Revisiting the role of factor H in age-related macular degeneration: insights from complement-mediated renal disease and rare genetic variants.

@article{Tzoumas2020RevisitingTR,
  title={Revisiting the role of factor H in age-related macular degeneration: insights from complement-mediated renal disease and rare genetic variants.},
  author={N Tzoumas and Dean Hallam and Claire Louise Harris and Majlinda Lako and David Kavanagh and David H. W. Steel},
  journal={Survey of ophthalmology},
  year={2020}
}
Ophthalmologists are long familiar with the eye showing signs of systemic disease, but the association between age-related macular degeneration (AMD) and abnormal complement activation, common to several renal disorders, has only recently been elucidated. Although complement activation products were identified in drusen almost three decades ago, it was not until the early 21st century that a single nucleotide polymorphism in the complement factor H (FH) gene was identified as a major heritable… Expand
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References

SHOWING 1-10 OF 266 REFERENCES
The complement system in age-related macular degeneration: A review of rare genetic variants and implications for personalized treatment
TLDR
An overview of rare variants identified in AMD patients are provided, functional consequences of rare genetic variation in complement genes on the complement system are summarized, and the relevance of this work in light of ongoing clinical trials that study the effectiveness of complement inhibitors against AMD is discussed. Expand
The pivotal role of the complement system in aging and age-related macular degeneration: Hypothesis re-visited
TLDR
This article revisits the original hypothesis that chronic local inflammatory and immune-mediated events at the level of Bruch's membrane play critical roles in drusen biogenesis and, by extension, in the pathobiology of AMD, and identifies and characterize the local complement system in the RPE-choroid complex. Expand
A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration.
TLDR
It is shown that factor H (HF1), the major inhibitor of the alternative complement pathway, accumulates within drusen and is synthesized by the retinal pigmented epithelium, implicating HF1 function in the pathogenetic mechanisms underlying AMD. Expand
Complement factor H in AMD: Bridging genetic associations and pathobiology
TLDR
A model in which CFH H402 affects CFH binding to heparan sulfate proteoglycans leading to accelerated lipoprotein accumulation in BrM and drusen progression is proposed, based on the group's studies. Expand
Phenotypic Characterization of Complement Factor H R1210C Rare Genetic Variant in Age-Related Macular Degeneration.
TLDR
The typical phenotype of the complement factor H R1210C rare variant is associated with extensive drusen accumulation in the macula and throughout the fundus, as well as with a high risk for having advanced disease. Expand
Human complement factor H Y402H polymorphism causes an age-related macular degeneration phenotype and lipoprotein dysregulation in mice
TLDR
A functional consequence of the Y402H polymorphism in vivo is demonstrated, which promotes AMD-like pathology development and affects lipoprotein levels in aged mice, and support targeting lipoproteins as a viable therapeutic strategy for treating AMD. Expand
Rare CFH mutations and early‐onset age‐related macular degeneration
TLDR
A novel missense mutation, CFH P139A, was identified, for which the G allele contributed 13 of 1061 reads from the pooled DNA and was verified in a single contributing individual by Sanger sequencing. Expand
Loss-of-Function Mutations in the CFH Gene Affecting Alternatively Encoded Factor H-like 1 Protein Cause Dominant Early-Onset Macular Drusen
TLDR
It is proposed that haploinsufficiency of FHL-1, the main regulator of the complement pathway in BrM, where drusen develop, is an important mechanism underpinning the development of EOMD in a number of cases. Expand
Multilocus analysis of age-related macular degeneration
TLDR
This study validates the complement pathway's involvement in AMD and suggests that allelic variants in complement genes have a direct role in disease. Expand
Rare Variants in the Functional Domains of Complement Factor H Are Associated With Age-Related Macular Degeneration.
TLDR
In this large A-AMD cohort, rare variants in the CFH gene were enriched and tended to be located in functional sites or led to low serum levels, which strongly implicate complement activation in A- AMD etiopathogenesis as CFH and CFI interact to inhibit the alternative pathway. Expand
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