C 2 and CFB Genes in Age-Related Maculopathy and Joint Action with CFH and LOC 387715 Genes

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 CFHLOC387715 model is statistically significant. Citation: Jakobsdottir J, Conley YP, Weeks DE, Ferrell RE, Gorin MB (2008) C2 and CFB Genes in Age-Related Maculopathy and Joint Action with CFH and LOC387715 Genes. PLoS ONE 3(5): e2199. doi:10.1371/journal.pone.0002199 Editor: Michael Nicholas Weedon, Peninsula Medical School, United Kingdom Received December 7, 2007; Accepted April 11, 2008; Published May 21, 2008 Copyright: 2008 Jakobsdottir et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was supported by NEI grant R01EY009859, The Steinbach Foundation, New York, Research to Prevent Blindness, New York, the Eye and Ear Foundation of Pittsburgh, American Health Assistance Foundation, Clarksburg, Maryland, and the Jules Stein Eye Institute, Los Angeles, California (all to M.B.G.). Competing Interests: The authors are listed as the inventors in a patent filed by the University of Pittsburgh for the ARMS2 locus. * E-mail: gorin@jsei.ucla.edu