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German COVID-19 Project Aims to Better Understand Role of Genetics in Disease Severity

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NEW YORK – A new German private-public research project will combine genotyping arrays, next-generation sequencing, and bioinformatics resources to identify variants that make patients with COVID-19 more likely to develop mild, severe, or fatal disease.

Atlas Biolabs, a Berlin-based biotechnology firm, is leading the effort, called Epi-Dx. The project has a budget of €890,000 ($1 million), mostly funded by the German government, and will run through the end of 2023. Epi-Dx also involves In.vent Diagnostica and MicroDiscovery, two other Berlin companies. Additionally, it will draw upon the resources of DiagnostikaNet BB, a network of companies and institutions in Berlin and the state of Brandenburg, which surrounds the nation's capital.

Karsten Heidtke, director of bioinformatics and research at Atlas Biolabs, said the new project emerged from discussions within DiagnostikaNet BB, which he termed a "one-stop shop" for such collaborations in Berlin, though it has members from elsewhere in Germany and Europe.

Initial dialogue about Epi-Dx started within DiagnostikaNet BB last June, and the German Federal Ministry of Education and Research agreed to fund it as of January 1. The government is providing roughly 80 percent of the total budget, while the partners will contribute the rest.

"We hopefully can identify variants that could explain severe cases," Heidtke said of Epi-Dx. "One should also keep in mind that we will share the data we generate within the community, and expect to access data from other projects. That way, we can increase the statistical power of our dataset."

The partners will generate the data using Thermo Fisher Scientific Axiom genotyping arrays, formerly sold by Affymetrix, as well as Illumina whole-exome sequencing assays. Atlas Biolabs is a service provider for both vendors. They intend to survey up to 500 people with SARS-CoV-2 by the end of the project, and will use bioinformatics tools to look for variants indicative of developing less or more severe symptoms in COVID-19 patients.

In.vent Diagnostica will provide access to patient samples, while MicroDiscovery will contribute data analysis expertise. "In.vent has good connections to medical care centers and physicians," noted Heidtke. "That will make it easy for us to get our hands on COVID-19 samples for the project."

Heidtke said one catalyst for Epi-Dx was Thermo Fisher Scientific's decision to customize its Axiom Precision Medicine Research Array to focus on two genes of interest, encoding the ACE2 receptor and the TMPRSS2 protease, which facilitate viral entry into the host cell. The researchers believe that differences in disease severity might be explained by the presence or absence of certain variants in these genes in different individuals. Genetic variants in SARS-CoV-2, the virus that causes COVID-19, will also be investigated during the study.

The ability to run the enhanced chip, called the Axiom Human Genotyping SARS-CoV-2 Research Array, in high throughput on the 96-well Axiom GeneTitan instrument will allow the researchers to generate data in a rapid fashion. Heidtke said he predicted that the first batch of data from about 100 patients could be generated by July. This could already result in some potential leads for the researchers' analysis pipeline. Yet the Epi-Dx team will not only use microarray analysis to search for variants of interest, Heidtke said.

"Of course, a microarray is usually a broad scan of known sites, so you don't have the exact sequence and can only look at specific SNPs and copy number variants," commented Heidtke. "As this research is all very new, we thought we should complement the microarray technology with next-generation sequencing."

By employing complementary techniques, the researchers will aim to discover more variants and validate their findings. "We will also have a more statistical basis for analysis and also will have a way to look for regions not covered by microarray that hold important variants that could have an impact on disease severity or for mild symptoms," said Heidtke. The researchers will also use next-generation sequencing to study families suffering from COVID-19 in greater depth.

The ultimate goal is to better understand epidemiological trends, as well as to potentially target care for patients. It is one shared by various other studies focused on disease susceptibility and severity, several of which were reported at the American Society of Human Genetics annual meeting in October. Heidtke noted that Epi-Dx has joined the COVID-19 Host Genetics Initiative, an international effort to pool data and information from various studies. 

Frank Bier, chair of molecular bioanalysis and bioelectronics at the University of Potsdam and a board member of DiagnostikaNet BB, noted that Epi-Dx is one of several ongoing projects focused on SARS-CoV-2 taking place with the help of the network. Other projects are dedicated to whole-proteome virus screening; benchmarking tests for SARS-CoV-2; developing rapid, point-of-care tests; creating more sensitive antigen tests; and setting up an AI-guided virtual test center for at-home SARS-CoV-2 testing with the assistance of city authorities in Berlin.

All of these efforts, including Epi-Dx, are necessary to better respond to the pandemic, Bier said.

"To combat the pandemic, vaccination is necessary, however this will take months, and the pandemic will not be over until everyone has been vaccinated," said Bier. "The virus will continue to mutate as long as it finds victims, and since this may last for decades, diagnostics will be needed." Because of this, innovation remains necessary in point-of-care testing, detecting a patient's susceptibility to developing severe disease, as well as antigen and antibody testing.

"COVID-19 is a disease that has to be treated individually, as in other cases of disease," noted Bier. "COVID-19 may hit everybody, but the response is individual and therefore we need to transfer the concept of personalized medicine that has been developed for cancer treatment to infectious diseases as well."

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