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Y402H Polymorphism of Complement Factor H Affects Binding Affinity to C-Reactive Protein¹

Matti Laine^*, Hanna Jarva^*,, Sanna Seitsonen, Karita Haapasalo^*, Markus J. Lehtinen^*, Nina Lindeman^*, Don H. Anderson, Patrick T. Johnson, Irma Järvelä^¶,||, T. Sakari Jokiranta^*,, Gregory S. Hageman^#, Ilkka Immonen and Seppo Meri^2,*,

^* Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland; Division of Immunology, HUSLAB Helsinki University Central Hospital Laboratory, Helsinki, Finland; Department of Ophthalmology, University of Helsinki, Helsinki, Finland; Center for the Study of Macular Degeneration, Neuroscience Research Institute, University of California, Santa Barbara, CA 93106; ^¶ Department of Medical Genetics, University of Helsinki, Helsinki, Finland; ^|| Laboratory of Molecular Genetics, Helsinki University Hospital, Helsinki, Finland; and ^# Department of Ophthalmology and Visual Sciences, Center for Macular Degeneration, University of Iowa, Iowa City, IA 52240

Complement factor H (FH) is an important regulator of the alternative complement pathway. The Y402H polymorphism within the seventh short consensus repeat of FH was recently shown to be associated with age-related macular degeneration, the most common cause of irreversible blindness in the Western world. We examined the effects of this polymorphism on various FH functions. FH purified from sera of age-related macular degeneration patients homozygous for the FH_402H variant showed a significantly reduced binding to C-reactive protein (CRP), an acute phase protein, as compared with FH derived from unaffected controls homozygous for the FH_402Y variant. Strongly reduced binding to CRP was also observed with a recombinant fragment of FH (short consensus repeat 5–7) containing the same amino acid change. Because the interaction of CRP and FH promotes complement-mediated clearance of cellular debris in a noninflammatory fashion, we propose that the reduced binding of FH_402H to CRP could lead to an impaired targeting of FH to cellular debris and a reduction in debris clearance and enhanced inflammation along the macular retinal pigmented epithelium-choroid interface in individuals with age-related macular degeneration.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Academy of Finland, Sigrid Jusélius Foundation, Helsinki University Central Hospital Funds (EVO), Päivikki and Sakari Sohlberg Foundation, Finska Läkaresällskapet, The Eye and Tissue Bank Foundation, The Eye Foundation (Helsinki, Finland), Kidneeds Foundation, the National Institutes of Health (EY11515), the American Macular Degeneration Foundation, and the Eye Research Institute.

² Address correspondence and reprint requests to Dr. Seppo Meri, Department of Bacteriology and Immunology, University of Helsinki, P.O. Box 21, Haartman Institute (Haartmaninkatu 3), FI-00014, Helsinki, Finland. E-mail address: seppo.meri{at}helsinki.fi

³ Abbreviations used in this paper: AMD, age-related macular degeneration; RPE, retinal pigmented epithelium; MAC, membrane attack complex; FH, factor H; SCR, short consensus repeat; CRP, C-reactive protein; FHL-1, complement FH-like protein 1; FHR, FH-related protein.

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