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Complement factor I and age-related macular degeneration.

AbstractPURPOSE:
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.
AuthorsPhilip Alexander, Jane Gibson, Angela J Cree, Sarah Ennis, Andrew J Lotery
JournalMolecular vision (Mol Vis) Vol. 20 Pg. 1253-7 ( 2014) ISSN: 1090-0535 [Electronic] United States
PMID25352734 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Complement Factor I
Topics
  • Aged
  • Aged, 80 and over
  • Case-Control Studies
  • Complement Factor I (genetics)
  • Female
  • Genetic Predisposition to Disease
  • Heterozygote
  • Humans
  • Macular Degeneration (genetics, pathology)
  • Male
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Severity of Illness Index

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