The Complement Factor H Y402H Polymorphism Associated with Age-Related Macular Degeneration Affects Interactions with Multiple Ligands

¹ Microbiology and Infectious Diseases, Flinders University of South Australia, Flinders Drive, Bedford Park, South Australia, 5142, Australia
² Department of Chemistry and Biomolecular Sciences and Biotechnology Research Institute, Macquarie University, North Ryde, New South Wales, Australia
³ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
⁴ Department of Microbiology and Infectious Diseases, Flinders Medical Centre and Flinders University of South Australia, Bedford Park, South Australia, Australia
⁵ Department of Ophthalmology, Flinders Medical Centre and Flinders University of South Australia, Bedford Park, South Australia, Australia
⁶ Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut, United States

^* To whom correspondence should be addressed. E-mail: rebecca.ormsby{at}flinders.edu.au.

	Abstract

PURPOSE. A Tyr to His (Y402H) sequence variant in the Factor H (FH) and Factor H like protein-1 (FHL-1) gene is strongly associated with an increased susceptibility for Age-Related Macular Degeneration (AMD). The aim 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) is affected. METHODS. 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. RESULTS. Binding of the FH and FH1-7 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. CONCLUSION. The FH Y402H polymorphism associated with AMD causes a reduction in binding of FH and FHL-1 to CRP and GAS 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.

Key Words: age-related macular degeneration, immunoregulation, molecular biology, complement, inflammation, C-reactive protein

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