Dataset Information

Copy number variation in the complement factor H-related genes and age-related macular degeneration.

ABSTRACT: To determine the contribution of copy number variation (CNV) in the regulation of complement activation (RCA) locus to the development of age-related macular degeneration (AMD).A multiplex ligation-dependent probe amplification assay was developed to quantify the number of copies of CFH, CFHR3, CFHR1, CFHR4, CFHR2, and CFHR5 in humans. Subjects with (451) and without (362) AMD were genotyped using the assay, and the impact on AMD risk was evaluated.Eight unique combinations of copy number variation were observed in the 813 subjects. Combined deletion of CFHR3 and CFHR1 was protective (OR=0.47, 95% confidence interval 0.36-0.62) against AMD and was observed in 88 (82 [18.6%] with one deletion, 6 [1.4%] with two deletions) subjects with AMD and 127 (108 [30.7%] with one deletion, 19 [5.4%] with two deletions) subjects without AMD. Other deletions were much less common: CFH intron 1 (n=2), CFH exon 18 (n=2), combined CFH exon 18 and CFHR3 (n=1), CFHR3 (n=2), CFHR1 (n=1), combined CFHR1 and CFHR4 (n=15), and CFHR2 deletion (n=7, 0.9%). The combined CFHR3 and CFHR1 deletion was observed on a common protective haplotype, while the others appeared to have arisen on multiple different haplotypes.We found copy number variations of CFHR3, CFHR1, CFHR4, and CFHR2. Combined deletion of CFHR3 and CFHR1 was associated with a decreased risk of developing AMD. Other deletions were not sufficiently common to have a statistically detectable impact on the risk of AMD, and duplications were not observed.

SUBMITTER: Kubista KE

PROVIDER: S-EPMC3156785 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Copy number variation in the complement factor H-related genes and age-related macular degeneration.

Kubista Katharina E KE Tosakulwong Nirubol N Wu Yanhong Y Ryu Euijung E Roeder Jaime L JL Hecker Laura A LA Baratz Keith H KH Brown William L WL Edwards Albert O AO

Molecular vision 20110806

<h4>Purpose</h4>To determine the contribution of copy number variation (CNV) in the regulation of complement activation (RCA) locus to the development of age-related macular degeneration (AMD).<h4>Methods</h4>A multiplex ligation-dependent probe amplification assay was developed to quantify the number of copies of CFH, CFHR3, CFHR1, CFHR4, CFHR2, and CFHR5 in humans. Subjects with (451) and without (362) AMD were genotyped using the assay, and the impact on AMD risk was evaluated.<h4>Results</h4 ...[more]

PMID: 21850184

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Project description:PurposeThe 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.MethodsWe 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.ResultsThe 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.ConclusionsOur 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.

Dataset Information

Copy number variation in the complement factor H-related genes and age-related macular degeneration.

Publications

Copy number variation in the complement factor H-related genes and age-related macular degeneration.

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