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H. P. Scholl, P. Charbel Issa, S. Janzer, L. Fritsche, N. V. Chong, R. Fimmers, T. Wienker, F. G. Holz, B. H. F. Weber, M. Oppermann; Genetic Variants of Complement Genes and Systemic Alterations of Complement Protein Markers in Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5067.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate genetic variants within genes coding for proteins involved in the alternative pathway of the complement (APC), complement factor H (CFH), factor B and complement component C2 (CFB-C2) and complement component C3, and to correlate these with plasma levels of complement proteins in patients with age-related macular degeneration (AMD) and controls. To compare the discriminative accuracy of genetic and protein markers.
AMD patients (n=112) and control subjects (n=67) were analyzed for six single nucleotide polymorphisms (SNPs) in CFH, five SNPs in CFB-C2 and rs2230199 in C3. Blood levels of APC substrates (CFB, C3, C4), markers for acute (C3a, C5a) and chronic APC activation (C3d, Ba, C5b-9) and APC regulators (CFH, factor D) were measured.
Four markers in CFH (rs800292, rs1061170, rs2274700, rs412852), two markers in CFB-C2 (rs547154, rs641153) and rs2230199 in C3 were significantly associated with AMD. For CFH, one haplotype conferring risk and two protective haplotypes were found. All protein markers of APC activation were significantly increased in the case cohort (see Abstract Charbel Issa et al.). Controls carrying the CFH risk alleles showed increased Ba levels (p=0.03), whereas AMD patients carrying the protective allele at rs2274700 exhibited reduced C3d levels (p=0.02). The controls carrying the protective CFH haplotypes showed reduced levels of Ba (p=0.04) and C3d (p=0.006), whereas AMD patients carrying the CFH risk haplotype exhibited increased Ba levels (p=0.03). Logistic regression analysis revealed that the discriminative accuracy of a model including only protein markers (82%) was considerably larger than that including only genetic markers (73%).
This study provides first evidence for a link between genetic variants of complement genes and complement protein markers. Therefore, to describe such variants as conferring risk for AMD or being protective appears to be biologically meaningful. The high discriminative accuracy of the APC proteins may suggest that such protein markers could have larger predictive ability for AMD than genetic markers.
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