Small Changes, Big Consequences

At the onset of the COVID-19 pandemic, Pandurangan Vijayanand was primed to tackle this new challenge. Trained as an immunologist with a specialization in genetics and genomics, he had already established a project called DICE, for database of immune cell gene expression, epigenomics, and expression quantitative trait loci (eQTLs), which helps elucidate the genetic basis of disease susceptibility. With DICE, scientists combine data from genome wide associate studies (GWAS) with additional supporting analyses to reveal how genetic variations affect the immune response. By querying a database of common circulating immune cell profiles, researchers gain insights into the molecular mechanisms responsible for cell type-specific immune responses observed in many different diseases.

Using DICE, Vijayanand and his team analyzed publicly-available data from GWAS for several COVID-19 phenotypes to find genetic variants with functional consequences. They assessed the effects of common COVID-19 variants and found a number that significantly affected gene expression in certain immune cell subsets.¹ These data shed light on COVID-19 disease mechanisms and could inform therapeutic development and precision medicine.

What inspired the DICE project?

Genetics play an important role in driving disease risk. A GWAS shows that there is a genetic component, but the study does not tell you what the variants do. We needed to connect genetic variation to specific molecular pathways and cell types to understand how they are affected.

Which genes and immune cells were most affected by common COVID-19 variants?

A single nucleotide polymorphism (SNP) that causes a large change in gene expression likely affects an important pathway. We found that some COVID-19 risk SNPs affected the expression of the interferon response genes OAS1 and OAS2 in non-classical monocytes, a rare type of innate immune cell that patrols the lungs and the vasculature. During coronavirus infection, these cells get infected, or they take up cells that are infected. If there is a defect in interferon response genes, which block viral replication, there will be uncontrolled replication, which will cause exaggerated symptoms later on.

We also found SNPs affecting gene expression of the IL-10 receptor in NK cells. IL-10 is a double-edged, immunomodulatory cytokine. There needs to be a sufficient anti-inflammatory signal to stop inflammation. If there is too much of it, the body will not mount a good response. If there is too little of it, there will be an exaggerated immune response. Our data suggests that the IL-10 pathway may be important in severe COVID-19 pathogenesis.

 What are your next steps to expand this study? 

COVID-19 is a disease that infects the lungs. Clearly, immune cells circulate, but there is a population of cells that reside in the tissue. These cells have different phenotypes from cells that circulate in the blood. We started a large-scale project prior to the pandemic to understand resident immune cells in the lung and ask how common variants influence them. I hope that in the next couple of months, we will be able to explain how these COVID variants affect lung resident immune cells.

What is the potential for using these genetic variant-function analyses in the future?

Getting to know these SNPs is likely to give you risk scores. I envision that in a few years, we will have clear genetic risk scores for viral susceptibility. Genetic stratification will be in mainstream clinical medicine, I hope, in the next five to ten years.

The GWAS space is expanding, which means that as we add more people to our studies, we will find rarer variants that link to COVID-19 susceptibility. The next step is to understand what those SNPs do—to understand the spectrum of molecular pathways that change or confer risk for severe disease. Drug companies keep a very close eye on this because genetics clearly predict better therapeutic efficacy. This is a resource for drug companies repurposing existing drugs or designing new drugs to target these pathways.

Also, COVID-19 it is not the last epidemic. These results highlight how an exaggerated immune response to viral infection causes serious consequences. The principles we learn will be broadly applicable.

This interview has been edited and condensed for clarity.

Reference

1. B.J. Schmiedel et al., “COVID-19 genetic risk variants are associated with expression of multiple genes in diverse immune cell types,” Nat Commun, 12:6760, 2021.