Introduction of diabetic retinopathy screening into an antenatal clinic: Impact on maternal screening and diagnosis rates.

Pregnancy is a risk factor for the development and progression of diabetic retinopathy (DR) in women with pre-gestational diabetes. However, a minority of pregnant women with diabetes adhere to retinal screening recommendations. The introduction of an onsite retinal camera at our tertiary maternity hospital significantly increased the proportion of women who received at least one retinal screen during pregnancy (93.0% vs 54.3%, P < 0.001) and the identification of both DR and DR progression. We conclude that the use of a retinal camera in similar clinics is a feasible option to improve DR screening and diagnosis rates in pregnancy.

Evaluation of focus and deep learning methods for automated image grading and factors influencing image quality in adaptive optics ophthalmoscopy.

Adaptive optics flood illumination ophthalmoscopy (AO-FIO) is an established imaging tool in the investigation of retinal diseases. However, the clinical interpretation of AO-FIO images can be challenging due to varied image quality. Therefore, image quality assessment is essential before interpretation. An image assessment tool will also assist further work on improving the image quality, either during acquisition or post processing. In this paper, we describe, validate and compare two automated image quality assessment methods; the energy of Laplacian focus operator (LAPE; not commonly used but easily implemented) and convolutional neural network (CNN; effective but more complex approach). We also evaluate the effects of subject age, axial length, refractive error, fixation stability, disease status and retinal location on AO-FIO image quality. Based on analysis of 10,250 images of 50 × 50 µm size, at 41 retinal locations, from 50 subjects we demonstrate that CNN slightly outperforms LAPE in image quality assessment. CNN achieves accuracy of 89%, whereas LAPE metric achieves 73% and 80% (for a linear regression and random forest multiclass classifier methods, respectively) compared to ground truth. Furthermore, the retinal location, age and disease are factors that can influence the likelihood of poor image quality.

Retinal Differential Light Sensitivity Variation Across the Macula in Healthy Subjects: Importance of Cone Separation and Loci Eccentricity.

Purpose: Microperimetry measures differential light sensitivity (DLS) at specific retinal locations. The aim of this study is to examine the variation in DLS across the macula and the contribution to this variation of cone distribution metrics and retinal eccentricity. Methods: Forty healthy eyes of 40 subjects were examined by microperimetry (MAIA) and adaptive optics imaging (rtx1). Retinal DLS was measured using the grid patterns: foveal (2°-3°), macular (3°-7°), and meridional (2°-8° on horizontal and vertical meridians). Cone density (CD), distribution regularity, and intercone distance (ICD) were calculated at the respective test loci coordinates. Linear mixed-effects regression was used to examine the association between cone distribution metrics and loci eccentricity, and retinal DLS. Results: An eccentricity-dependent reduction in DLS was observed on all MAIA grids, which was greatest at the foveal-parafoveal junction (2°-3°) (-0.58 dB per degree, 95% confidence interval [CI]; -0.91 to -0.24 dB, P < 0.01). Retinal DLS across the meridional grid changed significantly with each 1000 cells/deg2 change in CD (0.85 dB, 95% CI; 0.10 to 1.61 dB, P = 0.03), but not with each arcmin change in ICD (1.36 dB, 95% CI; -2.93 to 0.20 dB, P = 0.09). Conclusions: We demonstrate significant variation in DLS across the macula. Topographical change in cone separation is an important determinant of the variation in DLS at the foveal-parafoveal junction. We caution the extrapolation of changes in DLS measurements to cone distribution because the relationship between these variables is complex. Translational Relevance: Cone density is an independent determinant of DLS in the foveal-parafoveal junction in healthy eyes.

Management of conjunctivitis and other causes of red eye during the COVID-19 pandemic.

