Y402H polymorphism of complement factor H affects binding affinity to C-reactive protein
Open accessAbstract
Complement factor H (FH) is an important regulator of the alternative complement pathway. The Y402H polymorphism within the seventh short consensus repeat of FH was recently shown to be associated with age-related macular degeneration, the most common cause of irreversible blindness in the Western world. We examined the effects of this polymorphism on various FH functions. FH purified from sera of age-related macular degeneration patients homozygous for the FH402H variant showed a significantly reduced binding to C-reactive protein (CRP), an acute phase protein, as compared with FH derived from unaffected controls homozygous for the FH402Y variant. Strongly reduced binding to CRP was also observed with a recombinant fragment of FH (short consensus repeat 5–7) containing the same amino acid change. Because the interaction of CRP and FH promotes complement-mediated clearance of cellular debris in a noninflammatory fashion, we propose that the reduced binding of FH402H to CRP could lead to an impaired targeting of FH to cellular debris and a reduction in debris clearance and enhanced inflammation along the macular retinal pigmented epithelium-choroid interface in individuals with age-related macular degeneration.
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The risk-conferring Y402H CFH variant reduces binding affinity to C-reactive protein compared with the Y402Y variant.
“The risk-conferring Y402H CFH variant (genotype CC) has also been reported to reduce the binding affinity to C-reactive protein (CRP), a pro-inflammatory molecule, as compared with the Y402Y variant (genotype TT).”
From Molecular pathology of age-related macular degeneration (2009) · cites this paper as Laine et al., 2007
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- Authors
- Laine, M., Jarva, H., Seitsonen, S., Haapasalo, K., Lehtinen, M. J., Lindeman, N., Anderson, D. H., Johnson, P. T., Järvelä, I., Jokiranta, T. S., Hageman, G. S., Immonen, I., & Meri, S.
- Affiliations
- University of Helsinki (FI)
- University of California, Santa Barbara (US)
- Department of Medical Genetics, University of Helsinki , Helsinki ,
- University of Iowa (US)
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-03
- Volume
- 178
- Issue
- 6
- Pages
- 3831-3836
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC4853917
- OpenAlex
- W2151652430
- Cited by
- 246
- References
- 37
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 4 · 2023: 6 · 2022: 7 · 2021: 7 · 2020: 9 · 2019: 7 · 2018: 9 · 2017: 6 · 2016: 13 · 2015: 10 · 2014: 14 · 2013: 20 · 2012: 17
- FWCI
- 10.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Helsingin ja Uudenmaan Sairaanhoitopiiri
- Kidneeds
- Ögonfonden
- Academy of Finland
- Silmä- ja kudospankkisäätiö
- National Institutes of Health
- National Eye Institute (EY11515, R01EY011515, R24EY017404)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Biomarkers in Disease Mechanisms
- Keywords
- complement factor H, C-reactive protein, alternative complement pathway, age-related macular degeneration, short consensus repeats, protein-protein binding affinity, inflammation, retinal pigment epithelium, choroid
- MeSH terms
- Aged, Aged, 80 and over, C-Reactive Protein, Female, Homozygote, Humans, Inflammation, Macular Degeneration, Male, Middle Aged, Pigment Epithelium of Eye, Polymorphism, Genetic, Protein Binding, Retina, Complement Factor H
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