{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:58:43Z","timestamp":1791928723957,"version":"4.3.4"},"reference-count":44,"publisher":"Association for Research in Vision and Ophthalmology (ARVO)","issue":"6","license":[{"start":{"date-parts":[[2020,6,9]],"date-time":"2020-06-09T00:00:00Z","timestamp":1591660800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Invest. Ophthalmol. Vis. Sci."],"published-print":{"date-parts":[[2020,6,9]]},"DOI":"10.1167\/iovs.61.6.18","type":"journal-article","created":{"date-parts":[[2020,6,9]],"date-time":"2020-06-09T16:31:50Z","timestamp":1591720310000},"page":"18","source":"Crossref","is-referenced-by-count":59,"title":["Rare Genetic Variants in Complement Factor I Lead to Low FI Plasma Levels Resulting in Increased Risk of Age-Related Macular Degeneration"],"prefix":"10.1167","volume":"61","author":[{"given":"Thomas M.","family":"Hallam","sequence":"first","affiliation":[{"name":"Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom"},{"name":"National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom"},{"name":"Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin J.","family":"Marchbank","sequence":"additional","affiliation":[{"name":"Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom"},{"name":"National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire L.","family":"Harris","sequence":"additional","affiliation":[{"name":"Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom"},{"name":"National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clive","family":"Osmond","sequence":"additional","affiliation":[{"name":"MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria G.","family":"Shuttleworth","sequence":"additional","affiliation":[{"name":"Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom"},{"name":"National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Griffiths","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela J.","family":"Cree","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Kavanagh","sequence":"additional","affiliation":[{"name":"Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom"},{"name":"National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Lotery","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"27","reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"e106","DOI":"10.1016\/S2214-109X(13)70145-1","article-title":"Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis","volume":"2","author":"Wong","year":"2014","journal-title":"Lancet Glob Health"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1172\/JCI20465","article-title":"VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment","volume":"113","author":"Cursiefen","year":"2004","journal-title":"J Clin Invest"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"2920","DOI":"10.1172\/JCI31692","article-title":"CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration","volume":"117","author":"Combadi\u00e8re","year":"2007","journal-title":"J Clin Invest"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"1751","DOI":"10.1016\/j.ophtha.2016.03.045","article-title":"Five-year outcomes with anti\u2013vascular endothelial growth factor treatment of neovascular age-related macular degeneration: the comparison of age-related macular degeneration treatments trials","volume":"123","author":"Maguire","year":"2016","journal-title":"Ophthalmology"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/annotation\/32b9bc31-ed6d-4d31-9ce0-480407017bad","article-title":"Systemic complement activation in age-related macular degeneration","volume":"3","author":"Scholl","year":"2008","journal-title":"PLoS One"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"7227","DOI":"10.1073\/pnas.0501536102","article-title":"A common haplotype in the complement regulatory gene factor H (HF1\/CFH) predisposes individuals to age-related macular degeneration","volume":"102","author":"Hageman","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1126\/science.1110189","article-title":"Complement factor H polymorphism and age-related macular degeneration","volume":"308","author":"Edwards","year":"2005","journal-title":"Science"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1126\/science.1110359","article-title":"Complement factor H variant increases the risk of age-related macular degeneration","volume":"308","author":"Haines","year":"2005","journal-title":"Science"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1038\/ejhg.2008.140","article-title":"Variation near complement factor I is associated with risk of advanced AMD","volume":"17","author":"Fagerness","year":"2009","journal-title":"Eur J Hum Genet"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1038\/ng.2640","article-title":"A functional variant in the CFI gene confers a high risk of age-related macular degeneration","volume":"45","author":"van de Ven","year":"2013","journal-title":"Nat Genet"},{"key":"bib11","first-page":"1253","article-title":"Complement factor I and age-related