Complement factor H in AMD: Bridging genetic associations and pathobiology

Toomey, Christopher B.; Johnson, Lincoln V.; Rickman, Catherine Bowes

doi:10.1016/j.preteyeres.2017.09.001

Cited by 118 publications

(84 citation statements)

References 224 publications

(361 reference statements)

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“…Finally, the alternative pathway cascade results in the formation of the membrane attack complex, which causes cell lysis. To avoid tissue damage, complement activation is closely regulated by several complement inhibitory proteins, such as complement factor I (CFI) and complement factor H (CFH) …”

Section: Molecular Risk Factorsmentioning

confidence: 99%

Risk factors for progression of age‐related macular degeneration

Heesterbeek

Lorés‐Motta

Hoyng

et al. 2020

Ophthalmic Physiologic Optic

230

224

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Purpose Age‐related macular degeneration (AMD) is a degenerative disease of the macula, often leading to progressive vision loss. The rate of disease progression can vary among individuals and has been associated with multiple risk factors. In this review, we provide an overview of the current literature investigating phenotypic, demographic, environmental, genetic, and molecular risk factors, and propose the most consistently identified risk factors for disease progression in AMD based on these studies. Finally, we describe the potential use of these risk factors for personalised healthcare. Recent findings While phenotypic risk factors such as drusen and pigment abnormalities become more important to predict disease progression during the course of the disease, demographic, environmental, genetic and molecular risk factors are more valuable at earlier disease stages. Demographic and environmental risk factors such as age and smoking are consistently reported to be related to disease progression, while other factors such as sex, body mass index (BMI) and education are less often associated. Of all known AMD variants, variants that are most consistently reported with disease progression are rs10922109 and rs570618 in CFH, rs116503776 in C2/CFB/SKIV2L, rs3750846 in ARMS2/HTRA1 and rs2230199 in C3. However, it seems likely that other AMD variants also contribute to disease progression but to a lesser extent. Rare variants have probably a large effect on disease progression in highly affected families. Furthermore, current prediction models do not include molecular risk factors, while these factors can be measured accurately in the blood. Possible promising molecular risk factors are High‐Density Lipoprotein Cholesterol (HDL‐C), Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), zeaxanthin and lutein. Summary Phenotypic, demographic, environmental, genetic and molecular risk factors can be combined in prediction models to predict disease progression, but the selection of the proper risk factors for personalised risk prediction will differ among individuals and is dependent on their current disease stage. Future prediction models should include a wider set of genetic variants to determine the genetic risk more accurately, and rare variants should be taken into account in highly affected families. In addition, adding molecular factors in prediction models may lead to preventive strategies and personalised advice.

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Section: Molecular Risk Factorsmentioning

confidence: 99%

Risk factors for progression of age‐related macular degeneration

Heesterbeek

Lorés‐Motta

Hoyng

et al. 2020

Ophthalmic Physiologic Optic

230

224

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“…58 MAC (C5b-9) is the terminal effector of complement pathways, 59 of known AMD importance due to associations of complement gene sequence variants and complement proteins in drusen. 60 For ultrastructural evaluation of the RPE-BrM-choroid complex and BrM integrity and thickness, 57 4-mm-diameter punches centered at 2 to 4 mm temporal to the fovea were shipped to University Eye Hospital Erlangen for transmission electron microscopy (US-S).…”

Section: Follow-up Assessmentsmentioning

confidence: 99%

Apolipoprotein A-I Mimetic Peptide L-4F Removes Bruch's Membrane Lipids in Aged Nonhuman Primates

