title: Multifactor effects and evidence of potential interaction between complement factor H Y402H and LOC387715 A69S in age-related macular degeneration.
abstract: BACKGROUND
  Variants in the complement cascade genes and the LOC387715/HTRA1, have been widely reported to associate with age-related macular degeneration (AMD), the most common cause of visual impairment in industrialized countries.
  
  
  RESULTS
  We investigated the association between the LOC387715 A69S and complement component C3 R102G risk alleles in the Finnish case-control material and found a significant association with both variants (OR 2.98, p = 3.75 x 10(-9); non-AMD controls and OR 2.79, p = 2.78 x 10(-19), blood donor controls and OR 1.83, p = 0.008; non-AMD controls and OR 1.39, p = 0.039; blood donor controls), respectively. Previously, we have shown a strong association between complement factor H (CFH) Y402H and AMD in the Finnish population. A carrier of at least one risk allele in each of the three susceptibility loci (LOC387715, C3, CFH) had an 18-fold risk of AMD when compared to a non-carrier homozygote in all three loci. A tentative gene-gene interaction between the two major AMD-associated loci, LOC387715 and CFH, was found in this study using a multiplicative (logistic regression) model, a synergy index (departure-from-additivity model) and the mutual information method (MI), suggesting that a common causative pathway may exist for these genes. Smoking (ever vs. never) exerted an extra risk for AMD, but somewhat surprisingly, only in connection with other factors such as sex and the C3 genotype. Population attributable risks (PAR) for the CFH, LOC387715 and C3 variants were 58.2%, 51.4% and 5.8%, respectively, the summary PAR for the three variants being 65.4%.
  
  
  CONCLUSIONS
  Evidence for gene-gene interaction between two major AMD associated loci CFH and LOC387715 was obtained using three methods, logistic regression, a synergy index and the mutual information (MI) index.
authors.affiliation: Department of Ophthalmology, University of Helsinki, Helsinki, Finland. sanna.seitsonen@hus.fi
authors.forename: Sanna P
authors.initials: SP
authors.lastname: Seitsonen
authors.forename: Päivi
authors.initials: P
authors.lastname: Onkamo
authors.forename: Gang
authors.initials: G
authors.lastname: Peng
authors.forename: Momiao
authors.initials: M
authors.lastname: Xiong
authors.forename: Petri V
authors.initials: PV
authors.lastname: Tommila
authors.forename: Päivi H
authors.initials: PH
authors.lastname: Ranta
authors.forename: Juha M
authors.initials: JM
authors.lastname: Holopainen
authors.forename: Jukka A
authors.initials: JA
authors.lastname: Moilanen
authors.forename: Tapani
authors.initials: T
authors.lastname: Palosaari
authors.forename: Kai
authors.initials: K
authors.lastname: Kaarniranta
authors.forename: Seppo
authors.initials: S
authors.lastname: Meri
authors.forename: Ilkka R
authors.initials: IR
authors.lastname: Immonen
authors.forename: Irma E
authors.initials: IE
authors.lastname: Järvelä
mesh_terms: D000483:Alleles; D017242:Complement Factor H / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008268:Macular Degeneration / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D012307:Risk Factors
chemical_list: C514392:ARMS2 protein, human; D011506:Proteins; D017242:Complement Factor H