In the United States, two million individuals are legally blind and ten million more visually impaired from age-related macular degeneration (AMD). In the next decade, the incidence of this condition is expected to double. Currently, treatment is aimed toward limiting disease progression using dietary supplements and laser therapies. The long range goal associated with this research program is to better understand the genetic variation that underlies the condition in order to identify those at risk of the disease, provide insight into the molecular pathophysiology of AMD and establish prevention strategies and novel treatments. The objective of this particular renewal application is to continue and further our work to identify the genes involved in the development of AMD using extended families. Our central hypothesis remains that multiple genes are involved in determining disease susceptibility. We will be guided by our data from the first five years of investigation in which genetic linkage studies involving over one thousand individuals from more than one hundred extended families have identified several potential susceptibility loci and implicated the gene, hemicentin-1, in the pathogenesis of the condition. We propose to continue to test the hypothesis by pursuing the following specific aims: 1) collect and genotype additional subjects in order to expand previously ascertained families and add new large pedigrees; 2) undertake statistical analyses to identify and refine potential disease loci, to include a) parametric and nonparametric methods, b) sample stratification, and c) quantitative trait locus; and 3) find and identify AMD susceptibility genes by a) positional candidate gene association analyses of our pedigrees, b) positional candidate gene association analysis of our case-control cohorts, and c) identification of genes involved in epistatic interactions. We remain convinced that our approach is innovative because of our unique resource of extended families with this late-onset disease and significant because, based on the data collected to date, this study will continue to advance understanding of the genetics of age-related macular degeneration, the foremost cause of blindness in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY012203-06A2
Application #
6984629
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Chin, Hemin R
Project Start
1998-08-01
Project End
2008-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
6
Fiscal Year
2005
Total Cost
$469,854
Indirect Cost
Name
Oregon Health and Science University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Klein, Michael L; Ferris 3rd, Frederick L; Francis, Peter J et al. (2010) Progression of geographic atrophy and genotype in age-related macular degeneration. Ophthalmology 117:1554-9, 1559.e1
Francis, P J; Hamon, S C; Ott, J et al. (2009) Polymorphisms in C2, CFB and C3 are associated with progression to advanced age related macular degeneration associated with visual loss. J Med Genet 46:300-7
SanGiovanni, John Paul; Arking, Dan E; Iyengar, Sudha K et al. (2009) Mitochondrial DNA variants of respiratory complex I that uniquely characterize haplogroup T2 are associated with increased risk of age-related macular degeneration. PLoS One 4:e5508
Francis, Peter J; Appukuttan, Binoy; Simmons, Emily et al. (2008) Rhesus monkeys and humans share common susceptibility genes for age-related macular disease. Hum Mol Genet 17:2673-80
Klein, Michael L; Francis, Peter J; Rosner, Bernard et al. (2008) CFH and LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration. Ophthalmology 115:1019-25
Francis, Peter J; Zhang, Hong; Dewan, Andrew et al. (2008) Joint effects of polymorphisms in the HTRA1, LOC387715/ARMS2, and CFH genes on AMD in a Caucasian population. Mol Vis 14:1395-400
Francis, Peter J; Schultz, Dennis W; Hamon, Sara et al. (2007) Haplotypes in the complement factor H (CFH) gene: associations with drusen and advanced age-related macular degeneration. PLoS One 2:e1197
Seddon, Johanna M; Francis, Peter J; George, Sarah et al. (2007) Association of CFH Y402H and LOC387715 A69S with progression of age-related macular degeneration. JAMA 297:1793-800
Barral, Sandra; Francis, Peter J; Schultz, Dennis W et al. (2006) Expanded genome scan in extended families with age-related macular degeneration. Invest Ophthalmol Vis Sci 47:5453-9
Seddon, Johanna M; George, Sarah; Rosner, Bernard et al. (2006) CFH gene variant, Y402H, and smoking, body mass index, environmental associations with advanced age-related macular degeneration. Hum Hered 61:157-65

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