title: Analysis of rare variants in the C3 gene in patients with age-related macular degeneration.
abstract: Age-related macular degeneration (AMD) is a progressive retinal disorder affecting over 33 million people worldwide. Genome-wide association studies (GWASs) for AMD identified common variants at 19 loci accounting for 15-65% of the heritability and it has been hypothesized that the missing heritability may be attributed to rare variants with large effect sizes. Common variants in the complement component 3 (C3) gene have been associated with AMD and recently a rare C3 variant (Lys155Gln) was identified which exerts a large effect on AMD susceptibility independent of the common variants. To explore whether additional rare variants in the C3 gene are associated with AMD, we sequenced all coding exons in 84 unrelated AMD cases. Subsequently, we genotyped all identified variants in 1474 AMD cases and 2258 controls. Additionally, because of the known genetic overlap between AMD and atypical hemolytic uremic syndrome (aHUS), we genotyped two recurrent aHUS-associated C3 mutations in the entire cohort. Overall, we identified three rare variants (Lys65Gln (P=0.04), Arg735Trp (OR=17.4, 95% CI=2.2-136; P=0.0003), and Ser1619Arg (OR=5.2, 95% CI=1.0-25; P=0.05) at the C3 locus that are associated with AMD in our EUGENDA cohort. However, the Arg735Trp and Ser1619Arg variants were not found to be associated with AMD in the Rotterdam Study. The Lys65Gln variant was only identified in patients from Nijmegen, the Netherlands, and thus may represent a region-specific AMD risk variant.
authors.affiliation: Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Maheswara R
authors.initials: MR
authors.lastname: Duvvari
authors.affiliation: Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Codrut C
authors.initials: CC
authors.lastname: Paun
authors.affiliation: Department of Ophthalmology, Erasmus Medical Centre, Rotterdam, the Netherlands; Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands.
authors.forename: Gabriëlle H S
authors.initials: GH
authors.lastname: Buitendijk
authors.affiliation: Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Nicole T M
authors.initials: NT
authors.lastname: Saksens
authors.affiliation: Department of Pediatric Nephrology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Elena B
authors.initials: EB
authors.lastname: Volokhina
authors.affiliation: Department of Vitreoretinal Surgery, Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Ristau
authors.affiliation: Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Frederieke E
authors.initials: FE
authors.lastname: Schoenmaker-Koller
authors.affiliation: Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Johannes P H
authors.initials: JP
authors.lastname: van de Ven
authors.affiliation: Department for Health and Evidence, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Joannes M M
authors.initials: JM
authors.lastname: Groenewoud
authors.affiliation: Department of Pediatric Nephrology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Lambertus P W J
authors.initials: LP
authors.lastname: van den Heuvel
authors.affiliation: Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Aging, Netherlands Genomics Initiative, the Hague, the Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Vitreoretinal Surgery, Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Fauser
authors.affiliation: Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Aging, Netherlands Genomics Initiative, the Hague, the Netherlands; Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, the Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Ophthalmology, Erasmus Medical Centre, Rotterdam, the Netherlands; Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands.
authors.forename: Caroline C W
authors.initials: CC
authors.lastname: Klaver
authors.affiliation: Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Carel B
authors.initials: CB
authors.lastname: Hoyng
authors.affiliation: Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Eiko K
authors.initials: EK
authors.lastname: de Jong
authors.affiliation: Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D019943:Amino Acid Substitution; D016022:Case-Control Studies; D003176:Complement C3 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008268:Macular Degeneration / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D012720:Severity of Illness Index
chemical_list: D003176:Complement C3
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