Nutritional Metabolomics in Age-Related Macular Degeneration and Retinal Integrity

PROJECT SUMMARY Age-related macular degeneration (AMD) is a leading cause of vision loss in older adults; the burden of which is increasing. Existing research indicates that foods and nutrients influence AMD progression and may influence the structural integrity of the neurosensory retina. Studies have shown that there are differentiating metabolomic profiles between individuals with and without AMD. However, such studies have not examined metabolites using a hypothesis-driven approach focused on diet. Only two have been prospective in design but are limited by a small size or a small number of metabolomic biomarkers assessed. Cross-sectional or case- control designs are limited by their inability to determine if metabolomic signatures are biomarkers for disease incidence or progression or biomarkers of a current disease state. The Carotenoids in Age-Related Eye Disease Study (CAREDS), an ancillary study of the Women’s Health Initiative (WHI), was designed to study the role of nutrition in age-related eye disease in postmenopausal women with a baseline (2001-2004) and 15- year follow-up exam (2016-2019). CAREDS has detailed data on AMD phenotypes, other indicators of retinal health, dietary intake, genetic risk factors for AMD, and other participant characteristics. We proposed to analyze ~2,000 metabolites from targeted aqueous and lipid panels using stored participant serum from WHI onset (1993-1998). A novel aspect of this study is the derivation of Metabolomic Dietary Pattern Scores (MetDietPS) using data reduction of a set of pre-identified metabolomic biomarkers of nutrients, foods, and healthy diet patterns identified from feeding studies. The MetDietPS will not be prone to the same measure- ment error or the social desirability bias as with self-reported dietary intake. CAREDS has the largest sample of participants with measures of macular pigment optical density (MPOD), hypothesized to be associated with reduced risk of AMD, visual acuity, and contrast sensitivity. At CAREDS follow-up, we have optical coherence tomography measures used to determine the thickness of the retinal nerve fiber layer (RNFL) and the ganglion cell complex (GCC), both subclinical biomarkers for glaucoma. Using data from CAREDS, we propose to examine the exposures of (a) MetDietPS, (b) individual metabolites, and (c) metabolic pathways with the following outcomes: (Aim 1) prevalent AMD assessed at CAREDS baseline (n=1,874) and the incidence of AMD over 15 years (n=1,296), (Aim 2) MPOD at CAREDS baseline (n=1,805) and changes in the MPOD over 15 years (n=427), and (Aim 3) the structural integrity of the neurosensory retina as indicated by the thickness of the RNFL and GCC of the macula measured at the CAREDS follow-up exam (n=454). This study will deepen the understanding of the metabolic processes and pathways that link dietary intake to retinal health. Findings could lead to the identification of novel metabolomic biomarkers to predict incidence or progression of AMD, retinal degeneration with aging, or identify targets for therapeutic interventions of AMD. Such work has the potential to help personalize dietary recommendations to maintain the integrity of the retina.