Complement factor H genotypes impact risk of age-related macular degeneration by interaction with oxidized phospholipids

Abstract

The rs1061170T/C variant encoding the Y402H change in complement factor H (CFH) has been identified by genome-wide association studies as being significantly associated with age-related macular degeneration (AMD). However, the precise mechanism by which this CFH variant impacts the risk of AMD remains largely unknown. Oxidative stress plays an important role in many aging diseases, including cardiovascular disease and AMD. A large amount of oxidized phospholipids (oxPLs) are generated in the eye because of sunlight exposure and high oxygen content. OxPLs bind to the retinal pigment epithelium and macrophages and strongly activate downstream inflammatory cascades. We hypothesize that CFH may impact the risk of AMD by modulating oxidative stress. Here we demonstrate that CFH binds to oxPLs. The CFH 402Y variant of the protective rs1061170 genotype binds oxPLs with a higher affinity and exhibits a stronger inhibitory effect on the binding of oxPLs to retinal pigment epithelium and macrophages. In addition, plasma from non-AMD subjects with the protective genotype has a lower level of systemic oxidative stress measured by oxPLs per apolipoprotein B (oxPLs/apoB). We also show that oxPL stimulation increases expression of genes involved in macrophage infiltration, inflammation, and neovascularization in the eye. OxPLs colocalize with CFH in drusen in the human AMD eye. Subretinal injection of oxPLs induces choroidal neovascularization in mice. In addition, we show that the CFH risk allele confers higher complement activation and cell lysis activity. Together, these findings suggest that CFH influences AMD risk by modulating oxidative stress, inflammation, and abnormal angiogenesis.

The Proteomics of Drusen

“…CFH exhibiting the AMD risk 402H polymorphism was found to bind malondialdehyde or POVPC with less affinity than the CFH 402Y nonrisk variant (Weismann et al 2011;Shaw et al 2012). These independent studies also reported that inflammatory responses stimulated by malondialdehyde and POVPC in vitro and in vivo were stronger with the AMD risk variant of CFH than with the nonrisk CFH isoform, suggesting that the nonrisk isoform may help dampen inflammatory responses induced by oxidative modifications.…”

“…Other lipoxidation products in drusen appear to be ligands for CFH, including malondialdehyde (Weismann et al 2011) and 1-palmitoyl-2-(5 0 -oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) (Shaw et al 2012). CFH exhibiting the AMD risk 402H polymorphism was found to bind malondialdehyde or POVPC with less affinity than the CFH 402Y nonrisk variant (Weismann et al 2011;Shaw et al 2012).…”

“…Multiple lipoxidation products are present in drusen, Bruch's membrane, and the cellular debris that copurifies with RPE lipofuscin granules (Crabb et al 2002a;Gu et al 2003a;Schutt et al 2003;Shen et al 2007;Ng et al 2008;Weismann et al 2011;Shaw et al 2012). Lipoxidation in drusen is not surprising given the high amounts of cholesterol esters and phospholipids in drusen (Wang et al 2010).…”

Protective responses to sublytic complement in the retinal pigment epithelium

“…2D). Because vitamin A dimers, oxidized lipids, and lipoproteins are all implicated in the pathogenesis of macular dystrophies (8,10,18), our data point to excess cholesterol as a common etiological factor that could link these insults with abnormal complement activation in the outer retina.…”

“…The complement cascade is activated by insults that disturb RPE homeostasis, including defective clearance of phagocytosed photoreceptor outer segments (6) and abnormal accumulation of vitamin A dimers (7)(8)(9) or oxidized lipids (10) in the RPE. Studies also show that exposure to sublytic levels of MAC alters RPE barrier integrity, causes mitochondrial stress, and induces secretion of VEGF and proinflammatory cytokines (11,12).…”