4.5 Article

Rare genetic variants in the CFI gene are associated with advanced age-related macular degeneration and commonly result in reduced serum factor I levels

Journal

HUMAN MOLECULAR GENETICS
Volume 24, Issue 13, Pages 3861-3870

Publisher

OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddv091

Keywords

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Funding

  1. National Institute of Health [R01-EY11309, K08AR055688, U01HG0070033, F30HL103072, R01-AI041592, U54 HL112303]
  2. Edward N. & Della L. Thome Memorial Foundation
  3. Doris Duke Clinical Scientist Development Award
  4. Protein Core Facility of the Rheumatic Diseases Core by National Institute of Arthritis and Musculoskeletal and Skin Diseases part of the National Institutes of Health [P30 AR48335]
  5. Massachusetts Lions Eye Research Fund, Inc.
  6. Foundation Fighting Blindness
  7. Research to Prevent Blindness
  8. American Macular Degeneration Foundation
  9. Macular Degeneration Research Fund of the Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine
  10. Fight for Sight
  11. Wellcome Trust

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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 x 10(-8)). In addition, we examined eight coding variants with counts a parts per thousand yen5 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 x 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 x 10(-4)), and also compared with control individuals without a rare CFI variant (OR 19.0, P = 1.1 x 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.

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