Helgason, Hannes, Sulem, Patrick, Duvvari, Maheswara R., Luo, Hongrong, Thorleifsson, Gudmar, Stefansson, Hreinn ORCID: 0000-0002-9331-6666, Jonsdottir, Ingileif, Masson, Gisli, Gudbjartsson, Daniel F., Walters, G. Bragi ORCID: 0000-0002-5415-6487, Magnusson, Olafur Th, Kong, Augustine ORCID: 0000-0001-8193-5438, Rafnar, Thorunn, Kiemeney, Lambertus A. ORCID: 0000-0002-2368-1326, 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 ORCID: 0000-0002-4549-1697, Jonasson, Fridbert, Sigurdsson, Haraldur, Thorsteinsdottir, Unnur and Stefansson, Kari (2013). A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration. Nature Genet., 45 (11). S. 1371 - 1377. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1546-1718

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Abstract

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 x 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 x 10-10, resulting in OR = 3.65 and P = 8.8 x 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Helgason, HannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sulem, PatrickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duvvari, Maheswara R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luo, HongrongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thorleifsson, GudmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stefansson, HreinnUNSPECIFIEDorcid.org/0000-0002-9331-6666UNSPECIFIED
Jonsdottir, IngileifUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Masson, GisliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gudbjartsson, Daniel F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walters, G. BragiUNSPECIFIEDorcid.org/0000-0002-5415-6487UNSPECIFIED
Magnusson, Olafur ThUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kong, AugustineUNSPECIFIEDorcid.org/0000-0001-8193-5438UNSPECIFIED
Rafnar, ThorunnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kiemeney, Lambertus A.UNSPECIFIEDorcid.org/0000-0002-2368-1326UNSPECIFIED
Schoenmaker-Koller, Frederieke E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhao, LingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boon, Camiel J. F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Song, YaojunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fauser, SaschaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pei, MichelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ristau, TinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Patel, ShirrinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liakopoulos, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van de Ven, Johannes P. H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoyng, Carel B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ferreyra, HenryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duan, YaouUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bernstein, Paul S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geirsdottir, AsbjorgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Helgadottir, GudleifUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stefansson, EinarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
den Hollander, Anneke I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhang, KangUNSPECIFIEDorcid.org/0000-0002-4549-1697UNSPECIFIED
Jonasson, FridbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sigurdsson, HaraldurUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thorsteinsdottir, UnnurUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stefansson, KariUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-473612
DOI: 10.1038/ng.2740
Journal or Publication Title: Nature Genet.
Volume: 45
Number: 11
Page Range: S. 1371 - 1377
Date: 2013
Publisher: NATURE PUBLISHING GROUP
Place of Publication: NEW YORK
ISSN: 1546-1718
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOME-WIDE ASSOCIATION; CFH; MACULOPATHY; IMPUTATION; FRAMEWORK; DISEASES; LOCIMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/47361

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