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C. C. Klaver, D. D. G. Despriet, A. Bakker, P. T. V. M. de Jong, B. H. F. Weber, A. A. B. Bergen; Haplotype Analysis of the Complement Factor H Gene in Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3004.
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Recent studies demonstrated that at least 20 single nucleotide polymorphisms (SNPs) in the Complement Factor H (CFH) gene are associated with Age-related Macular Degeneration (AMD). Many of these are in high linkage disequilibrium, and it is as yet unclear which SNPs are functionally involved in the disease pathology. The present study aimed to assess which combination of SNPs in the coding region describe the risk of AMD most accurately.
In a clinic-based setting, 360 unrelated patients with early and late AMD and 183 age-matched control subjects were diagnosed according to the international classification system. All exons and flanking introns of the CFH gene were amplified by PCR, and analyzed for sequence variations by denaturing high-performance liquid chromatography. Variants were validated by direct sequencing. Haplotypes were estimated using the expectation-maximization algorithm, and the risk of AMD for each haplotype was determined with HAPLO.STATS 1.2.2.
We identified a total of 25 SNPs and 85 haplotypes. In the univariate analyses, A473A, followed by Y402H, showed the strongest positive association; V62I had the strongest protective effect. Of the haplotypes, only 16 had a frequency of > 0.5%, and only 7 had a distribution that was significantly different in cases and controls. Compared to the most frequent (45% cases vs 33% controls) haplotype, which contained both Y402H and A307A, two haplotypes had a significant higher risk of AMD. One comprised only Y402H; the other comprised IVS10 -98 G>T and E963D. The remaining 5 haplotypes all had a significant protective effect (ORs <0.5; P<0.05).
Our results suggest that the haplotype with only Y402H confers the highest risk of AMD, and that haplotypes with Y402H in combination with other SNPs have lower risks. It is plausible that Y402H is a SNP that functionally disturbs CFH protein function.
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