes up to 55% of cases of wet AMD in Asian patients. In contrast to the choroidal neovascularization (CNV) subtype, the genetic risk factors for PCV are relatively unknown. Exome sequencing analysis of a Han Chinese cohort followed by replication in four independent cohorts identified a rare c.986A>G (p.Lys329Arg) variant in the FGD6 gene as significantly associated with PCV (P = 2.19 × 10(-16), odds ratio (OR) = 2.12) but not with CNV (P = 0.26, OR = 1.13). The intracellular localization of FGD6-Arg329 is distinct from that of FGD6-Lys329. In vitro, FGD6 could regulate proangiogenic activity, and oxidized phospholipids increased expression of FGD6. FGD6-Arg329 promoted more abnormal vessel development in the mouse retina than FGD6-Lys329. Collectively, our data suggest that oxidized phospholipids and FGD6-Arg329 might act synergistically to increase susceptibility to PCV.

Comparison of swept source optical coherence tomography and spectral domain optical coherence tomography in polypoidal choroidal vasculopathy.

BACKGROUND: Swept source optical coherence tomography (SS-OCT, Topcon Medical System, Japan) is known to have longer wavelength than spectral domain OCT (SD-OCT, Spectralis, Heidelberg Engineering, Germany), allowing a deeper penetration into retina and choroidal layers. This objective of this study was to compare the visibility of retinal and choroidal features in polypoidal choroidal vasculopathy (PCV) using SS-OCT and SD-OCT. DESIGN: This study employs prospective comparative observational case series in Singapore National Eye Center. PARTICIPANTS: There were 20 eyes (20 patients) with PCV confirmed with indocyanine green angiogram. METHODS: Six pre-specified OCT parameters (presence of polyps, sharp pigment epithelial detachment [PED] peak, notched PED and visibility of full maximum height of PED, inner segment/outer segment [IS/OS] line and choroid-scleral interface [CSI]) were graded using SS-OCT and SD-OCT. MAIN OUTCOME MEASURES: The Kappa statistics between the two imaging modalities were calculated. RESULTS: Both SS-OCT and SD-OCT were able to detect polypoidal lesions in the majority of eyes (90% and 85%, respectively). However, SS-OCT had better detection for CSI and IS/OS lines (CSI: 80% vs 45%, P = 0.05; IS/OS line: 65% vs 45%, P = 0.34). For sharp PED peak, notched PED, ability to visualize the full PED height and retinal pigment epithelial line, both OCT machines were able to detect in ≥80% of the eyes. CONCLUSION: In conclusion, SS-OCT and SD-OCT appeared to be similarly effective at detecting most features associated with PCV. However, SS-OCT is more superior in detecting the CSI.

New loci and coding variants confer risk for age-related macular degeneration in East Asians.

Age-related macular degeneration (AMD) is a major cause of blindness, but presents differently in Europeans and Asians. Here, we perform a genome-wide and exome-wide association study on 2,119 patients with exudative AMD and 5,691 controls, with independent replication in 4,226 patients and 10,289 controls, all of East Asian descent, as part of The Genetics of AMD in Asians (GAMA) Consortium. We find a strong association between CETP Asp442Gly (rs2303790), an East Asian-specific mutation, and increased risk of AMD (odds ratio (OR)=1.70, P=5.60 × 10(-22)). The AMD risk allele (442Gly), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17 mmol l(-1) (P=5.82 × 10(-21)) in East Asians (n=7,102). We also identify three novel AMD loci: C6orf223 Ala231Ala (OR=0.78, P=6.19 × 10(-18)), SLC44A4 Asp47Val (OR=1.27, P=1.08 × 10(-11)) and FGD6 Gln257Arg (OR=0.87, P=2.85 × 10(-8)). Our findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asians may also have a distinct genetic signature.

Association of genetic variants on 8p21 and 4q12 with age-related macular degeneration in Asian populations.

