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The Coimbra Eye Study has identified phenotypic differences between carriers and non-carriers of rare variants of the CFH gene

Researchers at the Coimbra Institute for Clinical and Biomedical Research, University of Coimbra, Portugal, have reported a clear association between rare genetic variants in complement factor H (CFH), and phenotypic features in age-related macular degeneration (AMD).  The study showed significant differences between carriers and non-carriers of rare variants in CFH, indicating more severe disease, superior drusen burden, pigment epithelial detachments and thinner retinas in patients with AMD. The researchers reported that the rare variant P258L may be associated with subretinal drusenoid deposits and these patients may be at increased risk of disease progression.


The Coimbra Eye Study (CES) is an epidemiologic study for the estimation of prevalence and 6.5-year incidence of AMD in a Portuguese population.  AMD is a complex multifactorial disease, influenced by demographic, environmental and genetic factors and the objective in this recent research was to explore rare variants in the CFH gene, and in particular to their relationship with the phenotype of AMD patients.  The study used methods for standard ophthalmic exams, colour fundus photography, SD-OCT, FAF, next-generating sequencing (NGS) and other analyses.  The results of the study recruited 23 patients carrying rare CFH variants, compared to assessing 188 non-carriers of the rare CFH variants.  The outcomes indicated that drusen (in the ETDRS grid) reported inner circle of an odds ratio (OR) of 5.44, an outer circle OR of 4.37, and an all subfields OR of 4.82. In addition, SD-OCT, showed that carrier patients had a lower total macular volume (OR, 0.449) and lower inner retinal layers’ volume (OR, 0.496), and pigment epithelial detachments (PEDs) (OR, 5.24).  Commenting on the study, the Portuguese researchers stated that, “the AMD phenotype characterized by thinner choroid and SDD seems to be more common in carriers of rare CFH variants, namely the association of SDD (subretinal drusenoid deposits) with the P258L variant, as well as having MNV (macular neovascularization) in late stages, although these differences did not reach statistical significance in our analyzed population”.


In summary, the research published in the journal Investigative Ophthalmology & Visual Science (IOVS, 2022;63[9]:5.) showed that there were clear phenotypic differences between carriers and noncarriers of rare CFH variants in AMD patients, including the SD-OCT quantification from inner retinal layers, as described for the first time of the correlation. The researchers concluded that carriers of rare variants of CFH “presented with more severe disease, including superior drusen burden in the macula, PEDs, hyperreflective foci, and thinner retinas, mainly at the level of the inner retinal layers. Our results also suggest that exudative late AMD and the phenotype of SDD with thin choroid seem to be more prevalent in carriers, which was especially true for those carrying the variant P258L. These patients might be at increased risk of progression, and identification of such features can help in the selection of those who could benefit from genetic investigation”.