Genetic variants in the complement system predisposing to age-related macular degeneration: a review

Abstract

Age-related macular degeneration (AMD) is a major cause of visual impairment in the western world. It is characterized by the presence of lipoproteinaceous deposits (drusen) in the inner layers of the retina. Immunohistochemistry studies identified deposition of complement proteins in the drusen as well as in the choroid. In the last decade, genetic studies have linked both common and rare variants in genes of the complement system to increased risk of development of AMD. Here, we review the variants described to date and discuss the functional implications of dysregulation of the alternative pathway of complement in AMD.

Keywords: Age-related macular degeneration; Alternative pathway; Complement system; Genetic variants.

Figure 1

A cross-section diagram of the human eye (A) indicating the location of the retina and macula. In early AMD (B) accumulation of subretinal drusen can block nutrient uptake and cause damage in the photoreceptor cell layer, eventually leading to geographic atrophy (or `dry') AMD (C) with complete RPE cell loss and photoreceptor neurodegeneration. Neovascular or `wet' AMD (D) is characterized by invasion of abnormal, leaky blood vessels and macrophages in the retina, leading to photoreceptor cell degeneration.

Figure 2

Schematic diagram of single nucleotide polymorphisms in Factor H and the Factor H related proteins (A). Factor H (B) is composed of 20 CCP repeats with multiple ligand binding sites. Locations of the variants associated with AMD are indicated. Factor I (C) is composed of two chains (heavy and light). The number of variants identified in each domain are indicated for the cases (above) and controls (below). C3 (D) is composed of two chains (α and β); variants associated with AMD in C3 are indicated.