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

Abstract

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 histo-compatibility 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.Correspondence should be addressed to R.A. (rla22@columbia.edu) or M.D. (dean@ncifcrf.gov). Note: Supplementary information is available on the Nature Genetics website. AUTHOR CONTRIBUTION STATEMENTThe AMD Genetics Clinical Study Group includes Stanley Chang, Lawrence A. Yannuzzi, John C. Merriam and Irene Barbazetto (Department of Ophthalmology, Columbia University, New York); Leonid E. Lerner (F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia) and Stephen Russell, Jamal Hoballah, Jill Hageman and Heather Stockman (Department of Ophthalmology and Visual Sciences, Center for Macular Degeneration, University of Iowa, Iowa City, Iowa, USA). COMPETING INTERESTS STATEMENTThe authors declare competing financial interests (see the Nature Genetics website for details).Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/ NIH Public Access Inflammation has a central role in the pathobiology of AMD 9-14 . Dysfunction of the complement pathway is proposed to induce significant damage to macular cells, leading to atrophy, degeneration and the elaboration of choroidal neovascular membranes 3,[15][16][17] . Activation of the alternative pathway is initiated by cleavage of C3b-bound factor B (BF), resulting in the formation of the C3Bb complex (C3 convertase). This complex is stabilized by properdin, whereas its dissociation is accelerated by regulatory proteins, including complement factor H (CFH), the major inhibitor of the alternative complement pathway. As CFH haplotypes are associated with AMD 3 , we hypothesized that the same may be true for activators of the same pathway, such as complement factor B (BF). BF and compl...

Classical complement activation and acquired immune response pathways are not essential for retinal degeneration in the rd1 mouse

“…Recent genetic evidence has strongly implicated polymorphisms in the complement control protein factor H (Edwards et al 2005;Hageman et al 2005;Haines et al 2005;Klein et al 2005;Umeda et al 2005) and factor B (Gold et al 2006) as major risk (or, depending on the polymorphism, protective) factors for AMD. Based on these results, it has been proposed that inadequate control of complement-driven immune-response may be an important factor in the pathogenesis of AMD.…”

“…Local inflammation may not only be involved in the formation of drusen, a hallmark of AMD (Hageman et al 2001;Johnson et al 2002) but inflammation triggered by the debris generated by dying RPE cells may also lead to photoreceptor cell death and loss of vision (Johnson et al 2002). Furthermore, mutations in complement factor H and factor B were shown to significantly increase the risk to develop age-related macular degeneration (AMD) (Edwards et al 2005;Hageman et al 2005;Haines et al 2005;Klein et al 2005;Umeda et al 2005;Gold et al 2006). Topographical analysis of retinas affected by AMD revealed that rod cell death precedes cone cell death (Curcio 2001).…”

HTRA1 Variant Confers Similar Risks to Geographic Atrophy and Neovascular Age-related Macular Degeneration

“…AMD risk associated variants in genes encoding alternative complement pathway members include CFH (complement factor H), and factor B/C2. 2,[19][20][21][22] Together, CFH Together, CFH and HTRA1 confer a major risk in AMD patients with an estimated population attributable risk of 75%. .…”

Clusterin in the eye: An old dog with new tricks at the ocular surface

“…They are comprised of carbohydrates, zinc, and proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease, and include CLU and other apolipoproteins, as well as complement components [86][87][88][89][90][91][92][93]. DNA sequence variants in several complement proteins found in drusen are associated with increased disease risk [94][95][96][97], but no variants in CLU have yet been associated with disease. [98].…”