Purpose
To determine the association between rare genetic variants in complement factor H (
CFH
) and phenotypic features in age-related macular degeneration (AMD) patients from the Coimbra Eye Study (CES).
Methods
AMD patients from the Incidence CES (NCT02748824) underwent ophthalmologic examination and color fundus photography, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence, and near-infrared imaging. Multimodal phenotypic characterization was carried out in a centralized reading center. The coding and splice-site regions of the
CFH
gene were sequenced through single-molecule molecular inversion probe–based next-generation sequencing in association with the EYE-RISK consortium. Variants with minor allele frequency <0.05 resulting in splice-site or protein change were selected. Differences in phenotypic features between carriers and noncarriers were analyzed using generalized estimated equations logistic regression models, considering intereye correlations.
Results
We included 39 eyes of 23 patients carrying rare
CFH
variants and 284 eyes of 188 noncarriers. Carrier status was associated with having higher drusen burden in the macula in the inner Early Treatment Diabetic Retinopathy Study circle (odds ratio [OR], 5.44 [95% confidence interval {CI}, 1.61–18.37];
P
= 0.006), outer circle (OR, 4.37 [95% CI, 1.07–17.77];
P
= 0.04), and full grid (OR, 4.82 [95% CI, 1.13–20.52];
P
= 0.033). In SD-OCT, a lower total macular volume and lower inner retinal layers’ volume (OR, 0.449 [95% CI, 0.226–0.894];
P
= 0.023; OR, 0.496 [95% CI, 0.252–0.979];
P
= 0.043) and pigment epithelial detachments (PEDs) (OR, 5.24 [95% CI, 1.08–25.44];
P
= 0.04) were associated with carrying a rare
CFH
variant. Carriers with subretinal drusenoid deposits (SDD) had the rare variant P258L in all cases except one.
Conclusions
We identified in our cohort phenotypic differences between carriers and noncarriers of rare variants in the
CFH
gene. Carriers had more severe disease, namely superior drusen burden, PEDs, and thinner retinas. The rare variant P258L may be associated with SDD. Carriers are probably at increased risk of progression.