期刊
HUMAN MOLECULAR GENETICS
卷 24, 期 13, 页码 3861-3870出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddv091
关键词
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资金
- National Institute of Health [R01-EY11309, K08AR055688, U01HG0070033, F30HL103072, R01-AI041592, U54 HL112303]
- Edward N. & Della L. Thome Memorial Foundation
- Doris Duke Clinical Scientist Development Award
- 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]
- Massachusetts Lions Eye Research Fund, Inc.
- Foundation Fighting Blindness
- Research to Prevent Blindness
- American Macular Degeneration Foundation
- Macular Degeneration Research Fund of the Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine
- Fight for Sight
- Wellcome Trust
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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