title: Complement factor I and age-related macular degeneration.
abstract: OBJECTIVE
  The complement system has been implicated in the pathogenesis of age-related macular degeneration (AMD). Complement factor I (CFI) is a serum protease that inhibits all complement pathways. A previous multicenter study identified a single missense CFI mutation (p.Gly119Arg) in 20/3,567 (0.56%) of AMD cases versus 1/3,937 (0.025%) of controls, thus suggesting that this mutation confers a high risk of AMD. A second CFI mutation, p.Gly188Ala, was identified in one patient with AMD.
  
  
  METHODS
  We screened 521 unrelated AMD cases and 627 controls for the p.Gly119Arg and p.Gly188Ala variants. All participants were Caucasian and >55 years, and recruited through Southampton Eye Unit or research clinics in Guernsey. All participants underwent dilated fundal examination by an experienced retinal specialist. SNP assays were performed using KASP™ biochemistry.
  
  
  RESULTS
  The p.Gly119Arg mutation was identified in 7/521 AMD cases compared to 1/627 age-matched controls (odds ratio [OR] = 8.47, confidence interval [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 or end-stage wet AMD and 3/267 dry AMD cases (1.1%). The p.Gly188Ala substitution was identified in 1/521 cases and 1/627 controls.
  
  
  CONCLUSIONS
  Our results identified a much higher frequency of heterozygosity for p.Gly119Arg in both cases and controls than in previous studies. Of note is that our sub-cohort from Guernsey had a particularly high frequency of p.Gly119Arg heterozygosity in affected individuals (4%) compared to our sub-cohort from the mainland (0.71%). Although these data support the conclusions of van de Ven et al. that the p.Gly119Arg substitution confers a high risk of AMD, our data suggest that this missense mutation is not as rare or as highly penetrant as previously reported. There was no difference in frequency for a second CFI variant, p.Gly188Ala, between the cases and the controls.
authors.affiliation: Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Alexander
authors.affiliation: Centre for Biological Sciences, Faculty of Natural and Environmental Studies University of Southampton, Southampton, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Gibson
authors.affiliation: Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Cree
authors.affiliation: Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ennis
authors.affiliation: Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lotery
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D017244:Complement Factor I / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index
chemical_list: D017244:Complement Factor I