A ‘behind-the research’ conversation with René L. Warren on unravelling the genetic clues to COVID-19 severity

By: Shantala Hari Dass

As the world grappled with the complexities of the COVID-19 pandemic, scientists raced to comprehend the factors influencing the severity of the disease. Intrigued by the spectrum of COVID-19 severity, researchers from Dr. Inanc Birol’s group at Vancouver’s Michael Smith Genome Sciences Centre, led by Bioinformatics Team Leader René L. Warren, embarked on a quest to understand the spectrum of COVID-19 severity, including possible links to immune genes.

The Human Leukocyte Antigens (HLAs) are such genes and, for the central role they play in human immunity, they are disease determinants. Because versions of HLA genes (called HLA alleles) are found at different frequencies within human populations, they could be a molecular clue to explain why certain groups might be more susceptible to infection and exhibit more or less severe symptoms. HLAs can be likened to servers presenting food in a restaurant. When the body encounters a pathogen, it breaks it down into protein fragments, presented by HLA ‘servers’ to immune cells, triggering an immune response. However, these ‘servers’ are selective in what they present. Several HLA variants, such as HLA-C*04:01, bind to viral degradation fragments from the SARS family, which includes the coronavirus responsible for COVID-19. In our analogy of ‘server’ genes, HLA-C*04:01, contrary to most HLA variants, can be seen as serving only a restricted number of viral fragments to the host immune system, potentially limiting the immune system’s ability to combat the COVID-19 virus.

At the start of the COVID-19 pandemic, multiple research groups began probing for possible associations between HLAs and COVID-19 disease outcomes. Such studies had to march in real-time with efforts to collect data and build datasets. Warren aimed to investigate whether our HLA makeup influences susceptibility to and severity of COVID-19, and they had the exact tool to do it.

“We had developed a bioinformatics tool called HLAminer a decade ago, aimed at determining HLA types from next-generation sequencing datasets. We saw potential in applying this tool to explore this research question,” Warren explains

The research team began analyzing existing data, starting with whole genome sequences from eight COVID-19 patients at the Wuhan seafood market, leading to the first publication of this research in 2020. They expanded their analyses to include a genomic dataset with meta/clinical variables from COVID-19 patients in New York. While these initial studies revealed an intriguing (but weak) association between an HLA allele-C*04:01- and severe COVID-19, they were limited by the small sample sizes of 100 patients.Since the initial report of an association between HLA-C*04:01 alleles and COVID-19 severity, many other research teams have confirmed these findings in patient cohorts worldwide, including in Europe, India, Armenia, Spain, and the United Arab Emirates. However, these studies were also limited by small (in the range of 100s) sample sizes.

Since the initial report of an association between HLA-C*04:01 alleles and COVID-19 severity, many other research teams have confirmed these findings in patient cohorts worldwide, including in Europe, India, Armenia, Spain, and the United Arab Emirates. However, these studies were also limited by small (in the range of 100s) sample sizes.

A pivotal step for Warren was analyzing the HostSeq dataset. HostSeq is a first-of-its-kind Canadian genomic and clinical databank driven by CGEn and COVID-19 studies from across Canada, that is broadly consented for health research. The databank contains genomes, and health metadata for 10,000+ participants affected by COVID-19. “Working on the HostSeq dataset was our plan from the start,” he says. This collaboration enabled the team to leverage a larger dataset, essential for robust conclusions.

Their findings were confirmatory – certain HLA alleles, such as C*04:01 and A*11:01, emerged as potential markers for severe COVID-19 cases (measured as the requirement for mechanical ventilation). However, the authors remain cautious, merely having these genes does not necessarily mean one will develop severe COVID-19, just that the probability is higher

What might the clinical implications of this study be? Characterizing the HLA alleles of COVID-19 patients could serve as a valuable prognostic tool. While COVID-19 is no longer a pandemic, these findings could help in guiding public health decisions for COVID-19 — such as vaccine dissemination strategies and disease management.

Using existing publicly available datasets, Warren and the research team were able to extend their expertise to address a topical and timely challenge. Looking ahead, the researchers hope to validate their findings on an even larger scale and with diverse datasets.

Footnote:

The research story captured here was published in Establishing association between HLA-C*04:01 and severe COVID-19, HLA. 2024 Jan;103(1)
The HostSeq databank (genomic data and health metadata) is accessible to the Canadian and international research community. The data has been consented for use in any approved health research project. More details about the phenotype variables can be found on the data portal. Currently, over 30 research projects have been approved to use this data.If you would like to learn more about HostSeq and the data access process please click here.