BACKGROUND: Patients with red eyes frequently present to general practitioners (GPs). Although infrequent, some patients with COVID-19 may present with features typical of viral conjunctivitis. SARS-CoV-2 is expressed at a low rate in tears, which may be a source of infection to GPs caring for patients at high risk of COVID­19. OBJECTIVE: The aims of this article are to outline: 1) ophthalmic complications of SARS-CoV-2 infection, 2) triage and management of patients with potential COVID-19 conjunctivitis, and 3) triage and management of patients with red eyes during the current COVID-19 pandemic. DISCUSSION: It is important that GPs: 1) have a high index of suspicion that patients with apparently typical viral conjunctivitis may have an uncommon presentation of COVID-19 illness, 2) develop appropriate telephone triage systems to reduce patient consultations, and 3) foster relationships with their ophthalmologist and optometrist colleagues who can provide phone advice, guidance on treatment initiation and definitive care when necessary.

Management of conjunctivitis during the COVID-19 pandemic 2020.

Conjunctivitis may be a feature of COVID-19, with tears containing SARS-CoV-2 virus, and a source of potential transmission via aerosols.

Perifoveal interdigitation zone loss in hydroxychloroquine toxicity leads to subclinical bull's eye lesion appearance on near-infrared reflectance imaging.

PURPOSE: To characterize the ultrastructural and functional correlates of hydroxychloroquine (HCQ)-induced subclinical bull's eye lesion seen on near-infrared reflectance (NIR) imaging. METHODS: An asymptomatic 54-year-old male taking HCQ presented with paracentral ring-like scotoma, abnormal multifocal electroretinography (mfERG) and preserved ellipsoid zone on optical coherence tomography (OCT). Dense raster OCT was performed to create en face reflectivity maps of the interdigitation zone. Macular Integrity Assessment (MAIA) microperimetry and mfERG findings were compared with NIR imaging, en face OCT, retinal thickness profiles and wave-guiding cone density maps derived from flood-illumination adaptive optics (AO) retinal photography. RESULTS: The bull's eye lesion is an oval annular zone of increased reflectivity on NIR with an outer diameter of 1450 µm. This region corresponds exactly to an area of preserved interdigitation zone reflectivity in en face OCT images and of normal cone density on AO imaging. Immediately surrounding the bull's eye lesion is an annular zone (3°-12° eccentricity) of depressed retinal sensitivity on MAIA and reduced amplitude density on mfERG. Wave-guiding cone density at 2° temporal was 25,400 per mm2. This declined rapidly to 12,900 and 1200 per mm2 at 3° and 4°. CONCLUSION: Multimodal imaging illustrated pathology in the area surrounding the NIR bull's eye, characterized by reduced reflectance, wave-guiding cone density and retinal function. Further studies are required to investigate whether the bull's eye on NIR imaging and en face OCT is prominent or consistent enough for diagnostic use.

Impact of Raised Serum Cobalt Levels From Recalled Articular Surface Replacement Hip Prostheses on the Visual Pathway.

BACKGROUND: The articular surface replacement (ASR) was recalled in 2010 because of higher than expected revision rates. Patients reported symptoms of neurologic dysfunction including poor vision. This cohort study, using objective measurements, aimed to establish whether a higher incidence of visual function defects exists in ASR patients. METHODS: Thirty-three ASR patients and 33 non-ASR controls (control 1) were recruited. Data were compared with normative population data from the visual electrophysiology database (control 2). Patients underwent investigations for serum cobalt levels, psychophysical visual tests, and extensive electrophysiological visual testing. RESULTS: After excluding 2 subjects with pre-existing eye disease, data from 33 ASR patients were compared with the 2 control cohorts. The median serum cobalt level in the ASR group (median, 52 nmol/L [interquartile range, 14-151 nmol/L]) was significantly higher than that in the control 1 cohort (median, 7 nmol/L [interquartile range, 5-14 nmol/L]; P < .0001). The photoreceptor function of patients with an ASR of the hip showed significantly larger electroretinography mixed rod-cone b-wave amplitudes than both control 1 and control 2 cohorts (P = .0294 and .0410, respectively). Abnormalities in macular function as reflected by multifocal and scotopic electroretinography were more prevalent in control 1 (P = .0445 and .0275, respectively). Optic nerve pathway measurements using visual-evoked potential latency was significantly longer in the ASR group compared with those in the control 2 cohort (P = .0201). There were no statistical differences in visual acuity. CONCLUSION: A statistically significant disturbance in visual electrophysiology was found in the ASR group when compared with the control groups. These differences did not translate to identifiable clinical visual deficits. Orthopedic surgeons need to be aware of the possibility of visual dysfunction in patients with ASR and other metal-on-metal hip arthroplasties; however, routine visual testing is not recommended.

