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 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.