title: Rare genetic variants in the CFI gene are associated with advanced age-related macular degeneration and commonly result in reduced serum factor I levels.
abstract: To assess a potential diagnostic and therapeutic biomarker for age-related macular degeneration (AMD), we sequenced the complement factor I gene (CFI) in 2266 individuals with AMD and 1400 without, identifying 231 individuals with rare genetic variants. We evaluated the functional impact by measuring circulating serum factor I (FI) protein levels in individuals with and without rare CFI variants. The burden of very rare (frequency <1/1000) variants in CFI was strongly associated with disease (P = 1.1 × 10(-8)). In addition, we examined eight coding variants with counts ≥5 and saw evidence for association with AMD in three variants. Individuals with advanced AMD carrying a rare CFI variant had lower mean FI compared with non-AMD subjects carrying a variant (P < 0.001). Further new evidence that FI levels drive AMD risk comes from analyses showing individuals with a CFI rare variant and low FI were more likely to have advanced AMD (P = 5.6 × 10(-5)). Controlling for covariates, low FI increased the risk of advanced AMD among those with a variant compared with individuals without advanced AMD with a rare CFI variant (OR 13.6, P = 1.6 × 10(-4)), and also compared with control individuals without a rare CFI variant (OR 19.0, P = 1.1 × 10(-5)). Thus, low FI levels are strongly associated with rare CFI variants and AMD. Enhancing FI activity may be therapeutic and measuring FI provides a screening tool for identifying patients who are most likely to benefit from complement inhibitory therapy.
authors: Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, UK.
authors: David
authors: D
authors: Kavanagh
authors: Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, MA, USA.
authors: Yi
authors: Y
authors: Yu
authors: Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors: Elizabeth C
authors: EC
authors: Schramm
authors: Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors: Michael
authors: M
authors: Triebwasser
authors: Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, MA, USA.
authors: Erin K
authors: EK
authors: Wagner
authors: Partners HealthCare Center for Personalized Genetic Medicine, Boston, MA, USA, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA, Division of Genetics, Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA, USA, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
authors: Soumya
authors: S
authors: Raychaudhuri
authors: Partners HealthCare Center for Personalized Genetic Medicine, Boston, MA, USA, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA, Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
authors: Mark J
authors: MJ
authors: Daly
authors: Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors: John P
authors: JP
authors: Atkinson
authors: Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, MA, USA, Department of Ophthalmology, Tufts University School of Medicine, Boston, MA, USA and Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, USA jseddon@tuftsmedicalcenter.org.
authors: Johanna M
authors: JM
authors: Seddon
mesh_terms: D017244:Complement Factor I / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005340:Fibrinogen / Q000378:metabolism*; D014644:Genetic Variation; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male
chemical_list: D005340:Fibrinogen; C493611:CFI protein, human; D017244:Complement Factor I