Rare variants in CFH and phenotype in Age-related Macular Degeneration in the Coimbra Eye Study.

Abstract

Purpose : To determine the associations between rare genetic variants in the complement factor H(CFH) and the phenotypic characteristics of age-related macular degeneration(AMD) patients from the Coimbra Eye Study(CES).

Methods : AMD patients from the Incidence Study(NCT02748824) underwent multimodal imaging: color fundus photography(CFP), spectral-domain optical coherence tomography(SD-OCT), fundus autofluorescence(FAF), near-infrared imaging(NIR). Phenotypic characterization of both eyes was performed in a centralized reading center. The coding and splice-site regions of the CFH gene were sequenced in collaboration with the EYERISK consortium. Variants with MAF<0.05 resulting in splice-site or protein change(nonsynonymous) were selected. Differences in phenotypic features between carriers and noncarriers were analyzed using generalized estimated equations logistic regression models, considering inter-eye correlations and controlling for age, sex and AMD stage.

Results : We included 39 eyes of 23 carriers and 284 eyes of 188 noncarriers. Carrying rare CFH variants was associated with larger drusen areas in the inner ETDRS circle (OR,3.29[95%CI,1.16–8.98];p=0.025); and having a total area occupied by drusen of 10-50% in: inner ETDRS circle (OR,5.53[95%CI,1.63–18.82;p=0.006), outer ETDRS circle (OR,4.39[95%CI,1.10–17.49];p=0.036), and full ETDRS grid (OR,4.89[95%CI,1.17–20.37];p=0.024). In SD-OCT a lower total macular volume (OR,0.456[95%CI,0.254–0.946];p=0.034) and of the inner retinal layers (OR,0.490[95%CI,1.25–22.59];p=0.024) was more common in carriers. Despite not reaching statistical significance, hard drusen were more common in non-carriers, and intermediate/large drusen were more common in carriers. Plus, carriers had thinner choroids (208.7±83.8μm vs 228.3±87.7μm), larger pseudodrusen areas (7.89±16.8mm² vs 4.64±10.10mm²), and a trend of more pigment epithelial detachments (12.82% vs 3.17%, p=0.062) and hyperreflective foci (28.21% vs 15.85%, p=0.073).

Conclusions : We identified phenotypic differences between carriers and non-carriers of CFH variants in AMD patients. Carriers seem to present with more severe disease, including superior drusen burden and thinner retinas, independently of AMD stage. These patients are probably at increased risk for progression, and identification of such features could direct towards further genetic investigation if complement targeted therapies are to be pursued.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.