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Invest Ophthalmol Vis Sci. 2008 May;49(5):1763-70. doi: 10.1167/iovs.07-1297. Epub 2008 Feb 8.

Functional and structural implications of the complement factor H Y402H polymorphism associated with age-related macular degeneration.

Author information

  • 1Department of Microbiology and Infectious Diseases, Flinders Medical Centre and Flinders University of South Australia, Bedford Park, SA 5042, Australia. rebecca.ormsby@flinders.edu.au

Abstract

PURPOSE:

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.

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 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.

CONCLUSIONS:

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.

PMID:
18263814
[PubMed - indexed for MEDLINE]
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