Purchase this article with an account.
Philip Alexander, Jane Gibson, Angela Cree, Sarah Ennis, Andrew Lotery; Complement Factor I and Age Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2211.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
The complement system has been implicated in the pathogenesis of Age-related Macular Degeneration (AMD). Complement Factor I (CFI) is a serum protease capable of inhibiting all complement pathways. Seddon et al (Nat Genet 2013) showed that rare missense variants in CFI are more common in AMD cases than controls (7.8% vs. 2.3%), but were unable to identify individual CFI variants associated with AMD. In contrast, van de Ven et al (Nat Genet 2013) found a single missense CFI mutation (p.Gly119Arg) in 20/3567 AMD cases vs. 1/3938 controls, thereby conferring a high risk for AMD. A second CFI mutation, p. Gly188Ala, was identified in one AMD patient and three affected family members, but not in 809 unrelated AMD cases.
We screened 521 unrelated AMD cases and 627 controls for the p.Gly119Arg and p.Gly188Ala variants. All participants were white, >55 years, and recruited through Southampton Eye Unit or research clinics in Guernsey. All participants underwent dilated fundal examination by an experienced retinal specialist (AL). SNP assays were performed using KASPar biochemistry (LGC genomics). Recruitment was approved by Southampton and Southwest Hants local research ethics committee and followed the tenets of the Declaration of Helsinki.
These data support a significant excess of the allele in CFI encoding p. Gly119Arg in AMD cases compared to age-matched controls (OR 8.47, CI 1.04-69.00, p=0.027). There was a varied phenotype among the seven cases with the mutation, which was present in 4/254 (1.6%) cases with active/end-stage wet AMD, and 3/267 dry AMD cases (1.1%). Table 1 compares our results to those reported by van de Ven et al. The p.Gly188Ala substitution was identified in 1/521 cases and 1/627 controls.
Our results identified a much higher prevalence of heterozygosity for p.Gly119Arg in both cases and controls than in the cohort reported by van de Ven. Of note is that our sub-cohort from Guernsey has a particularly high prevalence of p.Gly119Arg heterozygosity in affected individuals compared to our sub-cohort from the mainland. These data support the conclusions of van de Ven that the p. Gly119Arg substitution is rare, highly penetrant and confers a high risk of AMD. However, our data suggest that this missense mutation is not as rare nor as highly penetrant as previously reported. There was no difference in prevalence for a second CFI variant, p.Gly188Ala, between cases and controls.
This PDF is available to Subscribers Only