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Erin Wagner, David Kavanagh, Yi Yu, Elizabeth Schramm, Michael Triebwasser, Soumya Raychaudhuri, Mark Daly, John Atkinson, Johanna M Seddon; Rare genetic variants in the CFI gene are associated with advanced age-related macular degeneration and commonly result in reduced serum Factor I level. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):782.
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Age-related macular degeneration (AMD) is a common disease with multifactorial etiology. In addition to behavioral and environmental factors, several common genetic loci have been associated with advanced AMD (aAMD), including many in the complement system. Investigators recently identified the association of rare genetic variants in the complement factor I gene (CFI) with aAMD (Seddon et al. Nat Gen 2013; van de Ven et al. Nat Gen 2013). The Factor I protein (FI) is a serum serine protease that is a critical mediator of complement regulation by cleaving C3b and C4b in the presence of its cofactors. We assessed serum FI as a potential diagnostic and therapeutic biomarker for aAMD.
We sequenced the CFI gene in 2,266 individuals with aAMD and 1,400 without AMD, identifying 231 individuals with rare genetic variants. We evaluated the functional impact by measuring circulating FI protein levels in a subgroup with and without rare CFI variants.
In the targeted sequencing study, 71 unique non-synonymous CFI variants were detected. The burden of very rare (frequency < 1/1000) variants in CFI is strongly associated with aAMD (P=1.1x10-8). We examined 8 rare coding variants with counts ≥5 and saw evidence for association with aAMD in 3 variants: 2 risk variants (p.P553S, odds ratio [OR] 2.69, P=0.027; p.A240G, OR 7.43, P=0.023) and 1 protective variant (p.R406H, OR 0.10, P=0.015). Individuals with aAMD carrying a rare CFI variant had lower mean serum FI compared to non-AMD subjects without a variant (P< 0.001). Further new evidence that FI levels drive aAMD risk is derived from analyses showing individuals with a CFI rare variant and low FI were more likely to have aAMD (P=5.6 x 10-5). Controlling for covariates, low serum FI strongly increased the risk of aAMD among those with a variant compared to non-AMD subjects with and without a variant (OR 13.6, P=1.6 x 10-4; OR 19.0, P=1.1 x 10-5, respectively).
Low serum FI levels are strongly associated with rare CFI variants and aAMD. Identification of individuals with CFI mutations associated with low FI levels will allow targeting of those most likely to benefit from complement inhibitory therapy and pave the way for personalized medicine in AMD.
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