PURPOSE: To evaluate the association of genetic variants at chromosomes 8p21 and 4q12 with the risk of developing AMD and its two main subtypes, choroidal neovascular membrane (CNV) and polypoidal choroidal vasculopathy (PCV), in Asian populations. METHODS: The study population comprised 2360 patients with neovascular AMD (1013 typical AMD-CNV and 1282 PCV), and 3598 controls from four independent cohorts, two of Japanese (n = 4859) and two of Chinese (n = 1099) ethnicity. We performed a meta-analysis in case-control studies of two reported single nucleotide polymorphisms (SNPs) (rs13278062 at TNFRSF10A-LOC389641 on 8p21 and rs1713985 at REST-C4orf14-POLR2B-IGFBP7 on 4q12) by using logistic regression analysis adjusted for age and sex. Subgroup analysis by CNV and PCV subtypes were performed to evaluate the significance of these two variants. RESULTS: The reported association between rs13278062 at 8p21 and neovascular AMD was replicated in this population (P = 1.12 × 10(-4), odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.70-0.89). However, there was no association of rs1713985 at 4q12 with neovascular AMD, or its two subtypes, typical AMD-CNV and PCV (all P > 0.05). The study sample size had a statistical power of greater than 99% to detect an association of a risk allele with AMD with an OR of 1.30, as reported in the original study of rs1713985 and AMD. CONCLUSIONS: The present results did not replicate the reported association between rs1713985 at 4q12 and neovascular AMD. However, we confirmed the association between rs13278062 at 8p21 and neovascular AMD in Asian populations.

Cystoid macular edema in acute presentation of central retinal artery occlusion.

A seventy-six-year-old lady with poor vision of the left eye due to previous retinal detachment presented with acute visual loss of her right eye secondary to central retinal artery occlusion. Clinical examination showed a pale right optic disc, macular edema, and a cherry red spot. Optical coherence tomography done four hours after onset showed right acute cystoid macular edema and diffuse inner retinal thickening. Subsequent treatment with intravenous carbonic anhydrase inhibitor resulted in some visual improvement. Central retinal artery occlusion has been known to produce diffuse intraretinal edema instead of cystoids changes. We would like to discuss a case of acute cystoid macular edema in acute central retinal artery occlusion.

Toll-like receptor 3 polymorphism rs3775291 is not associated with choroidal neovascularization or polypoidal choroidal vasculopathy in Chinese subjects.

BACKGROUND/AIMS: Age-related macular degeneration (AMD) is a leading cause of visual impairment. A single-nucleotide polymorphism (SNP; rs3775291) in the Toll-like receptor 3 (TLR3) gene has recently been implicated in the pathogenesis of AMD in Caucasian populations. The aim of this study was to examine this association in Chinese persons with choroidal neovascularization (CNV) secondary to AMD and polypoidal choroidal vasculopathy (PCV). METHODS: This was an observational cross-sectional study in Singapore. Study subjects were of Chinese ethnicity and included patients with exudative maculopathy and normal control subjects. The diagnoses of CNV and PCV were made based on fundus examination, fluorescein angiography and indocyanine green angiography findings. Genomic DNA was extracted, and genotypes were determined by bidirectional DNA sequencing. We compared the allele and genotype frequencies between subjects with CNV and PCV with controls using the software PLINK. RESULTS: A total of 246 subjects with exudative maculopathy (consisting of 126 with CNV and 120 with PCV) and 274 normal control subjects were recruited. The distribution of rs3775291 SNP genotypes for CNV and PCV was not significantly different from that for normal controls. CONCLUSION: This study indicates that the TLR3 rs3775291 gene polymorphism is not associated with CNV and PCV in Singaporean Chinese patients.

Polypoidal choroidal vasculopathy and neovascular age-related macular degeneration: same or different disease?

Neovascular age-related macular degeneration (nAMD) is the commonest cause of severe visual impairment in older adults in Caucasian white populations. Polypoidal choroidal vasculopathy (PCV) has been described as a separate clinical entity differing from nAMD and other macular diseases associated with subretinal neovascularization. It remains controversial as to whether or not PCV represents a sub-type of nAMD. This article summarizes the current literature on the clinical, pathophysiological and epidemiological features and treatment responses of PCV and compares this condition to nAMD. Patients with PCV are younger and more likely Asians, and eyes with PCV lack drusen, often present with serosanguinous maculopathy or hemorrhagic pigment epithelial detachment, and have differing responses to photodynamic therapy and anti-vascular endothelial growth factor (VEGF) agents. There are also significant differences in angiographic and optical coherence tomography features between PCV and nAMD. Histopathological studies suggest differences in the anatomical details of the associated vascular abnormalities in the retina and choroids and the relative role of VEGF. There is emerging evidence of common molecular genetic determinants involving complement pathway and common environmental risk factors (e.g. smoking). Such information could further assist clinicians involved in the care of elderly patients with these conditions.

