Overview
We are driven by the long-term goal of developing personalized treatment regimens for patients with degenerative retinal diseases, such as age-related macular degeneration (AMD), diabetic retinopathy (DR), and primary open angle glaucoma (POAG). Our current research aims to uncover metabolomic and genetic influences on the development and progression of these blinding diseases. Our work also investigates metabolomic associations with treatment response for AMD. The results of these metabologenetic and pharmacometabolomic studies should help us predict how a disease will manifest and which course of treatment will be most effective in an individual based on his or her unique genotype and metabolic profile.
Investigations
Metabolomic and Genetic Interactions in AMD
AMD is the most common cause of irreversible vision loss in the elderly in the Western world. Genetics and environmental exposures both contribute to the risk of developing AMD and its progression to the sight-threatening advanced stages. Numerous genetic polymorphisms have been linked to AMD, but these account for only a portion of AMD risk. Because neither genetic variants nor individual molecular biomarkers effectively predict AMD progression or response to treatment, we are using comprehensive metabolic profiling combined with genetic analyses to refine the evaluation of AMD risk. We have performed the first metabolome-wide association study (MWAS) of neovascular AMD and have identified individual molecules and molecular pathways that are altered in the disease. We are currently studying these altered metabolites and pathways in a targeted fashion.
Metabolomic and Genetic Interactions in Diabetic Retinopathy
Diabetic retinopathy (DR), the leading cause of blindness in working-age adults in the United States, leads to complications including macular edema and abnormal retinal blood vessel growth. We have recruited over 600 patients from the VEI for a longitudinal study on the metabologenetics of diabetic retinopathy. Our initial work has identified pathways, many related to mitochondria, which are altered in Type 2 diabetics with retinopathy compared to controls. We also recently discovered an association between particular mitochondrial haplogroups and severity of diabetic retinopathy. Our current work is investigating the relationship between these metabolic and genetic findings.
Metabolomics of POAG
While POAG may not be typically thought of as a retinal disease, it is the loss of retinal ganglion cells that ultimately leads to vision loss in glaucoma. We have recently carried out an MWAS of POAG and discovered that carnitines and vitamin D2 metabolites were altered in glaucoma patients compared to controls. Ongoing work is designed to understand the specifics of the carnitine metabolite alterations and how these changes may be related to fatty acid oxidation in the mitochondria.
Selected Recent Publications
Burgess LG, Uppal K, Walker DI, Roberson RM, Tran V, Parks MB, Wade EA, May AT, Umfress AC, Jarrel KL, Stanley BOC, Kuchtey J, Kuchtey RW, Jones DP, Brantley MA Jr. Metabolome-wide association study of primary open angle glaucoma. Invest Ophthalmol Vis Sci, 2015, 56:5020-8.
Estopinal CB, Chocron IM, Parks MB, Wade EA, Roberson RM, Burgess LG, Brantley MA Jr, Samuels DC. Mitochondrial haplogroups are associated with severity of diabetic retinopathy. Invest Ophthalmol Vis Sci, 2014, 55:5589-95.
Kuchtey J, Kunkel J, Burgess LG, Parks MB, Brantley MA Jr, Kuchtey RW. Elevated transforming growth factor beta-1 in plasma of primary open angle glaucoma patients. Invest Ophthalmol Vis Sci, 2014, 55:5291-7.
Osborn MP, Park Y, Parks MB, Burgess LG, Uppal K, Lee K, Jones DP, Brantley MA Jr. Metabolome-wide association study of neovascular age-related macular degeneration. PLoS ONE 2013, 8(8): e72737. Doi:10.137/journal.pone.0072737.
Brantley MA Jr, Osborn MP, Sanders BJ, Rezaei KA, Lu P, Li C, Milne GL, Cai J, Sternberg P Jr. The short-term effects of antioxidant and zinc supplements on oxidative stress biomarker levels in plasma: a pilot investigation. Am J Ophthalmol, 2012, 153:1104-9.
Brantley MA Jr, Osborn MP, Sanders BJ, Rezaei KA, Lu P, Li C, Milne GL, Cai J, Sternberg P Jr. Plasma biomarkers of oxidative stress and genetic variants in age-related macular degeneration. Am J Ophthalmol 2012; 153:460-7.
Lee AY, Raya AK, Kymes SM, Shiels A, Brantley MA Jr. Pharmacogenetics of Complement Factor H (Y402H) and treatment of exudative age-related macular degeneration with ranibizumab. Br J Ophthalmol 2009; 93:610-3.
Brantley MA Jr, Fang AM, King JM, Tewari A, Kymes SM, Shiels A. Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to intravitreal bevacizumab. Ophthalmology 2007; 114:2168-73.