Rudolf

Curcio

Schlötzer‐Schrehardt

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Multiple evidence lines support Bruch's membrane lipid deposition as a major precursor of soft drusen and age-related macular degeneration as including a potentially treatable atherosclerosis-like progression in the subretinal pigment epithelium (RPE)-basal lamina space. We evaluated the effect of anti-inflammatory, antiatherogenic peptide L-4F on Bruch's membrane of aged nonhuman primates in a dose-escalating study. METHODS. Macaca fascicularis ‡20 years of age evaluated by color fundus photography and optical coherence tomography received monocular intravitreal injections of L-4F (n ¼ 7) or a placebo-scrambled peptide (n ¼ 2) in 6 doses of 25 to 175 lg over 6 months. Eyes were processed for detection and masked semiquantitative assessment of macular Bruch's membrane neutral lipid (oil red O staining), esterified cholesterol (filipin histochemistry), membrane attack complex (immunofluorescence), and paramacular thickness (transmission electron microscopy). RESULTS. Bruch's membrane neutral lipid, esterified cholesterol, and membrane attack complex were cleared and ultrastructure was improved in L-4F-injected eyes, compared to placebo-injected eyes. Fellow eyes were also affected to the same degree as the injected eyes. Punctate yellow fundus lesions without corresponding RPE elevations on optical coherence tomography correlated to RPE lipoidal degeneration (engorgement with lipid droplets), which was unchanged by this treatment. CONCLUSIONS. Clinical-stage apolipoprotein A-I mimetic peptide L-4F, delivered intravitreally in repeated doses, produced a substantial pharmacologic reduction of Bruch's membrane lipid and restoration of ultrastructure in a nonhuman primate model that exhibits an important precursor of soft drusen, if not soft drusen themselves.

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“…One paradigm is proposed in which ≪zip codes≫, formed by specific protein patterns of the Bruch's membrane (GAGs, heparin, and sulfation pattern), recruit FH with higher affinity than FH 402H , suggesting a lower level of this variant on the membrane in AMD (14). Furthermore, Toomey et al hypothesize that FH and RPE lipoproteins (with or without oxidative modifications) compete for binding to the GAGs ≪zip codes≫ observed on the Bruch's membrane leading to increased lipoprotein accumulation and drusen formation with the presence of FH 402H (36). Moreover, mixed data have been observed regarding the altered affinity of the FH 402H variant on RPE cells (10,16) or on a choroidal endothelial cell line (37).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of FH Protection Against Neovascular AMD

et al. 2020

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A common allele (402H) of the complement factor H (FH) gene is the major risk factor for age-related macular degeneration (AMD), the leading cause of blindness in the elderly population. Development and progression of AMD involves vascular and inflammatory components partly by deregulation of the alternative pathway of the complement system (AP). The loss of central vision results from atrophy and/or from abnormal neovascularization arising from the choroid. The functional link between FH, the main inhibitor of AP, and choroidal neovascularization (CNV) in AMD remains unclear. In a murine model of CNV used as a model for neovascular AMD (nAMD), intraocular human recombinant FH (recFH) reduced CNV as efficiently as currently used anti-VEGF (vascular endothelial growth factor) antibody, decreasing deposition of C3 cleavage fragments, membrane attack complex (MAC), and microglia/macrophage recruitment markers in the CNV lesion site. In sharp contrast, recFH carrying the H402 risk variant had no effect on CNV indicating a causal link to disease etiology. Only the recFH NT al region (recFH1-7), containing the CCPs1-4 C3-convertase inhibition domains and the CCP7 binding domain, exerted all differential biological effects. The CT al region (recFH7-20) containing the CCP7 and CCPs19-20 binding domains was antiangiogenic but did not reduce the microglia/macrophage recruitment. The antiangiogenic effect of both recFH1-20 and recFH-CCP7-20 resulted from thrombospondin-1 (TSP-1) upregulation independently of the C3 cleavage fragments generation. This study provides insight on the mechanistic role of FH in nAMD and invites to reconsider its therapeutic potential.

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Complement factor H in AMD: Bridging genetic associations and pathobiology

Cited by 118 publications

References 224 publications

Risk factors for progression of age‐related macular degeneration

Risk factors for progression of age‐related macular degeneration

Apolipoprotein A-I Mimetic Peptide L-4F Removes Bruch's Membrane Lipids in Aged Nonhuman Primates

Mechanisms of FH Protection Against Neovascular AMD

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