Individuals homozygous for the age-related macular degeneration risk-conferring variant of complement factor H have elevated levels of CRP in the choroid.
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.
Johnson
P T
PT
Center for the Study of Macular Degeneration, Neuroscience Research Institute, University of California, Santa Barbara, CA 93106-5060, USA.
Betts
K E
KE
Radeke
M J
MJ
Hageman
G S
GS
Anderson
D H
DH
Johnson
L V
LV
D017677:Age Distribution; D000368:Aged; D000369:Aged, 80 and over; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism*; D002829:Choroid / Q000378:metabolism* / Q000473:pathology*; D017242:Complement Factor H / Q000235:genetics / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010857:Pigment Epithelium of Eye / Q000378:metabolism; D012307:Risk Factors; D014158:Transcription, Genetic / Q000235:genetics
C493495:CFH protein, human; D015938:Complement Membrane Attack Complex; D017242:Complement Factor H; D002097:C-Reactive Protein