Abstract
PURPOSE. To genetically characterize a subphenotype of geographic atrophy (GA) in AMD associated with rapid progression and a diffuse-trickling appearance on fundus autofluorescence imaging. METHODS. Patients from the Fundus Autofluorescence in Age-Related Macular Degeneration Study were phenotyped for diffuse-trickling GA (dt-GA; n = 44). DNA was analyzed for 10 known AMD-associated genetic variants. A genetic risk score (GRS) was calculated and compared with patients with nondiffuse-trickling GA (ndt-GA; n = 311) and individuals from the 1000 genomes project (1000G; n = 267). Given the phenotypic overlap between diffusetrickling and late-onset retinal degeneration (LORD), all C1QTNF5 exons and their exon/ intron boundaries were sequenced. RESULTS. A statistically significant difference in allele frequencies between dt-GA and ndt-GA were found for CFH: rs1061170 and CFH: rs800292 (Pcorrected = 0.03). The ARMS2 variant rs10490924 was significantly more frequent in dt-GA than in 1000G individuals (Pcorrected < 0.01). The GRS of dt-GA patients was in-between the score of the 1000G individuals and that of patients with ndt-GA, significantly differing from both (Pcorrected <0.01). Sequencing of C1QTNF5 revealed 28 unique variants although none showed a statistically significant association with dt-GA when compared with 1000G individuals. CONCLUSIONS. The dt-GA phenotype shows a remarkably different genetic risk profile from other GA phenotypes secondary to AMD. Disease-associated C1QTNF5 mutations were not identified. Together, these results suggest that the dt-GA phenotype is associated with a genetic background substantially different from other GA phenotypes and underlines the necessity to refine the clinical phenotyping, specifically when aiming for individualized therapies in AMD.
Original language | English |
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Pages (from-to) | 2463-2471 |
Number of pages | 9 |
Journal | Investigative Ophthalmology and Visual Science |
Volume | 57 |
Issue number | 6 |
Early online date | 25 Mar 2016 |
DOIs | |
Publication status | Published - May 2016 |
Bibliographical note
AcknowledgmentsSupported by grants by the Deutsche Forschungsgemeinschaft (DFG-Germany Research Foundation, Bonn, Germany): Ho1926/3-1 (FGH), FL 658/4-1 (MF), and WE 1259/19-2 (BHFW), and the BONFOR program of the University of Bonn: O-137.0020 (ML; Bonn, Germany).
Keywords
- AMD
- C1QTNF5 gene
- Diffuse-trickling phenotype
- Fundus autofluorescence imaging
- Genetic risk factors
- Late-onset retinal degeneration