Rare genetic variants in the CFI gene are associated with advanced age-related macular degeneration and commonly result in reduced serum factor I levels.
Rare genetic variants in the CFI gene are associated with advanced age-related macular degeneration and commonly result in reduced serum factor I levels.
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DOI：
10.1093/hmg/ddv091
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发表时间：
2015-07-01
影响因子：
3.5
通讯作者：
Seddon JM
中科院分区：
文献类型：
--
作者：
Kavanagh D;Yu Y;Schramm EC;Triebwasser M;Wagner EK;Raychaudhuri S;Daly MJ;Atkinson JP;Seddon JM
为了评估年龄相关性黄斑变性（AMD）的潜在诊断和治疗生物标志物，我们对2266名AMD患者和1400名非AMD患者的补体因子I基因（CFI）进行了测序，确定了231名具有罕见遗传变异的个体。我们通过测量具有和不具有罕见CFI变体的个体的循环血清因子I（FI）蛋白水平来评估功能影响。CFI中非常罕见（频率<1/1000）变异的负担与疾病密切相关（P = 1.1 × 10−8）。此外，我们检查了8个计数≥5的编码变体，并在3个变体中发现了与AMD相关的证据。携带罕见CFI变异的晚期AMD患者与携带该变异的非AMD受试者相比，其平均FI较低（P < 0.001）。进一步的新证据表明，FI水平驱动AMD风险来自分析，显示具有CFI罕见变异和低FI的个体更有可能患有晚期AMD（P = 5.6 × 10−5）。控制协变量后，低FI增加了变异患者中晚期AMD的风险，与未患晚期AMD且伴有罕见CFI变异的个体相比（OR 13.6，P = 1.6 × 10−4），也与未患罕见CFI变异的对照个体相比（OR 19.0，P = 1.1 × 10−5）。因此，低FI水平与罕见的CFI变体和AMD密切相关。增强FI活性可能具有治疗作用，测量FI提供了一种筛选工具，用于识别最有可能从补体抑制治疗中受益的患者。
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.
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DOI：
10.4049/jimmunol.0804031
发表时间：
2009-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ferreira VP;Herbert AP;Cortés C;McKee KA;Blaum BS;Esswein ST;Uhrín D;Barlow PN;Pangburn MK;Kavanagh D
通讯作者：
Kavanagh D
影响因子：
8.8
作者：
Le Quintrec, M.;Lionet, A.;Fremeaux-Bacchi, V.
通讯作者：
Fremeaux-Bacchi, V.
影响因子：
4.6
作者：
Lay, E.;Nutland, S.;Lachmann, P. J.
通讯作者：
Lachmann, P. J.
影响因子：
5.2
作者：
Fagerness, Jesen A.;Maller, Julian B.;Seddon, Johanna M.
通讯作者：
Seddon, Johanna M.
影响因子：
30.8
作者：
Fritsche, Lars G.;Chen, Wei;Schu, Matthew;Yaspan, Brian L.;Yu, Yi;Thorleifsson, Gudmar;Zack, Donald J.;Arakawa, Satoshi;Cipriani, Valentina;Ripke, Stephan;Igo, Robert P., Jr.;Buitendijk, Gabrielle H. S.;Sim, Xueling;Weeks, Daniel E.;Guymer, Robyn H.;Merriam, Joanna E.;Francis, Peter J.;Hannum, Gregory;Agarwal, Anita;Armbrecht, Ana Maria;Audo, Isabelle;Aung, Tin;Barile, Gaetano R.;Benchaboune, Mustapha;Bird, Alan C.;Bishop, Paul N.;Branham, Kari E.;Brooks, Matthew;Brucker, Alexander J.;Cade, William H.;Cain, Melinda S.;Campochiaroll, Peter A.;Chan, Chi-Chao;Cheng, Ching-Yu;Chew, Emily Y.;Chin, Kimberly A.;Chowers, Itay;Clayton, David G.;Cojocaru, Radu;Conley, Yvette P.;Cornes, Belinda K.;Daly, Mark J.;Dhillon, Baljean;Edwards, Albert;Evangelou, Evangelos;Fagemess, Jesen;Ferreyra, Henry A.;Friedman, James S.;Geirsdottir, Asbjorg;George, Ronnie J.;Gieger, Christian;Gupta, Neel;Hagstrom, Stephanie A.;Harding, Simon P.;Haritoglou, Christos;Heckenlively, John R.;Hoz, Frank G.;Hughes, Guy;Ioannidis, John P. A.;Ishibashi, Tatsuro;Joseph, Peronne;Jun, Gyungah;Kamatani, Yoichiro;Katsanis, Nicholas;Keilhauer, Claudia N.;Khan, Jane C.;Kim, Ivana K.;Kiyohara, Yutaka;Klein, Barbara E. K.;Klein, Ronald;Kovach, Jaclyn L.;Kozak, Igor;Lee, Clara J.;Lee, Kristine E.;Lichtner, Peter;Lotery, Andrew J.;Meitinger, Thomas;Mitchell, Paul;Mohand-Saied, Saddek;Moore, Anthony T.;Morgan, Denise J.;Morrison, Margaux A.;Myers, Chelsea E.;Naj, Adam C.;Nakamura, Yusuke;Okada, Yukinori;Orlin, Anton;Ortube, M. Carolina;Othman, Mohammad I.;Pappas, Chris;Park, Kyu Hyung;Pauer, Gayle J. T.;Peachey, Neal S.;Poch, Olivier;Priya, Rinki Ratna;Reynolds, Robyn;Richardson, Andrea J.;Ripp, Raymond;Rudolph, Guenther;Ryu, Euijung;Sahel, Jose-Alain;Schaumberg, Debra A.;Scholl, Hendrik P. N.;Schwartz, Stephen G.;Scott, William K.;Shahid, Humma;Sigurdsson, Haraldur;Silvestri, Giuliana;Sivakumaran, Theru A.;Smith, R. Theodore;Sobrin, Lucia;Souied, Eric H.;Stambolian, Dwight E.;Stefansson, Hreinn;Sturgill-Short, Gwen M.;Takahashi, Atsushi;Tosakulwong, Nirubol;Truitt, Barbara J.;Tsironi, Evangelia E.;Uitterlinden, Andre G.;van Duijn, Cornelia M.;Vijaya, Lingam;Vingerling, Johannes R.;Vithana, Eranga N.;Webster, Andrew R.;Wichmann, H-Erich;Winkler, Thomas W.;Wong, Tien Y.;Wright, Alan F.;Zelenika, Diana;Zhang, Ming;Zhao, Ling;Zhang, Kang;Klein, Michael L.;Hageman, Gregory S.;Lathrop, G. Mark;Stefansson, Kari;Allikmets, Rando;Baird, Paul N.;Gorin, Michael B.;Wang, Jie Jin;Klaver, Caroline C. W.;Seddon, Johanna M.;Pericak-Vance, Margaret A.;Iyengar, Sudha K.;Yates, John R. W.;Swaroop, Anand;Weber, Bernhard H. F.;Kubo, Michiaki;DeAngelis, Margaret M.;Leveillard, Thierry;Thorsteinsdottir, Unnur;Haines, Jonathan L.;Farrer, Lindsay A.;Heid, Iris M.;Abecasis, Goncalo R.
通讯作者：
Abecasis, Goncalo R.