macular degeneration","volume":"20","author":"Alexander","year":"2014","journal-title":"Mol Vis"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1038\/ng.3448","article-title":"A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants","volume":"48","author":"Fritsche","year":"2016","journal-title":"Nat Genet"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"1366","DOI":"10.1038\/ng.2741","article-title":"Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration","volume":"45","author":"Seddon","year":"2013","journal-title":"Nat Genet"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"2910","DOI":"10.1073\/pnas.69.10.2910","article-title":"Inactivator of the third component of complement as an inhibitor in the properdin pathway","volume":"69","author":"Alper","year":"1972","journal-title":"Proc Natl Acad Sci USA"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1084\/jem.141.5.1221","article-title":"The mechanism of action of the C3b inactivator (conglutinogen-activating factor) on its naturally occurring substrate, the major fragment of the third component of complement (C3b)","volume":"141","author":"Gitlin","year":"1975","journal-title":"J Exp Med"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1084\/jem.146.1.257","article-title":"Human complement C3b inactivator: isolation, characterization, and demonstration of an absolute requirement for the serum protein \u00df1H for cleavage of C3b and C4b in solution","volume":"146","author":"Pangburn","year":"1977","journal-title":"J Exp Med"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1126\/science.948757","article-title":"Modulation of C3b hemolytic activity by a plasma protein distinct from C3b inactivator","volume":"193","author":"Whaley","year":"1976","journal-title":"Science"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1016\/0019-2791(77)90345-7","article-title":"Mechanism of action of the C3b inactivator: requirement for a high molecular weight cofactor (C3b-C4bINA cofactor) and production of a new C3b derivative (C3b')","volume":"14","author":"Nagasawa","year":"1977","journal-title":"Immunochemistry"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1016\/0019-2791(75)90256-6","article-title":"Cleavage products of C4b produced by enzymes in human serum","volume":"12","author":"Shiraishi","year":"1975","journal-title":"Immunochemistry"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1084\/jem.156.6.1739","article-title":"Unique role of the complement receptor CR1 in the degradation of C3b associated with immune complexes","volume":"156","author":"Edward Medof","year":"1982","journal-title":"J Exp Med"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1146\/annurev.iy.09.040191.002243","article-title":"Membrane cofactor protein (MCP or CD46): newest member of the regulators of complement activation gene cluster","volume":"9","author":"Liszewski","year":"1991","journal-title":"Annu Rev Immunol"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1016\/j.imbio.2019.05.003","article-title":"Immunobiology: the story of complement factor I","volume":"224","author":"Lachmann","year":"2019","journal-title":"Immunobiology"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"300","DOI":"10.2215\/CJN.00620117","article-title":"Thrombotic microangiopathy and the kidney","volume":"13","author":"Brocklebank","year":"2018","journal-title":"Clin J Am Soc Nephrol"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1136\/jmedgenet-2015-103130","article-title":"Rare genetic variants in Tunisian Jewish patients suffering from age-related macular degeneration","volume":"52","author":"Pras","year":"2015","journal-title":"J Med Genet"},{"key":"bib25","first-page":"3861","article-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","volume":"24","author":"Kavanagh","year":"2015","journal-title":"Hum Mol Genet"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"e0195751","DOI":"10.1371\/journal.pone.0195751","article-title":"A monoclonal antibody targeting amyloid \u00df (A \u00df) restores complement factor I bioactivity: potential implications in age-related macular degeneration and Alzheimer's disease","volume":"13","author":"Lashkari","year":"2018","journal-title":"PLoS One"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"712","DOI":"10.4049\/jimmunol.181.1.712","article-title":"Altered function of factor I caused by amyloid \u00df: implication for pathogenesis of age-related macular degeneration from drusen","volume":"181","author":"Wang","year":"2008","journal-title":"J Immunol"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"1828","DOI":"10.1016\/S0140-6736(08)61348-3","article-title":"Association between the SERPING1 gene and age-related macular degeneration?: a two-stage case-control study","volume":"372","author":"Ennis","year":"2008","journal-title":"Lancet"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1038\/ng.2578","article-title":"Seven new loci associated with age-related macular degeneration","volume":"45","author":"AMD