Abstract

BackgroundAge-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 FindingsWe 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).ConclusionSoft 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.

Highlights

  • Age-related macular degeneration (AMD) includes a wide range of phenotypes

  • We show that the Y402H variant confers similar risk of soft drusen and both forms of advanced AMD (GA or neovascular AMD)

  • Soft drusen occur prior to progression to advanced AMD and represent a histological feature shared by neovascular AMD and geographic atrophy (GA)

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Summary

Introduction

AMD is characterized mainly by the presence of soft drusen in the macula without visual loss, while advanced AMD is characterized by geographic atrophy (GA or dry AMD) and neovascular AMD (wet AMD) with visual loss. Soft drusen and pigmentary abnormalities of the RPE are considered to be an early indication of risk of developing advanced AMD. Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the developed world. Soft drusen, characterized by deposits in the macula without visual loss, are considered to be a precursor of advanced AMD. The commonest cause of poor eyesight in later life in the developed world is known as age-related macular degeneration (AMD). Wet AMD occurs when abnormal, fragile blood vessels grow under the macula behind the retina. Dry AMD occurs as the light-sensitive cells in the macula (the rods and cones) break down

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