Analysis of copy number variation at DMBT1 and age-related macular degeneration.

BACKGROUND: DMBT1 is a gene that shows extensive copy number variation (CNV) that alters the number of bacteria-binding domains in the protein and has been shown to activate the complement pathway. It lies next to the ARMS2/HTRA1 genes in a region of chromosome 10q26, where single nucleotide variants have been strongly associated with age-related macular degeneration (AMD), the commonest cause of blindness in Western populations. Complement activation is thought to be a key factor in the pathogenesis of this condition. We sought to investigate whether DMBT1 CNV plays any role in the susceptibility to AMD. METHODS: We analysed long-range linkage disequilibrium of DMBT1 CNV1 and CNV2 with flanking single nucleotide polymorphisms (SNPs) using our previously published CNV and HapMap Phase 3 SNP data in the CEPH Europeans from Utah (CEU). We then typed a large cohort of 860 AMD patients and 419 examined age-matched controls for copy number at DMBT1 CNV1 and CNV2 and combined these data with copy numbers from a further 480 unexamined controls. RESULTS: We found weak linkage disequilibrium between DMBT1 CNV1 and CNV2 with the SNPs rs1474526 and rs714816 in the HTRA1/ARMS2 region. By directly analysing copy number variation, we found no evidence of association of CNV1 or CNV2 with AMD. CONCLUSIONS: We have shown that copy number variation at DMBT1 does not affect risk of developing age-related macular degeneration and can therefore be ruled out from future studies investigating the association of structural variation at 10q26 with AMD.

The effect of cobalt on the human eye.

PURPOSE: The effect of elevated serum cobalt on the human visual system has not yet been established. In light of recent reports of visual problems with elevated cobalt in association with hip prostheses, this review examines the literature for evidence regarding the effects of cobalt on human visual function. METHODS: A systematic literature review was undertaken in July 2013. The electronic databases of PubMed (1955 to July week 1 2013), Cochrane Library and EMBASE were searched. Only human studies or case reports written in English were included. RESULTS: Eight case reports were identified. Five case reports involved patients with metal hip arthroplasties, two cases involved patients exposed to environmental cobalt, and one case involved a patient treated medically for anaemia with cobalt chloride. No human prospective studies were identified. CONCLUSIONS: Several case reports showed that high serum cobalt may be associated with both irreversible and reversible visual loss, optic neuropathy and atrophy, electrophysiological evidence of abnormal retinal and retinal pigment epithelium function and fluorescein angiographic evidence of abnormal choroidal perfusion.

Retrospective analysis of the natural history and management of serpiginous choroiditis in Australia and New Zealand.

BACKGROUND: To examine the prevalence of serpiginous choroidopathy in a predominantly Caucasian community, to examine associations between serpiginous choroiditis and other systemic diseases, and to report on the effect of immunosuppression on the long-term course of serpiginous choroiditis. DESIGN: Retrospective cohort study with patients from tertiary care centres and private practices. PARTICIPANTS: 18 patients, mean age 48 years at baseline. One patient was seen only once. Median follow-up was 69 months (5.8 years, range 0.4-29.7 years). METHODS: Patients were identified using the Australian and New Zealand Ophthalmic Surveillance Unit. A chart analysis was performed for all patients. Three treatment groups were identified: no treatment, prednisolone monotherapy, or combination of prednisolone and immunosuppression. Negative binomial regression was used to calculate incidence rate ratios for patient relapse. MAIN OUTCOME MEASURES: Patient demographics, clinical features, associated systemic diseases, treatments administered and dates of relapse. RESULTS: The disease prevalence in Australia and New Zealand is 1 case per 1.5 million people. Five cases (28%) had a positive QuantiFERON. A total of 32 relapses were observed: 14 while receiving no treatment, 11 on prednisolone and 7 on combination therapy. Compared with the no treatment group, the incidence rate ratio for prednisolone monotherapy and combination therapy was 1.29 and 2.92, respectively (95% confidence interval 0.40-4.14 and 0.96-8.88). CONCLUSION: Although the confidence intervals indicate that the difference in incidence rate ratios are not significant, these results suggest that there is a group of patients who have a benign course without long-term immunosuppression or corticosteroid treatment.