Gene Consortium","year":"2013","journal-title":"Nat Genet"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"2150","DOI":"10.1681\/ASN.2005010103","article-title":"Mutations in complement factor I predispose to development of atypical hemolytic uremic syndrome","volume":"16","author":"Kavanagh","year":"2005","journal-title":"J Am Soc Nephrol"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1016\/j.imbio.2016.05.002","article-title":"Chromosomal rearrangement\u2014a rare cause of complement factor I associated atypical haemolytic uraemic syndrome","volume":"221","author":"Gleeson","year":"2016","journal-title":"Immunobiology"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1001\/jamaophthalmol.2013.2303","article-title":"C-reactive protein and the incidence of macular degeneration: pooled analysis of 5 cohorts","volume":"131","author":"Mitta","year":"2013","journal-title":"JAMA Ophthalmol"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"1694","DOI":"10.1111\/ajt.2008.8.issue-8","article-title":"Complement mutation-associated de novo thrombotic microangiopathy following kidney transplantation","volume":"8","author":"Le Quintrec","year":"2008","journal-title":"Am J Transplant"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"2464","DOI":"10.4049\/jimmunol.1701695","article-title":"Statistical validation of rare complement variants provides insights on the molecular basis of atypical haemolytic uraemic syndrome and C3 glomerulopathy","volume":"200","author":"Osborne","year":"2018","journal-title":"J Immunol"},{"key":"bib35","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1681\/ASN.2009070706","article-title":"Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations","volume":"21","author":"Fakhouri","year":"2010","journal-title":"J Am Soc Nephrol"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1038\/ki.2009.472","article-title":"Mutations in components of complement influence the outcome of factor I\u2013associated atypical hemolytic uremic syndrome","volume":"77","author":"Bienaime","year":"2010","journal-title":"Kidney Int"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.molimm.2007.05.004","article-title":"Characterization of mutations in complement factor I (CFI) associated with hemolytic uremic syndrome","volume":"45","author":"Kavanagh","year":"2008","journal-title":"Mol Immunol"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1136\/jmedgenet-2015-103130","article-title":"Rare genetic variants in Tunisian Jewish patients suffering from age-related macular degeneration","volume":"52","author":"Pras","year":"2015","journal-title":"J Med Genet"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"8502","DOI":"10.18632\/oncotarget.v9i9","article-title":"Serum complement factor I is associated with disease activity of systemic lupus erythematosus","volume":"9","author":"Tseng","year":"2018","journal-title":"Oncotarget"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1038\/eye.2016.328","article-title":"Local complement activation in aqueous humor in patients with age-related macular degeneration","volume":"31","author":"Schick","year":"2017","journal-title":"Eye"},{"key":"bib41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fimmu.2017.01778","article-title":"Bruch's membrane compartmentalizes complement regulation in the eye with implications for therapeutic design in age-related macular degeneration","volume":"8","author":"Clark","year":"2017","journal-title":"Front Immunol"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"1612","DOI":"10.1016\/j.ophtha.2013.01.004","article-title":"Age-related macular degeneration and modification of systemic complement factor H production through liver transplantation","volume":"120","author":"Khandhadia","year":"2013","journal-title":"Ophthalmology"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.preteyeres.2009.11.003","article-title":"The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited","volume":"29","author":"Anderson","year":"2010","journal-title":"Prog Retin Eye Res"},{"key":"bib44","doi-asserted-by":"publisher","first-page":"4001","DOI":"10.1093\/hmg\/ddu114","article-title":"Comprehensive analysis of gene expression in human retina and supporting tissues","volume":"23","author":"Li","year":"2014","journal-title":"Hum Mol Genet"}],"container-title":["Investigative Opthalmology & Visual Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/iovs.arvojournals.org\/article.aspx?articleid=2766324","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:31:15Z","timestamp":1791927075000},"score":1,"resource":{"primary":{"URL":"https:\/\/iovs.arvojournals.org\/article.aspx?articleid=2766324"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,9]]},"references-count":44,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2020,6,3]]}},"URL":"https:\/\/doi.org\/10.1167\/iovs.61.6.18","relation":{},"ISSN":["1552-5783"],"issn-type":[{"value":"1552-5783","type":"print"}],"subject":[],"published":{"date-parts":[[2020,6,9]]}}}