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Clinical researchers on rare variants of the CFH gene has reported significant burden of disease among AMD patients

Researchers at the Association for Innovation and Biomedical Research on Light and Image (AIBILI), Coimbra, and the University of Coimbra, Portugal, has reported phenotypic differences between carriers and noncarriers of rare variants in the CFH (complement factor H) gene. According to the researchers, carriers of age-related macular degeneration (AMD) patients with rare variants of the CFH appeared to have more severe disease, superior drusen burden, pigment epithelial detachments  (PEDs) and thinner retinas. In addition, the rare variant of P258L (nucleotide change of C773T) may be associated with subretinal drusenoid deposits (SDD) and carriers are probably at increased risk of progression.


While AMD is a complex multifactorial disease, characterised by environmental and genetic factors, a landmark genome-wide association study (GWAS) has previously identified 52 variants at 34 genomic regions associated with AMD – comprising 45 common variants and 7 rare variants. Common genetic variants located at the CFH and ARMS2/HTRA1 loci are well known however, a significant burden of rare variants have been observed in the CFH and CFI (complement factor 1), and these genes may confer a high risk of disease.  In the current Coimbra Eye Study, researchers 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 ETDRS circle (odds ratio [OR], 5.44 [95% confidence interval, 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 analysis, 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 (OR, 5.24 [95% CI, 1.08–25.44]; P = 0.04) were associated with carrying a rare CFH variant. Finally, carriers with subretinal drusenoid deposits (SDD) had the rare variant P258L in all cases except one.


In summary from the results, the researchers concluded that, “we identified phenotypic differences between carriers and noncarriers of rare CFH variants in AMD patients. Carriers 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. This can be especially relevant if complement-targeted therapies and genetic-based therapies are to be pursued in the future”.