Functional and Structural Implications of the Complement Factor H Y402H Polymorphism Associated with Age-Related Macular Degeneration

• Published in: Investigative ophthalmology & visual science 2008-05, Vol.49 (5), p.1763-1770
• Main Authors: Ormsby, Rebecca J, Ranganathan, Shoba, Tong, Joo Chuan, Griggs, Kim M, Dimasi, David P, Hewitt, Alex W, Burdon, Kathryn P, Craig, Jamie E, Hoh, Josephine, Gordon, David L
• Format: Article
• Language: English
• Subjects: Aged; Antigens, Bacterial - metabolism; Bacterial Outer Membrane Proteins - metabolism; Biological and medical sciences; C-Reactive Protein - metabolism; Carrier Proteins - metabolism; Cell Culture Techniques; Chromatography, Affinity; Complement C3b Inactivator Proteins; Complement Factor H - genetics; Complement Factor H - isolation & purification; Complement Factor H - metabolism; Enzyme-Linked Immunosorbent Assay; Eye and associated structures. Visual pathways and centers. Vision; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Heparin - metabolism; Humans; Macular Degeneration - genetics; Medical sciences; Middle Aged; Models, Molecular; Ophthalmology; Pigment Epithelium of Eye - metabolism; Polymorphism, Single Nucleotide - physiology; Protein Binding; Retinopathies; Vertebrates: nervous system and sense organs
• ISSN: 0146-0404; 1552-5783; 1552-5783
• DOI: 10.1167/iovs.07-1297

A Tyr-to-His (Y402H) sequence variant in the factor H (FH) and factor H-like protein (FHL-1) gene is strongly associated with an increased susceptibility for age-related macular degeneration (AMD). The purpose of this study was to understand how the Y402H variant in FH/FHL-1 contributes to the pathogenesis of AMD and, in particular, whether interactions mediated by FH/FHL-1, including binding to C-reactive protein (CRP), group A streptococcal M protein (GAS M6), heparin, and retinal pigment epithelial cells (RPE), are affected. FH was purified from sera of patients homozygous for FH(Y402) or (H402), and recombinant FH fragments representing FHL-1 were generated. Proteins were analyzed for binding to CRP, GAS M6, heparin, and RPE cells. Binding of the FH and FH1 to seven polymorphic variants to CRP and M protein was reduced. The variant did not influence the interaction of FH with heparin but did reduce binding of FHL-1. Binding of the FH and FHL-1 polymorphic variant to RPE cells was not affected. The FH Y402H polymorphism associated with AMD causes a reduction in binding of FH and FHL-1 to CRP and M protein. Both variants show comparable binding to RPE cells, indicating that AMD is unlikely to manifest as a result of impaired host cell-surface recognition. The decreased interaction between FH and CRP, which is essential for the anti-inflammatory function of CRP, provides a possible pathophysiological explanation for the association of the Y402H variant with AMD.