Abstract | PURPOSE: 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.
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Authors | Philip Alexander, Jane Gibson, Angela J Cree, Sarah Ennis, Andrew J Lotery |
Journal | Molecular vision
(Mol Vis)
Vol. 20
Pg. 1253-7
( 2014)
ISSN: 1090-0535 [Electronic] United States |
PMID | 25352734
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
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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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