Individuals homozygous for the age-related macular degeneration risk-conferring variant of complement factor H have elevated levels of CRP in the choroid.

Abstract

Polymorphisms in the complement factor H gene (CFH) are associated with a significantly increased risk for, or protection against, the development of age-related macular degeneration (AMD). The most documented risk-conferring single-nucleotide polymorphism results in a tyrosine-to-histidine substitution at position 402 (Y402H) of the CFH protein. In this work, we examined the ocular distributions and relative abundance of CFH, several CFH-binding proteins, and abundant serum proteins in the retinal pigmented epithelium (RPE), Bruch's membrane, and choroid (RPE-choroid) in CFH homozygotes possessing either the "at-risk" 402HH or "normal" 402YY variants. Although CFH immunoreactivity is high in the choroid and in drusen, no differences in CFH-labeling patterns between genotypes are apparent. In contrast, at-risk individuals have significantly higher levels of the CFH-binding protein, C-reactive protein (CRP), in the choroidal stroma. Immunoblots confirm that at-risk individuals have approximately 2.5-fold higher levels of CRP in the RPE-choroid; no significant differences in the levels of CFH or other serum proteins are detected. Similarly, we find no differences in CFH transcription levels in the RPE-choroid nor evidence for local ocular CRP transcription. Increased levels of CRP in the choroid may reflect a state of chronic inflammation that is a by-product of attenuated CFH complement-inhibitory activity in those who possess the CFH at-risk allele. Because the CRP-binding site in CFH lies within the domain containing the Y402H polymorphism, it is also possible that the AMD risk-conferring allele alters the binding properties of CFH, thereby leading to choroidal CRP deposition, contributing to AMD pathogenesis.

• Authors: P T Johnson, K E Betts, M J Radeke, G S Hageman, D H Anderson, L V Johnson
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 103 Issue 46 Pg. 17456-61 (Nov 14 2006) ISSN: 0027-8424 [Print] United States
• PMID: 17079491 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CFH protein, human
• Complement Membrane Attack Complex
• Complement Factor H
• C-Reactive Protein

Topics

• Age Distribution
• Aged
• Aged, 80 and over
• C-Reactive Protein (genetics, metabolism)
• Choroid (metabolism, pathology)
• Complement Factor H (genetics, metabolism)
• Complement Membrane Attack Complex (metabolism)
• Female
• Genetic Variation (genetics)
• Homozygote
• Humans
• Macular Degeneration (genetics, metabolism, pathology)
• Male
• Middle Aged
• Pigment Epithelium of Eye (metabolism)
• Risk Factors
• Transcription, Genetic (genetics)