Authors

Sanna P. Seitsonen, Department of Ophthalmology, University of Helsinki, Helsinki, Finland, 2 Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland; Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland
Päivi Onkamo, Department of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
Gang Peng
Momiao Xiong, School of Life Science, Fudan University, Fudan, China; Human Genetics Center, University of Texas School of Public Health, Houston, Texas, United States of AmericaFollow
Petri V. Tommila, Department of Ophthalmology, University of Helsinki, Helsinki, Finland, 2 Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland,
Päivi H. Ranta, Department of Ophthalmology, University of Helsinki, Helsinki, Finland, 2 Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland
Juha M. Holopainen, Department of Ophthalmology, University of Helsinki, Helsinki, Finland, 2 Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland
Jukka A. Moilanen, inki, Helsinki, Finland
Tapani Palosaari, Department of Ophthalmology, University of Oulu, Helsinki, Finland
Kai Kaarniranta, Department of Ophthalmology, University of Kuopio, Kuopio, Finland
Seppo Meri, Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland
Ilkka R. Immonen, inki, Helsinki, Finland
Irma E. Järvelä, Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland; Laboratory of Molecular Genetics, Helsinki University Central Hospital, Helsinki, Finland

Publication Date

2008

Journal

PLoS ONE. 2008;3(12):e3833. Epub 2008 Dec 2

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. METHODS/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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.

Keywords

Alleles, Complement Factor H, Genetic Predisposition to Disease, Genotype, Humans, Logistic Models, Macular Degeneration, Polymorphism, Single Nucleotide, Proteins, Risk Factors

Comments

PMCID: PMC2585793

Link to article in PLoS