Age-related macular degeneration (AMD), the leading cause of incurable blindness among older adults in the US, is caused by interactions between underlying genetic susceptibility and lifestyle risk factors. However, our knowledge of the network of contributors to the pathogenesis of AMD remains incomplete, and treatment is inadequate. The proposed studies build upon a strong and growing foundation of research and invaluable existing resources to comprehensively study the genetic epidemiology of AMD. Through its use of archived DNA specimens from several large prospective cohort studies, this proposal represents a cost-effective, efficient, and informative approach to investigate the following specific aims: 1) determine the incidence rate ratio and attributable fraction for AMD in relation to common variants within a group of strong candidate genes including complement factor H, HTRA1/LOC387715, and others (candidates identified based on position, function, expression, etc.) using both single locus and haplotype analyses for AMD overall as well as for both dry and neovascular subtypes, 2) effectively utilize data derived from RNA microarray analysis of sibpairs extremely discordant for AMD to inform selection of candidate genes, 3) estimate the magnitude and significance of any gene-gene, or gene-environment interactions among these candidates and risk factors such as cigarette smoking, obesity, diet, and serum inflammatory markers.
These aims will be accomplished through genotyping of >1300 confirmed incident AMD cases and >3000 controls in our high-tech core genotyping facility, along with direct sequencing when indicated for SNP discovery as well as to search for functional variants or disease-causing mutations if association analyses are significant. Unique strengths of this approach include the prospective design, large sample size, high-quality, high-throughput genotyping, integration with a study of extremely discordant sib-pairs, and state-of-the-art statistical analyses to provide precise estimates for effects of genes, gene-gene and gene-environment interactions. The proposed studies minimize bias through prospective assessment of exposures and AMD status, direct estimation of incidence rate ratios, novel candidate gene selection, and high statistical power. The long-term objective and clinical relevance of this research is to shed light on underlying biological mechanisms relevant to AMD, to suggest avenues for novel preventive or therapeutic approaches, and identify clinically useful risk assessments. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY017362-01A2
Application #
7319253
Study Section
Special Emphasis Panel (ZEY1-VSN (01))
Program Officer
Chin, Hemin R
Project Start
2007-09-30
Project End
2012-08-31
Budget Start
2007-09-30
Budget End
2008-08-31
Support Year
1
Fiscal Year
2007
Total Cost
$553,392
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Wu, Juan; Cho, Eunyoung; Giovannucci, Edward L et al. (2017) Dietary Intakes of Eicosapentaenoic Acid and Docosahexaenoic Acid and Risk of Age-Related Macular Degeneration. Ophthalmology 124:634-643
Wu, Juan; Cho, Eunyoung; Willett, Walter C et al. (2015) Intakes of Lutein, Zeaxanthin, and Other Carotenoids and Age-Related Macular Degeneration During 2 Decades of Prospective Follow-up. JAMA Ophthalmol 133:1415-24
Schaumberg, Debra A; Rose, Lynda; DeAngelis, Margaret M et al. (2014) Prospective study of common variants in CX3CR1 and risk of macular degeneration: pooled analysis from 5 long-term studies. JAMA Ophthalmol 132:84-95
Ratnapriya, Rinki; Zhan, Xiaowei; Fariss, Robert N et al. (2014) Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration. Hum Mol Genet 23:5827-37
Semba, Richard D; Cotch, Mary Frances; Gudnason, Vilmundur et al. (2014) Serum carboxymethyllysine, an advanced glycation end product, and age-related macular degeneration: the Age, Gene/Environment Susceptibility-Reykjavik Study. JAMA Ophthalmol 132:464-70
Wu, Juan; Uchino, Miki; Sastry, Srinivas M et al. (2014) Age-related macular degeneration and the incidence of cardiovascular disease: a systematic review and meta-analysis. PLoS One 9:e89600
Mitta, Vinod P; Christen, William G; Glynn, Robert J et al. (2013) C-reactive protein and the incidence of macular degeneration: pooled analysis of 5 cohorts. JAMA Ophthalmol 131:507-13
Jun, Gyungah; Nicolaou, Michael; Morrison, Margaux A et al. (2011) Influence of ROBO1 and RORA on risk of age-related macular degeneration reveals genetically distinct phenotypes in disease pathophysiology. PLoS One 6:e25775
Morrison, Margaux A; Silveira, Alexandra C; Huynh, Nancy et al. (2011) Systems biology-based analysis implicates a novel role for vitamin D metabolism in the pathogenesis of age-related macular degeneration. Hum Genomics 5:538-68
Schaumberg, Debra A; Chasman, Daniel; Morrison, Margaux A et al. (2010) Prospective study of common variants in the retinoic acid receptor-related orphan receptor ? gene and risk of neovascular age-related macular degeneration. Arch Ophthalmol 128:1462-71

Showing the most recent 10 out of 13 publications