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Geographic Atrophy in Patients with Age-Related Macular Degeneration Is Associated with Rare Variants in Complement
Anita de Breuk1, Sarah de Jong1, Bjorn Bakker1
1Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands.
Insights
Rare variants in complement factor H (CFH) and complement factor I (CFI) genes are linked to a more severe age-related macular degeneration (AMD) phenotype, including geographic atrophy at an earlier age.
Area of Science:
- Ophthalmology
- Genetics
- Complement System
Background:
- Age-related macular degeneration (AMD) is a leading cause of vision loss.
- Genetic factors, particularly in the complement pathway, play a significant role in AMD pathogenesis.
- Rare variants in complement factor H (CFH) and complement factor I (CFI) genes are implicated in AMD, but their specific phenotypic associations require detailed description.
Purpose of the Study:
- To characterize the clinical phenotype of patients with age-related macular degeneration (AMD) who carry rare genetic variants in the complement factor H (CFH) and complement factor I (CFI) genes.
- To compare the phenotypic features of AMD carriers of rare CFH/CFI variants with non-carriers.
Main Methods:
- A cross-sectional study involving 234 AMD patients with rare CFH variants and 234 AMD patients with rare CFI variants, compared against 234 AMD non-carriers.
- Genetic data from the European Genetic Database were filtered for rare coding and splice-site variants in CFH and CFI.
- Phenotypic characteristics were assessed from color fundus photographs using the Rotterdam Classification and analyzed using generalized estimating equations with logistic regression, with Bonferroni correction.
Main Results:
- Carriers of rare pathogenic CFH variants showed associations with geographic atrophy, intermediate AMD, drusen type, drusen size, and drusen area.
- Carriers of rare pathogenic CFI variants were associated with geographic atrophy, intermediate AMD, drusen size, drusen area, and pigmentation.
- CFH variant carriers were younger and had a lower genetic risk score for common AMD variants compared to non-carriers.
Conclusions:
- Patients with AMD carrying rare variants in CFH and CFI exhibit a distinct, more severe drusen phenotype and a higher frequency of geographic atrophy at an earlier age.
- Identifying this specific phenotype can help in selecting individuals likely to benefit from complement-inhibiting therapies.
- These findings highlight the critical role of rare variants in CFH and CFI in AMD progression and suggest potential therapeutic targets.
Purpose:
To describe the phenotype of patients with age-related macular degeneration (AMD) carrying rare genetic variants in the complement factor H (CFH) and complement factor I (CFI) genes.
Design:
Cross-sectional study.
Participants:
Two hundred thirty-four patients with AMD carrying rare variants in CFH (n = 134) and CFI (n = 100) and 234 AMD noncarriers.
Methods:
Genetic data of patients with AMD from the European Genetic Database were filtered for rare coding and splice-site variants in CFH and CFI. For each carrier, an age-matched (±2 years) patient with AMD without rare variants in CFH and CFI (noncarrier) was selected. Phenotypic characteristics on color fundus photographs were graded according to the Rotterdam Classification and compared between carriers and noncarriers by univariate generalized estimating equations with binary logistic regression analyses, applying a Bonferroni correction for multiple comparisons. We performed subanalyses for pathogenic rare variants only, and we analyzed CFH and CFI carriers separately.
Main Outcome Measures:
Phenotypic characteristics on color fundus photographs.
Results:
Geographic atrophy and intermediate AMD, along with features such as predominant drusen type, largest drusen size, and drusen area, were associated with carriership of rare pathogenic variants in CFH (P < 0.001, P = 0.002, P < 0.001, and P < 0.001, respectively). Geographic atrophy and intermediate AMD, along with features such as drusen size, drusen area, and pigmentation, were associated with carriership of rare pathogenic variants in CFI (P = 0.01, P = 0.006, P < 0.001, and P = 0.006, respectively). Furthermore, carriers of rare pathogenic variants in CFH were younger (P < 0.001) and had a lower genetic risk score for common AMD-associated variants compared with noncarriers (mean [standard deviation] genetic risk score 0.83 [1.01] vs. 1.41 [1.21], P = 0.03).
Conclusions:
In this study, patients with AMD carrying rare variants in CFH and CFI had a more severe drusen phenotype, and a higher frequency of geographic atrophy at a relatively early age. Identifying this distinct phenotype could aid in pinpointing individuals who are more likely to benefit from complement-inhibiting therapies.
Financial Disclosures:
The authors have no proprietary or commercial interest in any materials discussed in this article.
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