Genetic influences on plasma CFH and CFHR1 concentrations and their role in susceptibility to age-related macular degeneration.

It is a longstanding puzzle why non-coding variants in the complement factor H (CFH) gene are more strongly associated with age-related macular degeneration (AMD) than functional coding variants that directly influence the alternative complement pathway. The situation is complicated by tight genetic associations across the region, including the adjacent CFH-related genes CFHR3 and CFHR1, which may themselves influence the alternative complement pathway and are contained within a common deletion (CNP147) which is associated with protection against AMD. It is unclear whether this association is mediated through a protective effect of low plasma CFHR1 concentrations, high plasma CFH or both. We examined the triangular relationships of CFH/CFHR3/CFHR1 genotype, plasma CFH or CFHR1 concentrations and AMD susceptibility in combined case-control (1256 cases, 1020 controls) and cross-sectional population (n = 1004) studies and carried out genome-wide association studies of plasma CFH and CFHR1 concentrations. A non-coding CFH SNP (rs6677604) and the CNP147 deletion were strongly correlated both with each other and with plasma CFH and CFHR1 concentrations. The plasma CFH-raising rs6677604 allele and raised plasma CFH concentration were each associated with AMD protection. In contrast, the protective association of the CNP147 deletion with AMD was not mediated by low plasma CFHR1, since AMD-free controls showed increased plasma CFHR1 compared with cases, but it may be mediated by the association of CNP147 with raised plasma CFH concentration. The results are most consistent with a regulatory locus within a 32 kb region of the CFH gene, with a major effect on plasma CFH concentration and AMD susceptibility.

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.

Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype.

BACKGROUND: Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case-control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking. METHODS: To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, 'Y402H') with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26,494 individuals, including 14,174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene-smoking interaction; and 16 published studies from non-European ancestry. RESULTS: In individuals of European ancestry, there was a significant association between Y402H and late-AMD with a per-allele odds ratio (OR) of 2.27 [95% confidence interval (CI) 2.10-2.45; P = 1.1 x 10(-161)]. There was no evidence of effect modification by smoking (P = 0.75). The frequency of Y402H varied by ancestral origin and the association with AMD in non-Europeans was less clear, limited by paucity of studies. CONCLUSION: The Y402H variant confers a 2-fold higher risk of late-AMD per copy in individuals of European descent. This was stable to stratification by study design and AMD classification and not modified by smoking. The lack of association in non-Europeans requires further verification. These findings are of direct relevance for disease prediction. New research is needed to ascertain if differences in circulating levels, expression or activity of factor H protein explain the genetic association.

Genetic variation in complement regulators and susceptibility to age-related macular degeneration.

OBJECTIVES: Age-related macular degeneration (AMD) is the commonest cause of blindness in Western populations. Risk is influenced by age, genetic and environmental factors. Complement activation appears to be important in the pathogenesis and associations have been found between AMD and genetic variations in complement regulators such as complement factor H. We therefore investigated other complement regulators for association with AMD. METHODS: We carried out a case-control study to test for association between AMD and single nucleotide polymorphisms (SNPs) spanning the genes encoding complement factor P (CFP, properdin), CD46 (membrane cofactor protein, MCP), CD55 (decay accelerating factor, DAF) and CD59 (protectin). All cases and controls were examined by an ophthalmologist and had independent grading of fundus photographs to confirm their disease status. RESULTS: 20 SNPs were genotyped in 446 cases and 262 controls. For two SNPs with p-values approaching significance additional subjects were genotyped to increase the numbers to 622 cases and 359 controls. There was no evidence of association between AMD and any of the SNPs typed in CFP, CD46, CD55 or CD59. CONCLUSIONS: In a case-control sample that has shown the well established associations between AMD and variants in CFH, CFB and C3 there was absence of association with SNPs in CFP, CD46, CD55 and CD59. This suggests that these are not important susceptibility genes for AMD.

