Despite recent advances in treatment, age-related macular degeneration (AMD) remains the leading cause of irreversible blindness in the elderly population. A shift in the current therapy paradigm will require more sensitive methods of identifying patients at greatest risk for disease development, progression, and poor treatment response. Previously-investigated genetic polymorphisms account for only a portion of AMD risk. Other factors include not only health risks, such as smoking and exposure to other toxins, but also individual metabolism of toxins, drugs, dietary supplements, and perhaps even food. Indeed, comprehensive measurement of metabolites in fluid or tissue has successfully identified risk factors for other chronic diseases, including heart failure, diabetes, and Parkinson's disease. Nevertheless, metabolism is influenced largely by genetic factors. Thus, our long-term goal is to develop profiles combining genetic and metabolic factors to predict disease risk and treatment response in order to improve clinical outcomes for AMD patients. The objective of this proposal is more focused: to discern metabolic profiles related to AMD pathogenesis and determine their relationship to AMD-related genetic variants. Our central hypothesis posits that metabolic profiles combined with genetic variation drive an individual's risk for AMD development, progression, and response to treatment. Using high-resolution liquid chromatography-mass spectrometry (LC-MS) and Sequenom-based genotyping, we will test this hypothesis in two established independent cohorts, along with a new prospective patient cohort recruited from the Vanderbilt Eye Institute.
In Aim 1, measuring plasma metabolites in AMD patients and controls will tell us the metabolic differences between these groups and between different stages of AMD. These metabolic variances will point to molecules and pathways that are associated with AMD and could serve as targets for therapeutic intervention.
In Aim 2, we will combine these metabolic profiles with genotypes for known AMD-risk genes to determine how metabolites and gene variants interact to influence AMD development and progression. This approach will give us molecular insight into the variability in disease progression among patients. Finally, Aim 3 will prospectively evaluate the impact of metabolic and genetic profiles on intermediate AMD progression and NVAMD treatment response. Successful completion of these aims will provide critical knowledge of metabolic changes associated with AMD and will help identify patients at greatest risk for disease progression and poor treatment response.

Public Health Relevance

In conjunction with genetic variants, metabolic and exposure-related factors contribute to the risk of age-related macular degeneration (AMD), the leading cause of severe vision loss in the elderly in the United States. Investigations of non-genetic risk factors for AMD have thus far been limited by qualitative methodology or reliance on single biomarkers. The goal of this application is to combine high-resolution mass spectrometry- based metabolomics with genotyping in order to determine the combination of metabolic and genetic factors critical to AMD development, progression, and treatment response.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY022618-06
Application #
9352858
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Shen, Grace L
Project Start
2013-09-01
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2019-07-31
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Uppal, Karan; Ma, Chunyu; Go, Young-Mi et al. (2018) xMWAS: a data-driven integration and differential network analysis tool. Bioinformatics 34:701-702
Hajjar, Ihab; Hayek, Salim S; Goldstein, Felicia C et al. (2018) Oxidative stress predicts cognitive decline with aging in healthy adults: an observational study. J Neuroinflammation 15:17
Mitchell, Sabrina L; Neininger, Abigail C; Bruce, Carleigh N et al. (2017) Mitochondrial Haplogroups Modify the Effect of Diabetes Duration and HbA1c on Proliferative Diabetic Retinopathy Risk in Patients With Type 2 Diabetes. Invest Ophthalmol Vis Sci 58:6481-6488
Bregman, Jana A; Herren, David J; Estopinal, Christopher B et al. (2017) Mitochondrial Haplogroups Affect Severity But Not Prevalence of Diabetic Retinopathy. Invest Ophthalmol Vis Sci 58:1346-1351
Umfress, Allison C; Brantley Jr, Milam A (2016) Eye Care Disparities and Health-Related Consequences in Elderly Patients with Age-Related Eye Disease. Semin Ophthalmol 31:432-8
Rao, Anuradha; Kosters, Astrid; Mells, Jamie E et al. (2016) Inhibition of ileal bile acid uptake protects against nonalcoholic fatty liver disease in high-fat diet-fed mice. Sci Transl Med 8:357ra122
Burgess, L Goodwin; Uppal, Karan; Walker, Douglas I et al. (2015) Metabolome-Wide Association Study of Primary Open Angle Glaucoma. Invest Ophthalmol Vis Sci 56:5020-8
Estopinal, Christopher B; Chocron, Isaac M; Parks, Megan B et al. (2014) Mitochondrial haplogroups are associated with severity of diabetic retinopathy. Invest Ophthalmol Vis Sci 55:5589-95
Kuchtey, John; Kunkel, Jessica; Burgess, L Goodwin et al. (2014) Elevated transforming growth factor ?1 in plasma of primary open-angle glaucoma patients. Invest Ophthalmol Vis Sci 55:5291-7