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  • Periodic Reporting for period 1 - EYE-RISK (Exploring the combined role of genetic and non-genetic factors for developing Age-Related Macular Degeneration: A systems level analysis of disease subgroups, risk factors, and pathways)

EYE-RISK Report Summary

Project ID: 634479
Funded under: H2020-EU.3.1.1.

Periodic Reporting for period 1 - EYE-RISK (Exploring the combined role of genetic and non-genetic factors for developing Age-Related Macular Degeneration: A systems level analysis of disease subgroups, risk factors, and pathways)

Reporting period: 2015-05-01 to 2016-10-31

Summary of the context and overall objectives of the project

Age-related macular degeneration (AMD) is a chronic and progressive disease of the retina and is the most frequent cause for legal blindness in the EU. Patients suffering of late AMD lose their central vision. Because this impedes the ability to read and drive, AMD affects their quality of life. AMD is also causing increasing costs on the aging European society as it reaches a frequency of up to 25% in those aged 85 years and older. AMD is a complex disease caused by a combination of non-genetic as well as genetic factors. The most powerful factor influencing the risk for AMD is the factor “being over the age of 60”. AMD can affect the retina either as wet form (also called neovascular) or as dry form (also called atrophic). Neither form can be cured. There is a therapy for the slowing of progression to choroidal neovascularization; unfortunately, a therapy for the dry form is still lacking.

Research to understand AMD is aiming to predict, prevent and treat AMD. So far, genetic and epidemiologic studies have been able to pinpoint a number of genetic variants as well as environmental and lifestyle factors that define the individual risk for AMD. Turning this knowledge into prediction, prevention and treatment is difficult because disease progression varies widely between individuals and more than one cellular pathway contributes to the retinal degeneration in AMD.

The consortium EYE-RISK is using systems medicine to approach the difficulties to understand AMD. EYE-RISK chose systems medicine because it analyses current data from new angles and uses multiple methods to subject intermediate findings to rigorous test rounds for validation. This approach has an increased power to extract relevant information from existing databases and to validate new findings. EYE-RISK is funded by the EU programme Horizon2020 within its personalising health and care challenge PHC-01 “Understanding health, ageing and disease: determinants, risk factors and pathways”.

The planned output in EYE-RISK comprises i) an algorithm for predicting AMD risk; ii) predicting progression and conversion; iii) an array of proteins that confer risk; iv) identification of a molecular driver other than proteins for disease progression; v) a web-based prediction programme to be used by clinicians for patients at risk.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In the first period of the consortium, both clinical and laboratory efforts of EYE-RISK were put into gear. We have been performing in depth analyses of existing epidemiological and genetic data on pre-existing cohorts within the European Eye Epidemiology (E3), which collaborates with EYE-RISK. We calculated the current visual burden of disease and made projections for future disease occurrence showing a doubling of patients with AMD in the next 20 years. In addition we have been creating a network model of genes and their corresponding proteins mainly based on the genetic data, and in-depth investigated candidate markers and network components for their role in AMD pathogenesis. We focus on published loci strongly associated to AMD risk (International Age-related Macular Degeneration Genomics Consortium; Nature Genetics 2016 with contributions from EYE-RISK partners). This subset of loci is analysed in silico and in vitro. We built a computational simulation of disease pathways that centres on the genetic risk loci and we characterised several of these proteins by protein chemistry, cellular assays and mass spectrometry.

The output of this analysis has been subjected to patient versus control biomaterial for significance. Further cellular as well as organotypic models have been tested to functionally assess the role of specific candidate markers and network components potentially associated with AMD.

For in-depth analysis of multimodal data, an EYE-RISK database was set up and continuously supplied with data. This database is fed from cohort studies conducted in the framework of E3, the European Eye Epidemiology assembly. For data analysis, we have been using statistical as well as algorithmic software tools. Gene-environment interaction relationships for specific gene variants and non-genetic factors will be computed. We also extracted genotypic and phenotypic features that show significant correlation with clinically defined disease states. This will be used to build a prediction algorithm. In the laboratory approaches we are in the process of generating datasets for proteomic and transcriptomic information to refine the algorithms.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

EYE-RISK is in progress to analyse and compute the interrelationship between non-genetic as well as genetic risk factors for AMD. Specific emphasis is put on the question, how a combination of risks jointly shifts the regulation of cellular pathways towards a diseased state. Progress in the first period of the consortium has provided evidence on linking risks to the prevalence and incidence of AMD. This has generated a base for creating a risk score that will eventually allow the community to assess the AMD risk more properly as well as to determine future diagnostic and therapeutic opportunities and to generate clinical guidelines for the medical management of high-risk AMD patients.

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