Basic and clinical studies of AMD in future: questions more than answers

Epidemiology models herald a challenging future

According to various forecasting models, life expectancy is projected to increase worldwide. There is a more than a 50% probability that by 2030 in 35 industrialized countries studied, national female life expectancy will break the 90-year barrier. In several countries on the top of this list, there is a roughly 27% probability that by 2030, male life expectancy will surpass 85 years. As a consequence, by 2050 approximately a quarter of the world population will be the elderly. Longer life actually is an incredibly valuable resource, not a socioeconomic burden. However, aging that is defined as an age-specific decline in physiological function leads to an increase in age-specific diseases and mortality. A systematic literature review identified all population-based studies of age-related macular degeneration (AMD) published before May 2013. By using the standard classification and severity scale as described in Chapter 3, Chapter 4 , the prevalence of different ethnicity subgroups was also measured. Overall, it has shown that the projected number of people with AMD is around 196 million in 2020, increasing to 288 million in 2040. AMD affects central vision that significantly impairs patients’ life of quality. Despite such a high disease burden, to date there is no proven treatment for advanced dry AMD, and current treatment for wet AMD is incompletely efficacious. Both the patients and physicians are facing great challenges ahead.

Molecular genetics-based strategies for AMD prevention and treatment

Molecular genetics-based GWAS have identified numerous loci coding for rare and common variants for AMD risk (see Chapter 9). However, translation of these loci into biological insights remains a challenge, because it is difficult to pinpoint very small effects of common disease-associated variants. In addition, based on AMD-associated common variants, the genetics of AMD can only account for about 70% of the predicted risk. Future efforts will continue to identify rare and potentially highly penetrant variants in the genes already implicated from common loci, and discover other genes that may have been overlooked by traditional GWAS.

The goals of molecular genetics in future research are to better understand AMD pathogenesis and to identify potentially preventive and therapeutic targets, as outlined in the following. The first aim is how to predict AMD initiation. To date, the study of genetic risk of AMD is based on the primary endpoint of advanced stages of disease, that is, neovascular AMD (nAMD) or geographic atrophy (GA). It has been realized that the genetic risks for AMD initiation are not necessarily the same as those for AMD progression. The latter is anticipated to develop into advanced AMD. Because the presence of certain types of drusen can be defined as incident AMD, that is, the initiation of AMD pathology, the current genetic risk models are actually predicting disease progression beyond drusen formation. In other words, these models are not helpful for predicting incident AMD. Since the majority of the population has intermediate AMD risk, the predictive genetics for AMD progression would not be appropriate for predicting and preventing AMD initiation. Therefore, predictive genetic testing for incident AMD needs to be established.

The second aim is how to identify predictive genetics for AMD progression. The signaling pathways affected by functions of responsible genes will surely vary according to the gene involved. For instance, vascular endothelial growth factor receptor (VEGFR) gene variants may alter the risk of nAMD, but not play an important role in the initiation of AMD. One way to obtain risk models for AMD progression is to use a longitudinal approach, in which combined genetic, environmental, and retinal feature risk are included. Longitudinal risk models may be able to improve the prediction for AMD progression. The third aim is to correlate the genetic profiles of patients with the success or failure of their AMD treatment. The treatments for AMD are limited to date, comprising only nutritional supplements for certain types of dry AMD and anti-VEGF therapy for nAMD. The molecular genetic studies on the differential effect of the AREDS supplements among genotype groups have been inconclusive. A subgroup that could benefit from zinc supplementation in reducing progression to advanced AMD has been identified with risk allele for CFH or ARMS2 . In contrast, some reports have suggested that AREDS supplements are in fact harmful to a subset of patients. Thus, the effectiveness of AREDS supplement appears to differ by genotype. Further study is needed to determine the biological basis for the interplay between genetic risk in specific subgroups and AREDS supplement intervention. In terms of anti-VEGF strategy for nAMD, clinicians have been eager to identify the anti-VEGF treatment responsive patients, hopefully by genetic testing. Numerous epidemiological and clinical studies showed that the degree of differential response among current anti-VEGF agents is relatively small. Still, molecular genetic testing should be able to guide patients toward more effective prevention strategies, when considered in the context of environmental exposures, retinal or systemic biomarkers, and therapeutic options. At present, no genetic test can clearly establish if a patient is going to fail or succeed with a particular treatment protocol. In future research, genetics-based selection of therapies will only be relevant when there are multiple options. In the future, genetic testing may offer treatment choices for patients who are at the same stage of AMD.