Clinical Applications of Age-Related Macular Degeneration Genetics

Abstract

Understanding genetic causes of age-related macular degeneration (AMD) will eventually yield effective discoveries and improvements in predictive/prognostic methods. These include, but are not limited to, reliable disease prediction (screening for increased discrimination of clinical risk), differential classification of AMD subtypes with biomarkers (development of risk-linked molecular taxonomies), selection of optimal preventive and therapeutic interventions (guided by a biologically meaningful understanding of treatment response), and drug dosing. In this review, we discuss clinical applications informed by key findings in AMD genetics, and provide commentary on leveraging extant and forthcoming evidence to improve AMD risk prediction, AMD classification, and knowledge on the genetic basis of drug activity and toxicity. Advances in translating AMD genetics findings for AMD risk prediction require development of a genetics-based causality for AMD incidence and progression. Molecular subtyping of AMD phenotypes requires a set of dynamic biomarkers presenting prognostic value; although these have yet to be identified, the formation of multidisciplinary teams and their participation in large-scale consortia may yield promising results. Drugs targeting complement and vascular endothelial growth factor (VEGF) systems are under evaluation, and forthcoming work on rare variants and noncoding DNA in AMD pathogenesis will likely reveal biochemical pathways enriched with AMD-associated genetic variants. Pharmacologic targets in these pathways may inform a rational and effective therapeutic approach to preventing and treating this sight-threatening disease.A ge-related macular degeneration (AMD) is a complex sight-threatening disease of public health significance . Knowledge on the nature of AMD phenotypes and related pathogenic processes (as well as on constraints in approaches to investigation) has influenced our ability to make inferences on a geneticsbased causality of this disease. Such inferences are necessary in the development of feasible clinic-based approaches for effective AMD prevention, prognosis, and treatment (Gorin 2012). In this review we discuss clinical applications informed by key findings in AMD genetics, and provide commentary on leveraging extant and forthcoming evidence to improve AMD risk prediction, classification, and knowledge on the genetic basis of drug activity and toxicity. We start with a definition of AMD phenotypes and follow with an overview of what research in AMD genetics has told us about the nature and

Resveratrol Based Oral Nutritional Supplement Produces Long-Term Beneficial Effects on Structure and Visual Function in Human Patients

“…It is the study of non-DNA sequence-related heredity that helps explain the relationship between an individual’s genetic background, the environment, aging, and disease. In 2013, researchers from a multinational consortium reported results on 19 common susceptibility loci from DNA analyses on nearly 80,000 people, and in aggregate, these loci explain only 10%–30% of the phenotypic variation of AMD [ 28 , 29 ]. The epigenetic state varies among tissues during a lifetime, whereas the DNA sequence remains essentially the same.…”

Succinic semialdehyde dehydrogenase deficiency (SSADHD): Pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism

“…This finding might be correlated with reduced SSADH enzyme activity associated with TC and TT genotypes, potentially altering intracerebral GABA and GHB levels and a potentially enhanced metabolic interference with the role of methadone in blockade of opioid pathways (Antoniou and Tseng 2002). Further, SanGiovanni and colleagues (2014) identified a significant association between AMD (age-related macular degeneration) and ALDH5A1 gene structure. AMD patients showed different allele frequencies with respect to controls for three SNPs localized in intron 7 of ALDH5A1, and a second SNP in intron 8, pointing to an interaction of GABA metabolism with AMD.…”

An Updated Review of the Epigenetic Mechanism Underlying the Pathogenesis of Age-related Macular Degeneration

“…The susceptibility to AMD conferred by genetic variants has been revealed by genome-wide association studies, as mentioned above; these genes may predict the risk of AMD in less than half of the human population [ 21 , 22 ]. Seddon et al claimed that although 46-71% severity of AMD may be attributed to genetic background, the remaining 19-37% cases may be influenced by epigenetic factors [ 23 ] The pathogenesis of AMD, a complex disease, cannot be entirely explained by genetic variations; if the pathogenesis of AMD is solely controlled by genetic factors, theoretically, the disease should occur early rather than late in life.…”