S. V. Goverdhan

An analysis of the CFH Y402H genotype in AMD patients and controls from the UK, and response to PDT treatment

AimMutation in the complement factor H (CFH) gene is an important risk factor for age-related macular degeneration (AMD). In this study, we identified the strength of the CFH Y402H gene variant association in a UK AMD cohort and tested the hypothesis that this variant may influence the biological response of choroidal neovascularisation (CNV) following photodynamic therapy (PDT) for CNV.MethodsA total of 557 cases with AMD and 551 normal controls were genotyped for the CFH Y402H (1277 C/T) variant using the 5′ nuclease TaqMan assay for allelic discrimination. The CFH gene association for AMD, for the different CNV subtypes and for patients needing PDT was estimated. Twenty-seven PDT-treated patients were followed up for 15 months with ETDRS-derived vision, clinical examination, and fundus angiography. Individuals with different CFH genotypes were then analysed for any association with visual change following PDT.ResultsThe risk association for AMD with the CFH CC genotype (odd ratio (OR)=3.62, Pc<0.0001) was similar to that reported in other Caucasian cohorts. The magnitude and strength of this association was stronger in AREDS stages 2–4 (ORs=4.48, 2.69, and 5.17). ORs for the risk of predominantly classic CNV were significantly raised for both the CC (OR=17.87, P<0.0001) and CT (OR=9.06, P=0.0002) genotypes. The number of patients carrying the high-risk C allele was 70.4% in those requiring PDT as compared to 52.3% in the non-PDT group (OR=2.16, P=0.011), and presence of the CC genotype significantly increased the risk of PDT (OR=5.48, P=0.015). The degree of visual loss following PDT was significantly higher in the CFH CC genotype group (P=0.038); 50% of CC cases (n=13) and 45% of the CT cases (n=12) lost 15 or more ETDRS letters at final follow-up.ConclusionIn this UK cohort of AMD patients, the CFH Y402H variant was significantly enriched in patients with predominantly classic CNV. Patients homozygous for the CFH Y402H genotype seem to have worse visual acuity after PDT.

Intravitreal bevacizumab (Avastin) for the treatment of choroidal neovascularization in age-related macular degeneration: results from 118 cases

Several vascular endothelial growth factor inhibitors have recently been studied as treatments for neovascular AMD.1 2 Pegaptanib sodium improved visual acuity in 6% of patients at one year;1 Ranibizumab 0.5 mg improved vision by three lines in 33% of patients at one year.2 Michels et al. 3 initially reported the use of intravenous bevacizumab for the treatment of choroidal neovascularization (CNV), and others have found visual improvement and reduction in macular thickness with intravitreal bevacizumab.4–8 We present the results from 118 cases treated with intravitreal bevacizumab based at a single centre. A retrospective review of 115 consecutive patients (118 eyes) based at Southampton Eye Unit, treated with intravitreal bevacizumab for CNV was performed. Lesions of all types irrespective of size or location that were either ineligible for photodynamic therapy (PDT) under the National Health Service (including minimally classic and occult CNV) or those not responding to PDT (classic or predominantly classic CNV with recurrent or persistent CNV activity) were included in the study (table 1). All patients underwent visual acuity testing (best corrected Snellen), slitlamp examination and fundus fluorescein angiography. Central macular thickness (CMT) was assessed using Stratus optical coherence tomography (Carl Zeiss Meditec, USA). View this table: Table 1 Baseline characteristics After discussion about the off-label nature of treatment and the potential risks, informed …

Age-Related Macular Degeneration Is Associated with the HLA-Cw*0701 Genotype and the Natural Killer Cell Receptor AA Haplotype

PURPOSE To determine the association of human leukocyte antigen (HLA) C and its cognate killer cell immunoglobulin-like receptor (KIR) ligands with age-related macular degeneration (AMD). METHODS HLA class I allele groups including the HLA-C principal alleles were genotyped in a cohort of 104 AMD cases and 93 controls by using the PCR-SSP (sequence-specific primers) METHOD This cohort was then genotyped for 16 KIR genes by PCR-SSP. Frequencies of the tested HLA/KIR alleles were then compared between patients with AMD and normal control subjects. HLA-C1, -Cw*07, and -Cw*0701 genotypes and their combinations with KIR genotypes/haplotypes were tested for association with AMD. Probabilities were obtained with a two-tailed chi(2) test and Bonferroni correction applied for multiple testing (P(c)). RESULTS The HLA-Cw*0701 allele, in combination with the inhibitory KIR AA haplotype was associated with AMD after logistic regression analysis (P = 0.006, P(c) = 0.036, OR = 4.35, 95% CI = 1.41-13.44). CONCLUSIONS 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.

