Written by Charlotte Harrison, Science Writer.
Why do some people get seriously ill with COVID-19 while other people have only mild or absent symptoms? A new paper published in Nature sheds light on the genetic factors that underlie severe disease, and also highlights possible new treatments based on existing drugs.
Critical illness associations
The international team of researchers analysed over 24,000 cases of severe and critical COVID-19 based on microarray genotype and whole-genome sequencing data from the GenOMICC study, ISARIC4C and the SCOURGE consortium. They also used previously published work to conduct a meta-analysis, putting their results in the context of existing knowledge.
They found 49 genome-wide associations, and 16 of these had not been reported previously; a full list is available in Table 1 of the paper.
Many of the associations were linked to the pathogen–host interaction, including those previously identified, such as the entry receptor ACE2, the host protease TMPRSS2 that facilitates viral entry and RAB2A, which is involved in viral replication.
Disease mechanisms
The researchers then quantified the effect of gene expression in disease-relevant tissues, and found associations between severe COVID-19 and gene expression in lung, blood, and monocytes.
They also assessed the effect of the genetic variation on circulating protein levels, and identified 15 unique proteins linked to critical illness, several of which were not seen in previous studies. These proteins included those with known roles in sepsis and blood clotting, namely the neutrophil effector enzyme myeloperoxidase, the innate immune pattern recognition receptor MBL2 and ADAMTS13, which is involved in coagulation.
Druggable targets
Finally, the researchers assessed if any of the proteins that were linked to severe disease might be easily targeted through the use of existing drugs – that is, drug repurposing. To this end, they found potentially druggable targets including JAK1 (involved in inflammatory signalling), PDE4A (monocyte–macrophage activation) SLC2A5 and AK5 (immune metabolism) and TMPRSS2 and RAB2A (viral entry and replication).
Moreover, they found a positive association between the expression of the inflammatory cytokine tumour necrosis factor (TNF) and severe disease; this finding indicates that currently available TNF inhibitors might be effective in severe COVID-19.
“[The study] expands our understanding of how genetic differences between people lead to differences in their risk of developing life-threatening illness in Covid-19,” said study author Konrad Rawlik in a press release. “Most importantly, these results point us at already available drugs which could be repurposed to treat severe Covid-19.”
