A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration.

• Published in: Nature Genetics
• Main Authors: Helgason, Hannes, Sulem, Patrick, Duvvari, Maheswara R, Luo, Hongrong, Thorleifsson, Gudmar, Stefansson, Hreinn, Jonsdottir, Ingileif, Masson, Gisli, Gudbjartsson, Daniel F, Walters, G Bragi, Magnusson, Olafur Th, Kong, Augustine, Rafnar, Thorunn, Kiemeney, Lambertus A, Schoenmaker-Koller, Frederieke E, Zhao, Ling, Boon, Camiel J F, Song, Yaojun, Fauser, Sascha, Pei, Michelle, Ristau, Tina, Patel, Shirrina, Liakopoulos, Sandra, van de Ven, Johannes P H, Hoyng, Carel B, Ferreyra, Henry, Duan, Yaou, Bernstein, Paul S, Geirsdottir, Asbjorg, Helgadottir, Gudleif, Stefansson, Einar, den Hollander, Anneke I, Zhang, Kang, Jonasson, Fridbert, Sigurdsson, Haraldur, Thorsteinsdottir, Unnur, Stefansson, Kari
• Other Authors: deCODE Genet Amgen, Reykjavik, Iceland, Univ Iceland, Sch Engn & Nat Sci, Reykjavik, Iceland, Radboud Univ Nijmegen, Med Ctr, Dept Ophthalmol, NL-6525 ED Nijmegen, Netherlands, Univ Calif San Diego, Dept Ophthalmol, La Jolla, CA 92093 USA, Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA, Sichuan Univ, West China Hosp, Dept Ophthalmol, Chengdu 610064, Peoples R China, Sichuan Univ, West China Hosp, Mol Med Res Ctr, Chengdu 610064, Peoples R China, Natl Univ Hosp Reykjavik, Dept Immunol, Reykjavik, Iceland, Univ Iceland, Fac Med, Reykjavik, Iceland, Radboud Univ Nijmegen, Med Ctr, Dept Hlth Evidence, NL-6525 ED Nijmegen, Netherlands, Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6525 ED Nijmegen, Netherlands, Univ Hosp Cologne, Dept Ophthalmol, Cologne, Germany, Univ Utah, Moran Eye Ctr, Salt Lake City, UT USA, Natl Univ Hosp Reykjavik, Dept Ophthalmol, Reykjavik, Iceland, Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands, Radboud Univ Nijmegen, Med Ctr, Inst Genet & Metab Dis, NL-6525 ED Nijmegen, Netherlands, Vet Affairs Healthcare Syst, San Diego, CA USA
• Format: Article in Journal/Newspaper
• Language: English
• Published: Nature Publishing Group 2013
• Subjects: Frumurannsóknir; Erfðir; Ísland; Amino Acid Substitution; Base Sequence; Complement Activation; Complement C3; Complement C3b; Complement Factor H; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Genotype; Humans; Iceland; Macular Degeneration; Polymorphism; Single Nucleotide; Risk; Sequence Analysis; DNA
• Online Access: http://hdl.handle.net/2336/313317; https://doi.org/10.1038/ng.2740

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field. Through whole-genome sequencing of 2,230 Icelanders, we detected a rare nonsynonymous SNP (minor allele frequency = 0.55%) in the C3 gene encoding a p.Lys155Gln substitution in complement factor 3, which, following imputation into a set of Icelandic cases with age-related macular degeneration (AMD) and controls, associated with disease (odds ratio (OR) = 3.45; P = 1.1 × 10(-7)). This signal is independent of the previously reported common SNPs in C3 encoding p.Pro314Leu and p.Arg102Gly that associate with AMD. The association of p.Lys155Gln was replicated in AMD case-control samples of European ancestry with OR = 4.22 and P = 1.6 × 10(-10), resulting in OR = 3.65 and P = 8.8 × 10(-16) for all studies combined. In vitro studies have suggested that the p.Lys155Gln substitution reduces C3b binding to complement factor H, potentially creating resistance to inhibition by this factor. This resistance to inhibition in turn is predicted to result in enhanced complement activation. 973 program/2013CB967504 National Science Foundation of China/81130017 NEI/US National Institutes of Health Veterans Affairs Merit Award Netherlands Organization for Scientific Vidi Innovational Research Award/016.096.309 Foundation Fighting Blindness/C-GE-0811-0548-RAD04