A common genetic variant influencing the body’s initial defense against viruses has been identified as a factor increasing the risk of severe COVID-19, according to a new study led by the Spanish National Research Council (CSIC). The research, published recently in the journal iScience, reveals that a polymorphism in the OAS1 gene can impair the antiviral response, potentially leading to more serious illness.
The OAS1 gene produces a protein that recognizes viral signals and activates another protein, RNase L, which destroys the genetic material of viruses like SARS-CoV-2, hindering their replication. The study found that a specific variant of OAS1, known as rs10774671, reduces the effectiveness of this initial defense. Individuals inheriting two copies of this variant exhibit a heightened risk of developing severe COVID-19.
Researchers analyzed genetic samples from 342 patients between the ages of 18 and 65 who had been infected with SARS-CoV-2. Their genomes were sequenced to identify both rare and common variants in the OAS1, OAS2, and OAS3 genes, all involved in the early antiviral response. Experiments were then conducted using human cells and genetically modified mice lacking the OAS3 gene to observe the impact of these variants on the antiviral pathway.
The team observed that mice deficient in the OAS3 gene showed increased levels of cytokines – molecules used by cells to coordinate the immune response – after infection. Elevated cytokine levels can contribute to uncontrolled inflammation. This suggests that the protein produced by OAS3 helps regulate, or dampen down, inflammatory responses.
While the study confirms the role of the OAS1 variant (rs10774671) in disease severity, researchers emphasize that it does not solely determine clinical outcomes. Factors such as age, sex, and ethnicity also play a significant role. The variant modulates risk, but does not guarantee a severe illness. “Our work suggests that this is probably due to the fact that the OAS1 protein encoded by this polymorphism inhibits the replication of the SARS-CoV-2 virus less efficiently,” explained Jordi Pérez-Tur, a researcher involved in the study.
The findings align with previous research indicating that genes within the OAS family can influence the clinical course of COVID-19. The study indicates that the identified OAS1 variant plays a more significant role in severity than other, rarer variants previously considered decisive. Anna M. Planas, another researcher on the team, noted that possessing the polymorphism increases risk, but does not guarantee a severe outcome.
The OAS1 polymorphism is present in approximately one in five people and has an ancient evolutionary origin, tracing back to Neanderthals, according to the researchers. The study underscores the importance of understanding how genetics influences responses to SARS-CoV-2, both for identifying potential vulnerabilities and for informing diagnostic and preventative strategies in future health emergencies.
