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

被引:104
作者
Kavanagh, David [1 ]
Yu, Yi [2 ]
Schramm, Elizabeth C. [3 ]
Triebwasser, Michael [3 ]
Wagner, Erin K. [2 ]
Raychaudhuri, Soumya [4 ,5 ,6 ,7 ]
Daly, Mark J. [4 ,5 ,8 ]
Atkinson, John P. [3 ]
Seddon, Johanna M. [2 ,9 ,10 ]
机构
[1] Newcastle Univ, Int Ctr Life, Inst Med Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England
[2] Tufts Med Ctr, New England Eye Ctr, Ophthalm Epidemiol & Genet Serv, Boston, MA USA
[3] Washington Univ, Sch Med, Dept Med, Div Rheumatol, St Louis, MO 63110 USA
[4] Partners HealthCare Ctr Personalized Genet Med, Boston, MA USA
[5] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA
[6] Brigham & Womens Hosp, Div Genet Rheumatol Immunol & Allergy, Boston, MA 02115 USA
[7] Univ Manchester, Fac Med & Human Sci, Manchester, Lancs, England
[8] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA
[9] Tufts Univ, Sch Med, Dept Ophthalmol, Boston, MA 02111 USA
[10] Tufts Univ, Sackler Sch Grad Biomed Sci, Boston, MA 02111 USA
基金
美国国家卫生研究院; 英国惠康基金;
关键词
HEMOLYTIC-UREMIC SYNDROME; COMPLEMENT FACTOR-I; FACTOR-H; HIGH-RISK; MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS; CLINICAL PHENOTYPE; SYNDROME AHUS; MUTATIONS; ACTIVATION; CELLS;
D O I
10.1093/hmg/ddv091
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:3861 / 3870
页数:10
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