Age Related Macular Degeneration (AMD) is the leading cause of untreatable blindness in individuals over the age of 65. Currently, there is no effective treatment available for most patients with AMD. It is widely accepted that AMD is a multi-factorial disease involving the interaction of genetic and environmental factors. Genetic studies have identified a number of chromosomal loci that harbor potential AMD susceptibility genes. We and others have recently identified genetic variants in several genes [such as complement factor H (CFH), toll-like receptor 4 (TLR4) and apolipoprotein E (APOE)] that have been associated with susceptibility to AMD. The primary goals of our research are to dissect genetic and molecular mechanism(s) underlying AMD pathogenesis. In this project, we propose to test the following hypotheses: (i) genetic variations in multiple susceptibility loci predispose individuals to AMD pathogenesis; and (ii) some of the susceptibility loci encode gene products that are involved in stress response, lipid and/or cholesterol metabolism, and immune-modulation.
The specific aims are: (1) to collect detailed clinical findings, family history, ancillary data (such as, smoking and diet), and blood/DNA samples from 1500 unrelated AMD probands and their family members and 1000 unrelated age- (and ethnically) matched controls; (2) to refine the critical genomic regions on chromosomes 5p, 9q, 10q and 22q, which are suggested to harbor AMD susceptibility genes, using extensive single nucleotide polymorphism (SNP)-based association studies and to identify the genetic variations that are associated with late-stage AMD in our cohort; (3) to perform association studies in our cohort of case-controls using SNP markers from 100 selected candidate genes that encode proteins involved in stress response, lipid /cholesterol transport, and immune-modulation; and (4) to perform whole genome scan in a second independent sample of 400-500 AMD relative-pairs to identify and validate novel and established AMD susceptibility loci. Identification of susceptibility genes (and genetic variants) will advance our understanding of molecular and cellular pathways that contribute to the pathogenesis and progression of AMD. In addition, our proposed studies may lead to identification of diagnostic markers for AMD and possibly development of new therapies. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY016862-01A1
Application #
7094436
Study Section
Special Emphasis Panel (ZRG1-BDCN-H (90))
Program Officer
Chin, Hemin R
Project Start
2006-03-01
Project End
2011-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
1
Fiscal Year
2006
Total Cost
$375,900
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Lo, Yancy; Kang, Hyun M; Nelson, Matthew R et al. (2015) Comparing variant calling algorithms for target-exon sequencing in a large sample. BMC Bioinformatics 16:75
Oliver, Verity F; Jaffe, Andrew E; Song, Jin et al. (2015) Differential DNA methylation identified in the blood and retina of AMD patients. Epigenetics 10:698-707
Ozel, A Bilge; Moroi, Sayoko E; Reed, David M et al. (2014) Genome-wide association study and meta-analysis of intraocular pressure. Hum Genet 133:41-57
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
Zahid, Sarwar; Jayasundera, Thiran; Rhoades, William et al. (2013) Clinical phenotypes and prognostic full-field electroretinographic findings in Stargardt disease. Am J Ophthalmol 155:465-473.e3
Zhan, Xiaowei; Larson, David E; Wang, Chaolong et al. (2013) Identification of a rare coding variant in complement 3 associated with age-related macular degeneration. Nat Genet 45:1375-9
Oliver, Verity F; Franchina, Maria; Jaffe, Andrew E et al. (2013) Hypomethylation of the IL17RC promoter in peripheral blood leukocytes is not a hallmark of age-related macular degeneration. Cell Rep 5:1527-35
Sofat, Reecha; Casas, Juan P; Webster, Andrew R et al. (2012) Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype. Int J Epidemiol 41:250-62
McKay, Gareth J; Patterson, Chris C; Chakravarthy, Usha et al. (2011) Evidence of association of APOE with age-related macular degeneration: a pooled analysis of 15 studies. Hum Mutat 32:1407-16
Baratz, Keith H; Tosakulwong, Nirubol; Ryu, Euijung et al. (2010) E2-2 protein and Fuchs's corneal dystrophy. N Engl J Med 363:1016-24

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