DNA Day: CGEn Celebrates 10,000 Human Genomes in the Canadian HostSeq Databank

April 25, 2022 – CGEn, Canada’s national platform for genome sequencing and analysis, and its partners are marking World DNA Day by celebrating Canada’s landmark human genome sequencing initiative called HostSeq. Led by CGEn, the HostSeq databank will include the whole genomes (the full set of DNA) of 10,000 Canadians (“Hosts”) with the aim to help understand the genomic architecture of the host response to COVID-19. The HostSeq databank also includes linked standardized clinical information collected at multiple clinical sites across Canada over the past two years of the pandemic.

“The need for a national genomics databank grew very quickly early on in the pandemic. As soon as we started to observe differences of disease manifestation and symptoms in people infected with SARS-CoV-2 virus, we realized that there was an urgent need to collect and analyze population-wide host genetic data,” explains Dr. Naveed Aziz, Chair of the HostSeq Implementation Committee and Chief Executive Officer, CGEn. “The Government of Canada’s prior investment in CGEn allowed us to deploy our capacity to sequence genetic information of Canadians who were experiencing vastly different health outcomes in response to infection by the virus.”

The national HostSeq initiative, funded by the Federal government through Genome Canada’s Canadian COVID-19 Genomics Network (CanCOGeN), is accessible to Canadian and international researchers to help study the health outcomes of those affected by the virus and to identify the genetic contributors of disease severity. This first-of-its-kind Canadian genomics databank may help to better diagnose and treat those predisposed to severe illness, backed by their genomic data.

Owing to a concerted effort led by CGEn and its team, 14 clinical and research studies across the country were brought together to contribute to the databank that includes 10,000 study participants who have consented to the use of their genomic and clinical data for future research. The HostSeq databank will not only help to answer current research questions related to the virus, but will also serve as a resource when responding to future infections and preparing for future pandemics.

“We are thrilled to have a population-based whole genome sequencing effort in Canada,” says Dr. Lisa Strug, Director of the University of Toronto’s Data Sciences Institute and the Ontario regional Centre of the Canadian Statistical Sciences Institute; Senior Scientist, Genetics and Genome Biology, and Associate Director, The Centre for Applied Genomics, The Hospital for Sick Children (SickKids). “Many countries have whole genome sequencing cohorts that they have made available and have had an important impact in health research broadly. The HostSeq databank will provide the Canadian perspective, and reflect data from individuals living in Canada,” says Strug, who is part of the HostSeq Implementation Committee and Chair of the Genetic Epidemiology Committee.

The COVID-19 Host Genome Sequencing project (HostSeq) is Canada’s largest national genomic databank to date containing genome sequences linked to medical and clinical data from 10,000 individuals affected by COVID-19

The HostSeq databank gives Canadian scientists access to a rich dataset to help analyze and identify genetic determinants of susceptibility, severity and outcomes of COVID-19. It will also enable researchers to investigate population-level risks for many other diseases, including the potential to deliver new biomarkers that support prediction of risk, and novel therapeutic strategies.

This DNA Day, there are countless scientific advancements to celebrate, and Canadians can count the HostSeq databank as a major step in how important population-level data can be collected and shared to help advance research and health care in Canada.

“The delivery of the HostSeq project would not have been possible without the effort and commitment of its Implementation Committee, whose tireless efforts since the beginning of the project has allowed CGEn to play a key role in Canada’s response to the COVID-19 pandemic. The HostSeq project has proven that large-scale genomics is a present reality in Canada. The time is now for all partners and stakeholders to come together and build on the years of investment and effort towards a Canadian ecosystem where research is enabled by large datasets,” says Aziz.

Linked Resources

Read about the importance of Big Data in enabling data-driven Canadian research and discovery in Dr. Naveed Aziz’s latest blog post.

To apply for HostSeq data access, please visit the CGEn website.

About CGEn

CGEn is a federally funded national platform for genome sequencing and analysis. Established in 2014, CGEn employs over 200 staff, and is funded primarily by the Canada Foundation for Innovation (CFI) through its Major Science Initiatives Fund (MSI), leveraging investments from Genome Canada and other stakeholders. CGEn operates as an integrated national platform with nodes in Toronto (The Centre for Applied Genomics at The Hospital for Sick Children), Montréal, (McGill Genome Centre at McGill University) and Vancouver (Canada’s Michael Smith Genome Sciences Centre), providing genomic services, including genome sequencing and analysis, that enable research in agriculture, forestry, fishery, the environment, health sciences, and many other disciplines of interest to Canadians.

Tag: HostSeq