Gudleif Helgadottir

CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD

Background Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the developed world. The two forms of advanced AMD, geographic atrophy and neovascular AMD, represent different pathological processes in the macula that lead to loss of central vision. Soft drusen, characterized by deposits in the macula without visual loss, are considered to be a precursor of advanced AMD. Recently, it has been proposed that a common missense variant, Y402H, in the Complement Factor H (CFH) gene increases the risk for advanced AMD. However, its impact on soft drusen, GA, or neovascular AMD—or the relationship between them—is unclear. Methods and Findings We genotyped 581 Icelandic patients with advanced AMD (278 neovascular AMD, 203 GA, and 100 with mixed neovascular AMD/GA), and 435 with early AMD (of whom 220 had soft drusen). A second cohort of 431 US patients from Utah, 322 with advanced AMD (244 neovascular AMD and 78 GA) and 109 early-AMD cases with soft drusen, were analyzed. We confirmed that the CFH Y402H variant shows significant association to advanced AMD, with odds ratio of 2.39 in Icelandic patients (p = 5.9 × 10−12) and odds ratio of 2.14 in US patients from Utah (p = 2.0 × 10−9) with advanced AMD. Furthermore, we show that the Y402H variant confers similar risk of soft drusen and both forms of advanced AMD (GA or neovascular AMD). Conclusion Soft drusen occur prior to progression to advanced AMD and represent a histological feature shared by neovascular AMD and GA. Our results suggest that CFH is a major risk factor of soft drusen, and additional genetic factors and/or environmental factors may be required for progression to advanced AMD.

A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration

Through whole-genome sequencing of 2,230 Icelanders, we detected a rare nonsynonymous SNP (minor allele frequency = 0.55%) in the C3 gene encoding a p.Lys155Gln substitution in complement factor 3, which, following imputation into a set of Icelandic cases with age-related macular degeneration (AMD) and controls, associated with disease (odds ratio (OR) = 3.45; P = 1.1 × 10−7). This signal is independent of the previously reported common SNPs in C3 encoding p.Pro314Leu and p.Arg102Gly that associate with AMD. The association of p.Lys155Gln was replicated in AMD case-control samples of European ancestry with OR = 4.22 and P = 1.6 × 10−10, resulting in OR = 3.65 and P = 8.8 × 10−16 for all studies combined. In vitro studies have suggested that the p.Lys155Gln substitution reduces C3b binding to complement factor H, potentially creating resistance to inhibition by this factor. This resistance to inhibition in turn is predicted to result in enhanced complement activation.

Population-based incidence of exudative age-related macular degeneration and ranibizumab treatment load.

Background/aims The use of intravitreal vascular endothelial growth factor antibodies for exudative age-related macular degeneration (AMD) has stressed ophthalmology services and drug budgets throughout the world. The authors study the population-based incidence of exudative AMD in Iceland and the use of intravitreal ranibizumab in a defined population. Methods This is a prospective study of 439 consecutive patients aged 60 years and older with exudative AMD starting intravitreal ranibizumab for exudative AMD in Iceland from March 2007 to December 2009. All patients initially received three consecutive ranibizumab injections, with regular follow-up visits and re-treatment as needed. Results In total, 517 eyes from 439 patients received treatment for exudative AMD (mean age 79 years). The annual incidence of exudative AMD in the population 60 years and older is 0.29%. The incidence increased with advancing age, double for patients 85 years and older compared with those 75–79 years. Approximately 2400 ranibizumab injections per 100 000 persons aged 60 years and older were given each year for exudative AMD. Conclusions These data allow an estimation of the incidence of exudative AMD in a Caucasian population and the treatment load with ranibizumab, which may help plan anti-vascular endothelial growth factor treatment programmes and estimate costs.

Enucleation in Iceland 1992-2004: study in a defined population.

Purpose:  To determine the incidence rate as well as causative diagnoses and surgical indications of enucleation in Iceland during the years 1992–2004.

Geographic atrophy and choroidal melanoma located 3 mm apart

Editor, G eographic atrophy (GA) in agerelated macular degeneration (AMD) is rare in individuals under the age of 70 years. The prevalence in those aged 60–69 years has been estimated to be 1% in the USA (Friedman et al. 2004) and 1.2% in Iceland (Jonasson et al. 2003). The risk of malignant transformation of a choroidal nevus in the White population is low, with an annual incidence in the 60–69-year-old age group of 0.02% (Singh et al. 2005). We report a case of malignant melanoma developing from a pigmented lesion, judged to be a choroidal nevus located only 3 mm from an area of GA in a 66-year-old man. At 61 years of age, the subject’s vision deteriorated rapidly in both eyes over the course of 6 months. Visual acuity (VA) was 6 ⁄ 24 OD and 6 ⁄ 9 OS. Geographic atrophy was present in both eyes, but was more prominent in the right eye. A choroidal nevus was seen superior to the optic disc (Fig. 1A). With time the atrophic lesions increased in size concurrently with a slow decrease in VA. When the subject reached 64 years of age, fluorescein angiography confirmed that exudative AMD had developed in his left eye. Two years later, his VA had decreased to 2 ⁄ 60 OD and 6 ⁄ 60 OS and the atrophic area in his right eye was approximately 3000 lm in diameter. However, over the course of < 22 months the pigmented lesion had increased in size and formed a solid homogenous, 2.5-mm thick tumour (Fig. 1B). Features predictive of a developing malignant melanoma include male gender, presence of symptoms, increased tumour thickness ‡ 2.0 mm, proximity of tumour to foveola of < 3.0 mm, tumour margin adjacent to the optic disc and the presence of orange pigment and subretinal fluid (Shields et al. 2000; Singh et al. 2006). Moreover, tumour growth over a short period is one of the main characteristics of choroidal melanoma (Singh et al. 2006). Our patient was male and had apparent symptoms and the tumour possessed all the aforementioned features. Therefore, the tumour was considered to be a malignant melanoma of the choroid and was treated as such with a 20-mm notch Ruthenium 106 applicator, to a dose of 80 Gy, at a depth of 3.5 mm to include the thickness of the sclera. After the treatment the tumour showed slow, constant regression over the next few years. It is remarkable that in the same fundus, only 3 mm apart, one group of cells undergoes atrophy while another multiplies rapidly.