The key to reducing the individual and societal burden of age-related

The key to reducing the individual and societal burden of age-related macular degeneration (AMD)-related vision loss is to be able to initiate therapies that slow or halt the progression at a point that will yield the EDNRB maximum benefit while minimizing personal risk and cost. adaptation kinetics and/or critical flicker fusion frequencies) may be more subtle indicators of AMD-associated early retinal dysfunction. One can test for the relevance of these measures using genetic risk profiles based on known genetic risk variants. These functional measures may improve the sensitivity and specificity of predictive models for AMD and may also serve to delineate clinical subtypes of AMD that may differ with respect to prognosis and treatment. genes [6 7 in AMD risk. At approximately the same time two genome-wide association studies (GWA) SU 11654 studies [8 9 also identified associations of variants in these two genes with AMD. Multiple candidate gene association studies were undertaken (for review see: [10]) particularly of the genes regulating the alternative complement pathway confirming risk alleles in C2/BF C3 and others [11]. Later large-scale GWA studies with case-control cohorts confirmed these associations as well as with other genes in the complement pathway lipid metabolism pathways and extracellular matrix SU 11654 biosynthesis and regulation. In addition several genetic loci that were novel with respect to these pathways have also been found [10]. At present 20 autosomal genetic loci have common variants with statistically significant associations with AMD. Mitochondrial genetic variants [12 13 14 15 16 as well as rare variants in several genes notably and [17 18 19 20 21 have been implicated in AMD pathogenesis. Yet with all these discoveries we still cannot account for the complete heritability of AMD. There are individuals across the spectrum of AMD risk who will develop the condition despite relatively low genetic risk and others who will not progress to advanced disease even with several high-risk variants. Further our risk prediction models are SU 11654 inadequate for use in the preclinical AMD population. Some of this may be due to epigenetic phenomena that have not yet been considered gene-gene interactions or the effects of other exogenous contributors such as smoking and diet as well as the human microbiome. Further genetic studies may refine our risk models but it will remain a SU 11654 challenge to know how to interpret the impact of rare variants on genes associated with AMD particularly when those variants do not affect protein structure. If one of our primary goals in AMD research is to delineate the pathobiology of the condition then we are well on our way to achieving that goal though it will take more than population-based genetic association studies to understanding the underlying biological interactions and pathways. It is important to remember that complex genetic conditions are not simply heterogenous collections of disorders nor do they follow the classic laws of causality that are attributed to Mendelian genetic disorders. They represent relatively subtle derangements of normal biological processes that over time lead to a dysregulated state associated with a disease process [10]. Some rare variants related to AMD may have sufficient penetrance to mimic a Mendelian genetic disorder [18 19 20 but most of the common variants appear to have a probabilistic impact on disease risk rather than being necessary and sufficient. If we are hoping to use the molecular genetics of AMD as part of personalized medicine with the intention of the early recognition of at-risk individuals to prevent or reduce the impact of disease then we need to combine genetics with another set of tools to achieve the sensitivity and specificity to appropriately target the population for treatment. These tools are either to detect preclinical functional and/or structural derangements in the retina/RPE/choroid complex or to measure dynamic levels of molecules in the blood or eye (biomarkers) that are associated with AMD and which reflect both genetic and exogenous influences on pathways that contribute to AMD pathogenesis. There is obvious overlap of these two approaches since instruments that can measure levels of specific molecules in the eye and localize them are both defining.