The overall goal of our research is to elucidate underlying mechanisms, pathways and biological markers which may predispose individuals to advanced age-related macular degeneration (AMD) so that appropriate preventive and therapeutic targets can be developed. Commonly, the degeneration of the retina has already begun by the time the patient is diagnosed with AMD in the clinic. Most current treatments are directed against neovascular AMD (an advanced and more severe form of the disease), require invasive delivery methods, are limited in their applicability, and not capable of preventing or reversing vision loss over the long term. Significant work in AMD genetics has established alleles as well as haplotypes on chromosomes 1 and 10, particularly in CFH and LOC387715/ARMS2/HTRA1, as having large influences on AMD risk in populations of various ethnicities. As a result of the CFH findings, further investigation of the complement pathway has revealed associations between AMD risk and rare alleles in the C2/CFB, C3 and CFH1-5. Although these studies illustrate the importance of studying entire genetic pathways rather than one gene in isolation to develop effective therapies for common diseases such as AMD, there are many AMD free individuals in the population that harbor these disease susceptibility genotypes/haplotypes and a substantial number of AMD patients who lack risk variants in these loci. While these findings have begun to provide insights into AMD etiology, there are still many questions about AMD risk and pathogenesis that cannot be explained by the known AMD-related genes and therefore important loci remain to be identified and characterized. In this competitive renewal proposal, the applicants, working with leading investigators from diverse disciplines (molecular genetics, statistical genetics and proteomics), aim to further identify and evaluate the role of genetic variants using a phenotypically well-characterized and documented cohort of extreme sibpairs. The approach is multi-pronged and will employ state of the art methodologies to pinpoint biologically relevant disease targets and their modifiers that may predispose an individual to neovascular AMD. To this end, the applicants will initially evaluate data from high density SNP/CNV arrays that are directly relevant to specific candidate regions and genes obtained from preliminary findings of genomic convergence between linkage, genome wide association and gene expression analysis on risk of neovascular AMD. The applicants anticipate that results of this project will provide a solid foundation on which to build a better understanding of AMD pathogenesis and thereby furthering the development of strategies for therapy and prevention of this disease.

Public Health Relevance

Advanced age-related macular degeneration (AMD) is the most common cause of legal blindness in the United States. The major goal of this proposal is to identify quantifiable biomarkers that could be used as eventual targets for prevention or therapeutic intervention of progression to neovascular age-related macular degeneration (an advanced form of the disease). The risk factors we identify may be modifiable through therapeutic or behavioral intervention, thereby reducing or preventing the incidence of this disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
7R01EY014458-07
Application #
7915557
Study Section
Special Emphasis Panel (ZEY1-VSN (01))
Program Officer
Chin, Hemin R
Project Start
2002-12-01
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
7
Fiscal Year
2010
Total Cost
$711,564
Indirect Cost
Name
University of Utah
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Tsiloulis, A N; Zacharaki, F; Kotoula, M G et al. (2016) Genetic variants in complement pathway and ARMS2/HTRA1 genes and risk of age-related macular degeneration in a homogeneous population from central Greece. Ophthalmic Genet 37:339-44
Owen, Leah A; Morrison, Margaux A; Ahn, Jeeyun et al. (2014) FLT1 genetic variation predisposes to neovascular AMD in ethnically diverse populations and alters systemic FLT1 expression. Invest Ophthalmol Vis Sci 55:3543-54
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
Morgan, Denise J; DeAngelis, Margaret M (2014) Differential Gene Expression in Age-Related Macular Degeneration. Cold Spring Harb Perspect Med 5:a017210
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
Logue, Mark W; Schu, Matthew; Vardarajan, Badri N et al. (2014) Search for age-related macular degeneration risk variants in Alzheimer disease genes and pathways. Neurobiol Aging 35:1510.e7-18
Jacobo, Sarah Melissa P; Deangelis, Margaret M; Kim, Ivana K et al. (2013) Age-related macular degeneration-associated silent polymorphisms in HtrA1 impair its ability to antagonize insulin-like growth factor 1. Mol Cell Biol 33:1976-90
Feehan, Michael; Hartman, John; Durante, Richard et al. (2011) Identifying subtypes of patients with neovascular age-related macular degeneration by genotypic and cardiovascular risk characteristics. BMC Med Genet 12:83
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

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