The outer and inner retinal function in patients with multiple evanescent white dot syndrome.

BACKGROUND: To investigate the outer and inner retinal function in patients with multiple evanescent white dot syndrome (MEWDS). METHODS: The retinal function of three subjects with MEWDS was investigated using one or a combination of full-field electroretinography (ERG), multifocal electroretinography (mfERG) or recording of multifocal oscillatory potentials (mfOP). RESULTS: In case 1, the scotopic, maximal, photopic and flicker ERG responses of the two eyes were similar but the amplitudes of the dark- and light-adapted OPs were markedly reduced in the affected eye. In cases 2 and 3, the ERG responses were grossly reduced in amplitude and as expected the OPs were also diminished. However, using the mfERG a residual area of 'normal' retinal function in the affected eye was identified. The local OP, assessed by the mfOP, within the residual 'normal' retinal area was reduced as compared with the corresponding retinal area of the fellow unaffected eye. Subsequently, the mfERG responses of the 'normal' retinal area were also reduced. CONCLUSION: The OPs were reduced throughout the retina in patients with MEWDS, even in the area with a normal mfERG. The electrophysiological findings suggest that functional abnormality in MEWDS may occur initially in the inner retina and subsequently involves the outer retina.

Is routine pupil dilation safe among asian patients with diabetes?

PURPOSE: To investigate the risk of acute angle closure (AAC), changes in intraocular pressure (IOP), and factors associated with these outcomes after routine pupil dilation in a cohort of Asian subjects with diabetes mellitus. METHODS: The study was a prospective observational case series of 1910 consecutive Asian subjects newly referred for assessment of diabetic retinopathy at a tertiary clinic. All subjects underwent routine pupil dilation unless there was a prior history of angle-closure glaucoma. Noncontact air-puff tonometry was used to assess IOP, which was measured by the same observer before and 1 hour after pupil dilation. Subjects were assessed for signs and symptoms of AAC before leaving the clinic, and their charts were also subsequently reviewed for revisits with AAC. RESULTS: Of the 1910 subjects who participated, none developed AAC. Sixty-nine subjects (3.6%, 95% CI: 2.8%-4.5%) showed an increase in IOP of >or=5 mm Hg in the either eye, 37 subjects (1.9%, 95% CI: 1.4%-2.6%) had a postdilation IOP >25 mm Hg in either eye, and only 10 subjects (0.52%, 95% CI: 0.25%-0.96%) had an increase in IOP >or=5 mm Hg and had a postdilation IOP >25 mm Hg in either eye. The level of predilation IOP and a known history of glaucoma were significant risk factors for a postdilation IOP >or=25 mm Hg. CONCLUSIONS: In this cohort of Asian persons with diabetes, the risk of AAC was insignificant after routine dilation of pupils for fundus examination. These data substantiate the safety of routine dilation of pupils in Asian patients with diabetes.

Diabetic retinopathy in diabetics referred to a tertiary centre from a nationwide screening programme.

