C2 and CFB genes in age-related maculopathy and joint action with CFH and LOC387715 genes

Johanna Jakobsdottir, Yvette P Conley, Daniel E Weeks, Robert E Ferrell, Michael B Gorin, Johanna Jakobsdottir, Yvette P Conley, Daniel E Weeks, Robert E Ferrell, Michael B Gorin

Abstract

Background: Age-related maculopathy (ARM) is a common cause of visual impairment in the elderly populations of industrialized countries and significantly affects the quality of life of those suffering from the disease. Variants within two genes, the complement factor H (CFH) and the poorly characterized LOC387715 (ARMS2), are widely recognized as ARM risk factors. CFH is important in regulation of the alternative complement pathway suggesting this pathway is involved in ARM pathogenesis. Two other complement pathway genes, the closely linked complement component receptor (C2) and complement factor B (CFB), were recently shown to harbor variants associated with ARM.

Methods/principal findings: We investigated two SNPs in C2 and two in CFB in independent case-control and family cohorts of white subjects and found rs547154, an intronic SNP in C2, to be significantly associated with ARM in both our case-control (P-value 0.00007) and family data (P-value 0.00001). Logistic regression analysis suggested that accounting for the effect at this locus significantly (P-value 0.002) improves the fit of a genetic risk model of CFH and LOC387715 effects only. Modeling with the generalized multifactor dimensionality reduction method showed that adding C2 to the two-factor model of CFH and LOC387715 increases the sensitivity (from 63% to 73%). However, the balanced accuracy increases only from 71% to 72%, and the specificity decreases from 80% to 72%.

Conclusions/significance: C2/CFB significantly influences AMD susceptibility and although accounting for effects at this locus does not dramatically increase the overall accuracy of the genetic risk model, the improvement over the CFH-LOC387715 model is statistically significant.

Conflict of interest statement

Competing Interests: The authors are listed as the inventors in a patent filed by the University of Pittsburgh for the ARMS2 locus.

Figures

Figure 1. Linkage disequilibrium (LD) across the…
Figure 1. Linkage disequilibrium (LD) across the C2/CFB region in unrelated cases and controls.
The darker the boxes the higher the r2. The top number in each box is r2 and the bottom number is D'. Locations of the SNPs within the genes are shown. Red lines/boxes show the locations of exons in C2 and green lines/boxes the locations of exons in CFB.
Figure 2. Results of GMDR analyses.
Figure 2. Results of GMDR analyses.
A: Results of unadjusted GMDR analysis for the best two-factor model. B: Results of adjusted GMDR analysis for the best two-factor model. C: Results of unadjusted GMDR analysis for the three-factor model. D: Results of adjusted GMDR analysis for the three-factor model. Dark grey and light grey boxes correspond to the high- and low-risk genotype combinations, respectively. The black and white bars within each box correspond to cases and controls, respectively. The top number above each bar is number of individuals and the bottom number is the sum of scores for the corresponding group of individuals (cases or controls with particular three-locus genotype). The heights of the bars are proportional to the sum of scores in each group.

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