HLA and eye disease: a synopsis

Human leukocyte antigen (HLA) gene products have been implicated in the pathogenesis of an increasing number of eye diseases, mainly inflammatory in nature. This perspective reviews the current hypotheses for why HLA polymorphisms are associated with specific eye diseases. Statistical problems in studies involving HLA associations are discussed, and possible solutions outlined. The relevance of HLA testing in routine ophthalmic practice, its practical and cost implications is also assessed.

Radiotherapy for age-related macular degeneration: no more pilot studies please

Age-related macular degeneration (AMD) is a major health problem for the United Kingdom. Currently, AMD accounts for the majority of the 124 000 blind registrations in the over 65 age group. This demonstrates that AMD is also an immensely frustrating condition for patients and their doctors as current treatments are extremely limited both for the atrophic form and for choroidal neovascularization (CNV). CNV while accounting for 10% of the disease, disproportionately causes up to 88% of the legal blindness associated with AMD. Conventional laser treatments for CNV improve vision in only 5% of cases and are suitable only for a minority of patients. Therefore, there is a pressing need for novel and effective therapies. Investment in research makes sense financially as well, as the considerable costs to the NHS in managing visually impaired patients could be significantly reduced with better treatments for CNV. One possible novel therapy for the treatment of CNV associated with AMD is ionising radiation. Radiotherapy seems rational because of its known ability to inactivate rapidly proliferating cells such as the capillary endothelium of CNV. Such cells typically manifest impaired radiation damage repair relative to adjoining slowly proliferating cells. A differential survival response might therefore be exploited with CNV destroyed through DNA breaks that normal tissues have time to repair before undergoing cell division. Although radiation dose fractionation with multiple small treatments over many days is commonly used to reduce normal tissue complications in the treatment of malignancies, since CNV is not a true neoplasm, arguments have been made that there may be no therapeutic advantage to dose fractionation, especially if the volume irradiated can be restricted to the region of macula (it is an axiom of radiotherapy that the probability of complications is proportional to the size of the target volume). In the journal this month, however, a radiotherapy trial is reported which shows no benefit in AMD. Should we therefore abandon this treatment in AMD? The short answer is no, because of the theoretical rationale for why radiotherapy may work and a series of studies which have given enticing hints that it may still be of benefit in AMD. Research into radiotherapy as a treatment modality for AMD started in earnest 10 years ago after Chakravarthy et al demonstrated significant regression in (CNV) following external beam radiotherapy in an animal model and later in a phase I study. Since then a multitude of small pilot studies using standard fractions of 2–3 Gy with a total dose of 10–20 Gy have been published, some showing better maintenance of visual acuity in treated eyes, while others failed to show any benefit. Overall, prior to the study by Hoeller et al there have been 10 randomised control trials (RCT), three nonrandomised trials and eight case series each with over 100 people in the study (see Table 1). Among the above RCTs, three studies demonstrated a significant reduction in visual loss when comparing radiotherapy to very lowdose (effectively sham) radiotherapy or observation. The National Institute for Clinical Excellence recognises the modest benefits from radiotherapy while justifying its restricted usage within ethically approved quality clinical trials in the UK. Part of the challenge with radiotherapy is in finding an appropriate radiation regimen. The difficulty lies in the many different ways and dosage schedules by which ionising radiation can be applied to the eye. The biologically Received: 1 September 2004 Accepted: 1 September 2004 Published online: 22 October 2004 University of Southampton, UK

Macular degeneration associated with a novel Treacher Collins tcof1 mutation and evaluation of this mutation in age related macular degeneration

Treacher Collins syndrome (TCS) results from defects in a nucleolar trafficking protein (Treacle) coded for by the TCOF1 gene.1 The purpose of this report is, firstly, to describe an isolated male with TCS associated with macular degeneration who also had a novel TCOF1 gene mutation and, secondly, to evaluate this mutation in a well characterised cohort of 95 patients with age related macular degeneration (AMD). A 44 year old man presented with a 1 month history of metamorphopsia. He had minimal dysmorphic features but was noted to have an antimongoloid slant of the palpebral fissures with mild flattening of the midface. Sensorineural deafness had been diagnosed from childhood but the external ears were normal in appearance. Best corrected visual acuity was 6/9 (−2.25 DS) right eye and 6/24 (−1.50 DS) left eye. Ocular examination revealed bilateral posterior embryotoxon with adhesions between iris and Schwalbe’s line, and iris hypoplasia. No eyelid colobomata were present. Posterior segment examination (fig 1) revealed atrophic macular degeneration in both eyes and a choroidal neovascular membrane (CNV) in the …