INTRODUCTION: The aim of the study was to describe the prevalence and risk factors for diabetic retinopathy in a multi-ethnic diabetic patient cohort referred for retinal evaluation from a nationwide diabetic retinopathy screening programme in Singapore. MATERIALS AND METHODS: Seven hundred and forty-two patients, aged 21 to 95, referred for suspected diabetic retinopathy on annual one-field non-mydriatic 45 degree retinal photographs (Topcon TRC-NW6, Topcon Corporation, Tokyo, Japan) from primary care to the Singapore National Eye Centre diabetic retinopathy clinic were included. The photographs had been interpreted by 24 trained family physicians accredited every 2 years with a training programme. Patients underwent a standardised interview and examination. Fundi were examined with indirect ophthalmoscopy by 2 examiners. Presence and severity of diabetic retinopathy was graded into none, mild, moderate, severe, very severe non-proliferative diabetic retinopathy and proliferative diabetic retinopathy. Macular oedema and clinically significant macular oedema were also graded. RESULTS: Ninety-nine per cent of patients were type 2 diabetics. The prevalence of diabetic retinopathy was 38.1%, visionthreatening retinopathy was 11.8% and macular oedema was 6.9%. There were no racial differences. Significant predictors of any retinopathy were longer duration of diabetes, lower body mass index, being on treatment for hypertension, hypercholesterolaemia and use of diabetic medication. Predictors for vision-threatening retinopathy were younger age, longer duration of diabetes and lower body mass index. CONCLUSIONS: The use of one-field non-mydriatic 45 degree photography as a screening tool for diabetic retinopathy resulted in a cohort of which 38.1% had diabetic retinopathy. Risk factors for diabetic retinopathy of this cohort are also presented.

Association analysis of CFH, C2, BF, and HTRA1 gene polymorphisms in Chinese patients with polypoidal choroidal vasculopathy.

PURPOSE: Polypoidal choroidal vasculopathy (PCV) is a major cause of serosanguinous maculopathy in Chinese patients with age-related macular degeneration (AMD). Variants in the CFH and HTRA1/LOC387715 genes are strongly associated with AMD in Caucasians and Chinese. Variants in the C2 and BF genes have been found to confer a significantly reduced risk of AMD. This study was undertaken to determine whether these associations occur in Chinese patients with PCV. METHODS: Patients of Chinese ethnicity with clinically and angiographically diagnosed PCV and normal control subjects were recruited from the Singapore National Eye Centre. Five single-nucleotide polymorphisms (SNPs) in the CFH gene, two each within the C2 and BF genes and two variants located in the LOC387715 and HTRA1 genes, were screened in all patients and control subjects. RESULTS: Seventy-two patients with PCV and 93 normal control subjects were studied. A significant association was noted with CFH variants rs3753394 and rs800292 among the PCV cases (P = 0.0015 and P = 0.0045, respectively). Individuals homozygous for the TT genotype of rs3753394 had a significantly higher risk (P = 0.0076) of PCV (OR = 4.29; 95% CI: 1.47-12.50) than those carrying a single copy of the T allele (P = 0.3210; OR = 1.69; 95% CI: 0.60-4.78), after adjustment for such risk factors as age and sex. The genotype frequencies of rs11200638 and rs10490924 in HTRA1 and LOC387715, respectively, were also found to be significantly different between patients with PCV and normal control subjects (P = 0.00032 and P = 0.003, respectively). The AA genotype of rs11200638 and TT genotype of rs10490924 conferred a 4.9-fold (95% CI: 1.85-12.95) and 4.89-fold (95% CI: 1.85-12.90) increased risk of PCV, respectively, after adjustment for age and sex. The Y402H variant of CFH (rs1061170) and the BF and C2 variants were not significantly different in patients and normal control subjects. CONCLUSIONS: The SNPs rs3753394 and rs800292 of CFH and rs11200638 of HTRA1 are significantly associated with the risk of PCV in Chinese patients.

Long-term evaluation of AAV-mediated sFlt-1 gene therapy for ocular neovascularization in mice and monkeys.

Vascular endothelial growth factor (VEGF) is one of the major mediators of retinal ischemia-associated neovascularization. We have shown here that adeno-associated virus (AAV)-mediated expression of sFlt-1, a soluble form of the Flt-1 VEGF receptor, was maintained for up to 8 and 17 months postinjection in mice and in monkeys, respectively. The expression of sFlt-1 was associated with the long-term (8 months) regression of neovascular vessels in 85% of trVEGF029 eyes. In addition, it resulted in the maintenance of retinal morphology, as the majority of the treated trVEGF029 eyes (75%) retained high numbers of photoreceptors, and in retinal function as measured by electroretinography. AAV-mediated expression of sFlt-1 prevented the development of laser photocoagulation-induced choroidal neovascularization in all treated monkey eyes. There were no clinically or histologically detectable signs of toxicity present in either animal model following AAV.sFlt injection. These results suggest that AAV-mediated secretion gene therapy could be considered for treatment of retinal and choroidal neovascularizations.