Genetic Risk in Families with Age-Related Macular Degeneration.
| Autor: | de Breuk A; Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands., Lechanteur YTE; Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands., Heesterbeek TJ; Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands., Fauser S; Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.; F. Hoffmann-La Roche, Basel, Switzerland., Klaver CCW; Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands.; Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.; Institute of Molecular and Clinical Ophthalmology, Basel, Switzerland., Hoyng CB; Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands., den Hollander AI; Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. |
|---|---|
| Jazyk: | angličtina |
| Zdroj: | Ophthalmology science [Ophthalmol Sci] 2021 Dec 06; Vol. 1 (4), pp. 100087. Date of Electronic Publication: 2021 Dec 06 (Print Publication: 2021). |
| DOI: | 10.1016/j.xops.2021.100087 |
| Abstrakt: | Purpose: To determine the contribution of common and rare genetic risk variants in families with age-related macular degeneration (AMD). Design: Case-control study. Participants: A family cohort (355 affected and 342 unaffected family members from 144 families with AMD) and an unrelated case-control cohort (1078 patients, 952 controls), recruited from the European Genetic Database. Methods: Genetic data of both cohorts were filtered for carriership of rare genetic variants in the coding and splice-site regions of the complement factor H ( CFH ) and complement factor I ( CFI ) genes, and 52 AMD-associated variants were extracted for calculation of genetic risk scores (GRS). To compare GRSs between familial and nonfamilial rare CFH and CFI variant carriers and noncarriers and between AMD disease stages, we performed a 2-way analysis of variance, with Bonferroni correction for multiple testing. Within families with AMD carrying rare CFH and CFI variants, we analyzed segregation patterns by calculating the proportion of affected among carriers. Main Outcome Measures: GRSs and segregation of rare CFH and CFI variants. Results: We observed higher GRSs in familial versus nonfamilial individuals without rare CFH and CFI variants: mean GRS, 1.76 (standard error [SE], 0.08) versus 0.83 (SE, 0.03; P < 0.001). In 51 of 144 families (35.4%), rare CFH and CFI variants were identified. Within the AMD family cohort, carriers of rare CFH and CFI variants showed lower GRSs compared with noncarriers (mean GRS, 1.05 [SE, 0.23] vs. 1.76 [SE, 0.08]; P = 0.02). The proportion of affected family members with a high GRS was 57.3% (176/307). Of the affected family members with a low or intermediate GRS, 40.0% carried rare CFH or CFI variants. Among carriers of 11 rare CFH or CFI variants, the proportion affected by AMD was more than 75%. Conclusions: Genetic risk in families with AMD often is attributed to high GRSs based on common variants. However, in part of the families with a low or intermediate GRS, rare CFH and CFI variants contributed to disease development. We recommend computing GRSs and sequencing the CFH and CFI genes in families with AMD, in particular in the light of ongoing gene-specific clinical trials. (© 2021 by the American Academy of Ophthalmology.) |
| Databáze: | MEDLINE |
| Externí odkaz: |
|