Age-related macular degeneration: the importance of family history as a risk factor.

BACKGROUND: Family history is considered a risk factor for age-related macular degeneration (AMD). With the advent of effective therapy for the disease, the importance of family history merits further investigation. This study quantifies the risk associated with family history, first, by a case-control study of reported family history and, second, by examining the siblings of AMD cases. METHODS: The authors recruited cases with advanced AMD, spouses and siblings. All subjects were carefully phenotyped. Clinical findings in the siblings were compared with spouses. Information about family history was collected. The ORs for reported family history of AMD were calculated. Analyses were adjusted for age, smoking and genotype. RESULTS: 495 AMD cases, 259 spouses and 171 siblings were recruited. The OR for AMD was 27.8 (CI 3.8 to 203.0; p=0.001) with a reported family history of an affected parent and 12.0 (CI 3.7 to 38.6; p<0.0001) with a history of an affected sibling. ORs adjusted for age and smoking were higher. Examination of siblings confirmed their increased risk with 23% affected by AMD and an OR of 10.8 (4.5 to 25.8; p<0.0001). Adjusting for age increased the OR to 16.1 (6.2 to 41.8). CONCLUSION: The risk of AMD is greatly increased by having an affected first-degree relative. Those at risk need to be made aware of this and AMD patients should advise siblings and children to seek prompt ophthalmological advice if they develop visual symptoms of distortion or reduced vision.

Gender differences on chest pain perception associated with acute myocardial infarction in Chinese patients: a questionnaire survey.

AIMS: To investigate gender differences in chest pain perception among Chinese patients with acute myocardial infarction. BACKGROUND: Thrombolytic therapy is beneficial to outcomes of acute myocardial infarction if administered within 12 hours from the onset of chest pain. However, cardiac symptom interpretation may impact time of presentation to hospital. Differences in cardiac symptom reports by gender partly explain misdiagnoses and delays in treatment, particularly among women. Whether, such trends apply to Chinese patients with myocardial infarction is unknown. DESIGN: A descriptive prospective study. METHODS: Using questionnaires, data on demographic variables, the number of patients reporting chest pain and other chest sensations at the onset of acute myocardial infarction and chest pain intensity, description, location and radiation across the chest were collected. RESULTS: A total of 128 participants equally divided by gender were recruited. Chest pain was more prevalent among men than women (84.37% vs. 67.19%, p < 0.05). Although no statistical significance was found, Chinese men had higher mean chest pain intensity scores (7.54 SD 2.35 vs. 7.51 SD 2.25) and reported less atypical chest pain (0.00% vs. 9.3%) compared with women. Men had more upper right sided chest pain (40.74% vs. 20.93%, p = 0.038) whereas women experienced increased neck pain and pain to the upper central chest, middle central chest, upper central back, middle central back and middle right back regions. CONCLUSIONS: Discreet gender differences in chest pain perceptions exist between Chinese men and women, with the latter group, who may be considered as a high-risk group for missed and delayed diagnosis from myocardial infarction, reporting more atypical presentations. RELEVANCE TO CLINICAL PRACTICE: Irrespective of culture, women with myocardial infarction tend to present with atypical chest pain symptoms and therefore they should be aggressively investigated.

Charles Bonnet syndrome in age-related macular degeneration: the nature and frequency of images in subjects with end-stage disease.

