Alleles in Complement Factor D but Not Complement Factor B or Component 2 Contribute to Risk for Neovascular Age-Related Macular Degeneration

Abstract

Purpose: : To examine the contribution that the genes for complement factor D (CFD), complement component 2 (C2), and complement factor B (CFB) make to neovascular AMD pathophysiology. While C2 and CFB have been shown to be associated with all types of AMD, to date the CFD gene has not.

Methods: : We ascertained 136 unrelated patients with neovascular AMD who had one sibling with normal maculae and was past the age at which the index patient was diagnosed with neovascular AMD, i.e., 136 extremely discordant sibpairs. Genotyping of CFD, C2 and CFB was performed by directly sequencing the coding region, flanking exon/intron junctions and promoter regions. McNemar’s test was used for statistical analysis. For each SNP, we tested the effect of the rare allele in the homozygous state and in the heterozygous state compared to the common allele in the homozygous state.

Results: : Of the 23 variants we identified which included insertions and deletions, 6 were novel. Only the non coding C>A variant in CFD was found to be significantly associated with neovascular AMD if an individual had at a least one risk allele (O.R: 3.57, 95% CI: 1.5-9.8, P = .002). Although we found similar allele frequencies to those reported by others for rs9332739, rs547154, rs4151667, rs641153, rs2972633 in both our affected and unaffected siblings, no significant association was observed between C2 and CFB and neovascular AMD risk.

Conclusions: : Alleles in CFD may increase an individual’s risk of advanced AMD by nearly 3-fold. Variants in C2 and CFB do not appear to modify risk of neovascular AMD. To further clarify the contribution that CFD makes to AMD risk, haplotype analysis and investigation of possible allelic interactions with smoking and CFH is ongoing.

Keywords: age-related macular degeneration • clinical (human) or epidemiologic studies: risk factor assessment • gene screening