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

Bert Gold¹, Joanna E Merriam², Jana Zernant², Lisa S Hancox³, Andrew J Taiber³, Karen Gehrs³, Kevin Cramer⁴, Julia Neel⁴, Julie Bergeron⁵, Gaetano R Barile², R Theodore Smith², Gregory S Hageman³, Michael Dean¹ & Rando Allikmets^2, 6

¹  Laboratory of Genomic Diversity, National Cancer Institute, Frederick, Maryland 21702, USA.

²  Department of Ophthalmology, Columbia University, New York, New York 10032, USA.

³  Department of Ophthalmology and Visual Sciences, Center for Macular Degeneration, University of Iowa, Iowa City, Iowa 52240, USA.

⁴  Sapio Sciences LLC, York, Pennsylvania 17402, USA.

⁵  SAIC-Frederick, Frederick, Maryland 21702, USA.

⁶  Department of Pathology & Cell Biology, Columbia University, New York, New York 10032, USA.

The AMD Genetics Clinical Study Group: The AMD Genetics Clinical Study Group includes Stanley Chang⁷, Lawrence A. Yannuzzi⁷, John C. Merriam⁷, Irene Barbazetto⁷, Leonid E. Lerner⁸, Stephen Russell⁹, Jamal Hoballah⁹, Jill Hageman⁹ & Heather Stockman⁹

⁷  Department of Ophthalmology, Columbia University, New York

⁸  F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia

⁹  Department of Ophthalmology and Visual Sciences, Center for Macular Degeneration, University of Iowa, Iowa City, Iowa, USA

Age-related macular degeneration (AMD) is the most common form of irreversible blindness in developed countries^{1, 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 AMD^{3, 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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