The promise of molecular genetics for investigating the influence of macular xanthophyllys on advanced age-related macular degeneration

Age-related macular degeneration (AMD) is the prime cause of vision loss in elderly people of Western European ancestry. Over 9 million U.S. residents are living with sight-threatening AMD. Biochemical analyses and in vivo imaging studies indicate that genetic, dietary, and environmental factors influence tissue concentrations of macular xanthophylls (MXs) within the retina. Photoreceptors, retinal cell types manifesting AMD pathology, have been shown to contain MXs. In this work, we comment on the putative role of the MXs (lutein, zeaxanthin, and meso-zeaxanthin) in AMD and report findings from our genome-wide analyses of AMD-associated genes that encode enzymes, transporters, ligands, and receptors influencing or influenced by MXs. Our cohorts contained a total of 1555 people with advanced AMD (AAMD) and 1170 of their peers who were both AMD-free and ≥65 years of age. Data from our 12-year prospective discovery sample (Age-Related Eye Disease Study [AREDS]) were used to investigate the age-, sex-, and smoking-adjusted relationships of AAMD (neovascular [NV] AMD and/or geographic atrophy [GA]) with allelic variation in 1060 single-nucleotide polymorphisms (SNPs) residing within 275 genes encoding products with the capacity to interact with MXs. We used age-, sex-, and smoking-adjusted meta-regression to analyze 2710 gene variants from these same genes within three university hospital-based cohorts (1177 people with AAMD and 1024 AMD-free controls) in our replication study. In both our discovery and replication cohorts, AMD-associated DNA sequence variants existed in genes encoding transporters and receptors reported to bind MXs in model systems (scavenger receptor class B type I [SCARB1], ATP-binding cassette transporter A1 [ABCA1], and tubulin gamma complex associated protein 3 [TUBGCP3]), nuclear hormone receptors that bind MXs (retinoic acid receptor gamma [RARG] and retinoic acid receptor beta [RARB]), growth factors influenced by carotenoids (insulin-like growth factor 1 receptor [IGF1R] and insulin-like growth factor binding protein 1 [IGFBP1]), and genes associated with both low levels of retinal MXs and inherited retinal degenerations (aldehyde dehydrogenase 3 family member A2 [ALDH3A2] and ABCA4). We have demonstrated that data from large-scale genotyping projects may be effectively applied to strengthen inferences and elucidate novel relationships on factors and processes influencing metabolism and metabolic fate of nutrients in the context of health and disease.