An imbalance of human complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age-related macular degeneration (AMD)
Open accessAbstract
A frequent deletion of complement factor H (CFH)-related genes CFHR3 and CFHR1 (ΔCFHR3/CFHR1) is considered to have a protective effect against age-related macular degeneration (AMD), although the underlying mechanism remains elusive. The deletion seems to be linked to one of the two protective CFH haplotypes which are both tagged by the protective allele of single nucleotide polymorphism rs2274700 (CFH:A473A). In a German cohort of 530 AMD patients, we now show that protection against AMD conferred by ΔCFHR3/CFHR1 is independent of the effects of rs2274700 and rs1061170 (CFH:Y402H). This suggests a functional role of CFHR1 and/or CFHR3 in disease pathogenesis. We therefore characterized the CFHR3 function and identified CFHR3 as a novel human complement regulator that inhibits C3 convertase activity. CFHR3 displays anti-inflammatory effects by blocking C5a generation and C5a-mediated chemoattraction of neutrophils. In addition, CFHR3 and CFHR1 compete with factor H for binding to the central complement component C3. Thus, deficiency of CFHR3 and CFHR1 results in a loss of complement control but enhances local regulation by factor H. Our findings allude to a critical balance between the complement regulators CFHR3, CFHR1 and factor H and further emphasize the central role of complement regulation in AMD pathology.
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Although a common deletion of CFHR1 and CFHR3 has been proposed, there was only modest signal in this study, likely due to linkage disequilibrium with the most significantly associated variants in the locus (r2=.31 between rs10737680 and 1000 Genomes Project MERGED_DEL_2_6731).
“Although a common deletion of the CFHR1 and CFHR3 genes has been proposed42,43, there was only modest signal in this study which is likely due to linkage disequilibrium with our most significantly associated variants in the locus (r2=.31 between rs10737680 and 1000 Genomes Project MERGED_DEL_2_6731) as previously suggested34.”
From Seven new loci associated with age-related macular degeneration (2013) · cites this paper as [43]
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- Authors
- Fritsche, L. G., Lauer, N., Hartmann, A., Stippa, S., Keilhauer, C. N., Oppermann, M., Pandey, M. K., Köhl, J., Zipfel, P. F., Weber, B. H. F., & Skerka, C.
- Affiliations
- University of Regensburg (DE)
- Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI) (DE)
- Augenklinik Universitätsklinikum Würzburg (DE)
- University of Göttingen (DE)
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Weber, Bernhard H.F.
- Skerka, Christine
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-09-15
- Volume
- 19
- Issue
- 23
- Pages
- 4694-4704
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2122311517
- Cited by
- 203
- References
- 40
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 11 · 2023: 4 · 2022: 11 · 2021: 12 · 2020: 6 · 2019: 9 · 2018: 12 · 2017: 10 · 2016: 18 · 2015: 20 · 2014: 17 · 2013: 20 · 2012: 21
- FWCI
- 7.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- GRO (submittedVersion, cc-by)
- Funders
- Deutsche Forschungsgemeinschaft (WE 1259/19-1)
- Alcon Research Institute
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Keywords
- age-related macular degeneration, complement regulatory proteins, CFHR1, CFHR3, complement factor H, C3 convertase inhibition, C5a, neutrophil chemotaxis, anti-inflammatory activity, complement regulation, genetic risk
- MeSH terms
- Aged, Aged, 80 and over, Blood Proteins, Complement C3b Inactivator Proteins, Enzyme-Linked Immunosorbent Assay, Genotype, Humans, Macular Degeneration, Middle Aged, Neutrophils, Risk Factors, Blotting, Western, Linkage Disequilibrium, Complement C5a, Complement Factor H, Gene Deletion, Polymorphism, Single Nucleotide, Complement C3-C5 Convertases
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