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I. J. Immonen, M. Laine, H. Jarva, S. Seitsonen, K. Haapasalo, M. J. Lehtinen, N. Lindeman, I. Järvelä, S. Jokiranta, S. Meri; Y402H Polymorphism of Complement Factor H Affects Binding Affinity to C-Reactive Protein. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2176.
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Y402H polymorphism of the complement factor H (FH) is a powerful risk factor for age-related macular degeneration (AMD). Since the Y402H occurs at the C-reactive protein binding region of the FH, we wanted to evaluate the the effect of the Y402H polymorphism on the interaction between FH and CRP at the protein level.
Serum FH and purified serum FH from AMD patients and control subjects with the normal genotype (TT) and from those homo- or heterotzygous (TT or CT) for the Y402H polymorphism was tested for binding into CRP-coated plate wells. In addition normal and Y402H recombinant constructs of the SCR5-7 fragments of FH were tested for CRP binding.
FH from sera of of AMD patients with the CC genotype showed a strongly reduced binding to CRP (0.369+0.102 U) compared to patients with the TT genotype (0.532+0.102 U). A similar difference was observed in age-mathed control subjects with the corresponding genotypes.Full length variants of FH purified from sera of subjects with the CC genotypes exhibited a weaker binding to CRP (0.470+ 0.033 U) compared to those of the TT genotype (0.688+0.103 U). An even more marked difference in CRP binding was observed between the recombinant FH SCR 5-7 402H or 402Yfragments (0.300 vs 0.05 U, correspondingly).
Y402H polymorphism interferes with CRP binding of serum FH.Since the decreased binding was detected also in SCR 5-7 constructs, the decrase was not solely due to the 3-dimensional configuration change predicted to occur in the FH molecule in Y402H polymorphism.The decrease in CRP binding was similar in AMD patients and in healthy controls with the polymorphism.
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