INTRODUCTION: The term Charles Bonnet syndrome (CBS) is used to describe visual hallucinations resulting from ocular pathology. As part of a larger case-control study we assessed factors which may predispose to this phenomenon in Age-related macular degeneration (AMD). METHODS: Three-hundred and sixty cases of late AMD underwent a detailed questionnaire about visual symptoms experienced. Potential ocular and environmental risk factors were compared in two groups; those experiencing symptoms of CBS (n = 97) and those not experiencing CBS symptoms (n = 263). RESULTS: Twenty-seven percent experienced CBS. Poor visual acuity was the only factor associated with the development of these images in AMD with an odds ratio of 3.50 (95% CI 1.64-7.48, p = 0.001) for those with best binocular visual acuity worse than 6/36. In those who experienced CBS, the images tended to be straight ahead (84.5%), colored (72.2%), have moving parts (62.9%), and occur on average once per day (34%). The most common visual image was of people (19.6%) followed by geometric patterns (15.8%). The majority (71.1%) felt the experience to be neither pleasant nor unpleasant. In 41% images were present throughout the course of their disease. There was no association between visual acuity and complexity of images. CONCLUSION: The prevalence of CBS in late AMD is high, the main risk factor being poor better eye visual acuity. The most commonly experienced hallucinations were of people. Although most patients were unperturbed by the images, reassurance of their benign nature was welcomed. Practitioners should be aware that resolution of symptoms over time does not always occur.

Complement C3 variant and the risk of age-related macular degeneration.

BACKGROUND: Age-related macular degeneration is the most common cause of blindness in Western populations. Susceptibility is influenced by age and by genetic and environmental factors. Complement activation is implicated in the pathogenesis. METHODS: We tested for an association between age-related macular degeneration and 13 single-nucleotide polymorphisms (SNPs) spanning the complement genes C3 and C5 in case subjects and control subjects from the southeastern region of England. All subjects were examined by an ophthalmologist and had independent grading of fundus photographs to confirm their disease status. To test for replication of the most significant findings, we genotyped a set of Scottish cases and controls. RESULTS: The common functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding to the electrophoretic variants C3S (slow) and C3F (fast), was strongly associated with age-related macular degeneration in both the English group (603 cases and 350 controls, P=5.9x10(-5)) and the Scottish group (244 cases and 351 controls, P=5.0x10(-5)). The odds ratio for age-related macular degeneration in C3 S/F heterozygotes as compared with S/S homozygotes was 1.7 (95% confidence interval [CI], 1.3 to 2.1); for F/F homozygotes, the odds ratio was 2.6 (95% CI, 1.6 to 4.1). The estimated population attributable risk for C3F was 22%. CONCLUSIONS: Complement C3 is important in the pathogenesis of age-related macular degeneration. This finding further underscores the influence of the complement pathway in the pathogenesis of this disease.

Complement factor H variant Y402H is a major risk determinant for geographic atrophy and choroidal neovascularization in smokers and nonsmokers.

PURPOSE: The complement factor H (CFH) gene polymorphism Y402H (1277T-->C) has been associated with susceptibility to age-related macular degeneration (AMD). The purpose of this study was to confirm this association in a U.K. population, to determine whether the association holds for both geographic atrophy (GA) and choroidal neovascularization (CNV), and to investigate interactions with smoking. METHODS: A case-control study was undertaken in 443 cases of AMD, with 262 spouses as control subjects. All subjects completed a health and lifestyle questionnaire, had an ophthalmic assessment with fundus photography, and were genotyped. RESULTS: The frequencies of the C allele and CC genotype were significantly higher in cases than in controls. In comparison to the TT genotype, the odds ratios for AMD associated with the CT and CC genotypes were 3.1 (CI 2.0-4.6) and 6.3 (CI 3.8-10.4), respectively. The results were similar in subgroup analyses confined to cases with GA or CNV. The findings were also similar for subgroup analyses restricted to subjects who had never smoked, moderate smokers, or heavier smokers (>20 pack years of smoking). Heavier smokers with the CC genotype may be particularly at risk. The frequency of the CC genotype did not differ significantly between cases with and without a family history of AMD. There was no evidence that genotype had any influence on age at onset of disease. CONCLUSIONS: The CFH Y402H variant is strongly associated with both GA and CNV in the U.K. population. This association is similar in smokers and nonsmokers. Heavier smokers with the CC genotype may be at particular risk.