Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration


Age-related macular degeneration (AMD) is the most common form of irreversible blindness in developed countries1,2. Variants in the factor H gene (CFH, also known as HF1), which encodes a major inhibitor of the alternative complement pathway, are associated with the risk for developing AMD3,4,5,6,7,8. Here we test the hypothesis that variation in genes encoding other regulatory proteins of the same pathway is associated with AMD. We screened factor B (BF) and complement component 2 (C2) genes, located in the major histocompatibility complex class III region, for genetic variation in two independent cohorts comprising 900 individuals with AMD and 400 matched controls. Haplotype analyses identify a statistically significant common risk haplotype (H1) and two protective haplotypes. The L9H variant of BF and the E318D variant of C2 (H10), as well as a variant in intron 10 of C2 and the R32Q variant of BF (H7), confer a significantly reduced risk of AMD (odds ratio = 0.45 and 0.36, respectively). Combined analysis of the C2 and BF haplotypes and CFH variants shows that variation in the two loci can predict the clinical outcome in 74% of the affected individuals and 56% of the controls. These data expand and refine our understanding of the genetic risk for AMD.

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Figure 1: Diagram and haplotype analysis of SNPs in BF and C2.
Figure 2: Combined complement gene analyses.
Figure 3: Immunolocalization of proteins along the retinal pigment epithelium (RPE)-choroid (Ch) complex in sections from an unfixed eye of a 72-year-old donor with early-stage AMD.

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We thank D. Anderson, L. Johnson, D. Bok, and P. Dudley for helpful discussions. We also acknowledge J. Sharp, T. Krezowik, T. Weingeist, C. Boldt, J. Folk, T. Johnson, M. Wilkinson, D. Zumbro, P. Gouras, W. Moscoso, C. McAvoy, S. Thompson, L. Arbisser and A. Arbisser for their assistance in recruiting patients; S. Baruah, R. Wolfe, S. McCormick, J. Donahue, A. Olsh, L. Buckta and M. Busuioc for technical assistance and Vision Share, the Iowa Lions Eye Bank and the Central Florida Lions Eye Banks for their efforts in procuring eyes from human donors. We are especially grateful to those individuals and families who unselfishly donated their time and/or the eyes of their loved ones to this research program. This work was supported in part by the US National Institutes of Health (NIH) (grants EY13435 (R.A.) and EY11515 (G.S.H.)), New York Community Trust (R.T.S.), Wallach Foundation (R.A., G.R.B.), Elyachar Foundation (R.A., G.R.B.), Kaplen Foundation (R.A., G.R.B.), Widgeon Point Charitable Foundation (R.A., J.E.M.), Macula Foundation (R.A.), the International Retina Research Foundation (G.S.H.), the American Macular Degeneration Foundation, Inc. (G.S.H.), the Eye Research Institute (G.S.H.), the Intramural Research Program of the NIH and the National Cancer Institute; by federal funds from the National Cancer Institute of the National Institutes of Health (contract NO1-CO-124000) and by unrestricted grants from Research to Prevent Blindness, Inc., to the University of Iowa Department of Ophthalmology and Visual Sciences and to the Department of Ophthalmology, Columbia University. G.S.H. currently holds an honorary professorship in the School of Medicine, Queen's University, Belfast. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.

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Correspondence to Michael Dean or Rando Allikmets.

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K.C. and J.N. are employees of Sapio Sciences LLC, York, Pennsylvania, USA.

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The AMD Genetics Clinical Study Group includes

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Supplementary Fig. 1

Linkage disequilibrium map of the complement region. (PDF 298 kb)

Supplementary Methods (PDF 360 kb)

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Gold, B., Merriam, J., Zernant, J. et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet 38, 458–462 (2006).

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