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Functional and structural implications of the complement factor H Y402H polymorphism associated with Age-Related macular degeneration

Citation

Ormsby, RJ and Ranganathan, S and Tong, JC and Griggs, KM and Dimasi, DP and Hewitt, AW and Burdon, KP and Craig, JE and Hoh, J and Gordon, DL, Functional and structural implications of the complement factor H Y402H polymorphism associated with Age-Related macular degeneration, Investigative Ophthalmology and Visual Science (Iovs), 49, (5) pp. 1763-1770. ISSN 0146-0404 (2008) [Refereed Article]


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Copyright Statement

Copyright 2008 Association for Research in Vision and Ophthalmology

DOI: doi:10.1167/iovs.07-1297

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 pathophys- iological explanation for the association of the Y402H variant with AMD.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Ophthalmology and Optometry
Research Field:Ophthalmology
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Hearing, Vision, Speech and Their Disorders
Author:Hewitt, AW (Dr Alex Hewitt)
Author:Burdon, KP (Associate Professor Kathryn Burdon)
ID Code:91059
Year Published:2008
Web of Science® Times Cited:56
Deposited By:Menzies Institute for Medical Research
Deposited On:2014-05-06
Last Modified:2016-11-30
Downloads:0

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