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K. Spencer, L. M. Olson, P. Gallins, W. K. Scott, N. Schnetz-Boutaud, A. Agarwal, E. A. Postel, M. A. Pericak-Vance, J. L. Haines; C3 R102G Polymorphism Is Associated With Increased Risk of Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2655.
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Inflammation has long been suspected to play a role in the pathogenesis of age-related macular degeneration (AMD). Association of variants in the complement factor H and complement factor B genes has targeted the search for additional loci to the alternative complement cascade, of which C3 is a major component. Two non-synonymous coding polymorphisms within C3, R102G and L314P, have previously been strongly associated with increased risk (Yates et al. 2007, Maller et al. 2007). These variants are in strong linkage disequilibrium (LD), making the contribution of this locus to AMD even more difficult to ascertain. We sought to determine whether the C3 association resulted primarily from only one of these two variants or from a combined effect of both.
We genotyped the variants using Taqman Assays on Demand from Applied Biosystems, and tested for allelic and genotypic association in 223 families and an independent dataset of 701 cases and 286 unrelated controls. Conditional analyses tested for an effect of R102G in L314P risk allele carriers and vice versa. We estimated the odds ratio for R102G after adjusting for the known AMD susceptibility factors age, smoking, CFH Y402H, LOC387715 A69S, and CFB R32Q, and determined the population attributable risk (PAR) at the C3 locus.
The C3 polymorphisms were in strong LD (D'>0.94, r2=0.85), and both were associated in the family-based and case-control datasets (R102G genoPDT p=0.02, case-control genotypic p=0.004; L314P genoPDT p=0.001, case-control genotypic p=0.04). In conditional analyses in the case-control dataset, R102G remained associated with disease in the L314P risk allele carriers (p=0.01), but there was no effect of L314P in the R102G risk allele carriers (p=0.2), implying that best model for disease in our dataset includes only the R102G variant. After adjusting for known susceptibility factors, the effect of R102G remained strong (p=0.015, odds ratio=1.55, 95% confidence interval 1.09 to 2.21, adjusted PAR=0.17).
Variation in C3 is associated with increased risk for AMD. While the strong LD between R102G and L314P makes it difficult to disentangle their individual effects on disease risk, the R102G polymorphism acting alone provides the best model for disease in our data. C3 represents yet another significant piece of the AMD genetics puzzle.
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