title: A common complement C3 variant is associated with protection against wet age-related macular degeneration in a Japanese population.
abstract: BACKGROUND
  Genetic variants in the complement component 3 gene (C3) have been shown to be associated with age-related macular degeneration (AMD) in Caucasian populations of European descent. In particular, a nonsynonymous coding variant, rs2230199 (R102G), is presumed to be the most likely causal variant in the C3 locus based on strong statistical evidence for disease association and mechanistic functional evidence. However, the risk allele is absent or rare (<1%) in Japanese and Chinese populations, and the association of R102G with AMD has not been reported in Asian populations. Genetic heterogeneity of disease-associated variants among different ethnicities is common in complex diseases. Here, we sought to examine whether other common variants in C3 are associated with wet AMD, a common advanced-stage manifestation of AMD, in a Japanese population.
  
  
  RESULTS
  We genotyped 13 tag single nucleotide polymorphisms (SNPs) that capture the majority of common variations in the C3 locus and tested for associations between these SNPs and wet AMD in a Japanese population comprising 420 case subjects and 197 controls. A noncoding variant in C3 (rs2241394) exhibited statistically significant evidence of association (allelic P = 8.32 × 10(-4); odds ratio = 0.48 [95% CI = 0.31-0.74] for the rs2241394 C allele). Multilocus logistic regression analysis confirmed that the effect of rs2241394 was independent of the previously described loci at ARMS2 and CFH, and that the model including variants in ARMS2 and CFH plus C3 rs2241394 provided a better fit than the model without rs2241394. We found no evidence of epistasis between variants in C3 and CFH, despite the fact that they are involved in the same biological pathway.
  
  
  CONCLUSIONS
  Our study provides evidence that C3 is a common AMD-associated locus that transcends racial boundaries and provides an impetus for more detailed genetic characterization of the C3 locus in Asian populations.
authors.affiliation: Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Suiho
authors.initials: S
authors.lastname: Yanagisawa
authors.forename: Naoshi
authors.initials: N
authors.lastname: Kondo
authors.forename: Akiko
authors.initials: A
authors.lastname: Miki
authors.forename: Wataru
authors.initials: W
authors.lastname: Matsumiya
authors.forename: Sentaro
authors.initials: S
authors.lastname: Kusuhara
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Tsukahara
authors.forename: Shigeru
authors.initials: S
authors.lastname: Honda
authors.forename: Akira
authors.initials: A
authors.lastname: Negi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics*; D003176:Complement C3 / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci / Q000235:genetics; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007564:Japan; D015810:Linkage Disequilibrium / Q000235:genetics; D016015:Logistic Models; D008268:Macular Degeneration / Q000235:genetics* / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D003176:Complement C3; D005819:Genetic Markers