By reanalyzing the AncestryDNA COVID-19 study, researchers have found that many genetic risk factors for COVID-19 and influenza do not overlap. The study found that risk factors for each of these respiratory illnesses do share a common feature—they are linked to cell surface proteins that may be required for viral entry—which, though not surprising, may offer treatment opportunities.
The study’s most promising lead, ST6GAL1, is an enzyme that adds a sialic acid to the cell surface, a linkage that has been previously shown to participate in the entry of the influenza virus into human cells. In this study, knockdown of ST6GAL1 using small interfering RNA (siRNA) reduced influenza infectivity by 57% in vitro. This initial experiment, which was performed using adenocarcinoma human alveolar basal epithelial cells (A549), is the first report of a genome-wide-significant loci for influenza, according to the authors.
Re-investigating the COVID-19 AncestryDNA cohort
While COVID-19 and influenza share symptoms and clinical risk factors, the extent to which these conditions have a common genetic etiology had not been fully clarified. This is partly because host genetic risk factors are well characterized for COVID-19 but not for influenza, with the largest published genome-wide association studies for these conditions including >2 million individuals and about 1,000 individuals, respectively.
To understand the extent to which the same host genetic factors influence the risk of coronavirus disease 2019 (COVID-19) and influenza, a genome-wide association study (GWAS) of influenza infection was performed that also used survey data from 296,313 participants of the AncestryDNA COVID-19 study who consented to the research. Although that study focused on risk factors for COVID-19, participants also indicated if they were tested for influenza in either the 2019–2020 or 2020–2021 flu seasons. Overall, 18,448 (6.2%) participants reported a positive test for influenza and thus were considered cases for our analysis, while the remaining 277,865 participants (including 23,985 with a negative test) were considered population-level controls.
Using these data from AncestryDNA, the study tested the association between reported influenza infection and 10 million common (frequency >1%) imputed variants. This analysis was performed separately in three ancestral groups (with >100 influenza cases) defined based on genetic similarity to three populations studied by the 1000 Genomes Project from Europe (254,750), Africa (12,951), and the Americas (26,928).
ST6GAL1 is linked to influenza infection
Two loci were identified that were associated with influenza infection at a commonly used significance threshold (P −8). These loci, noncoding variants found near the ST6GAL1 and B3GALT5 genes, were then evaluated for sensitivity and replication analyses in independent cohorts, using medical records across 1,153,291 individuals from seven biobanks and five ancestral groups, demonstrating the reproducibility of these associations.
ST6GAL1, which codes for the enzyme β-galactoside α-2,6-sialyltransferase 1 that catalyzes the addition of sialic acid to galactose, by an α-2,6 linkage, which is found on the human host cell surface glycoproteins and glycolipids in the upper respiratory tract and is used by the virus as attachment factors that facilitate the subsequent engagement with a functional receptor required to enter the target cell. Knockdown of ST6GAL1 results in approximately 50% reduction of in vitro influenza infectivity, consistent with previous findings. In contrast, knockdown of B3GALT5 expression was not associated with a consistent effect on influenza infectivity.
COVID-19 and influenza share little genetic etiologically
When compared to 24 variants associated with COVID-19 identified by the Host Genetics Initiative (HGI), ten had a consistent direction of effect on both influenza and COVID-19. One variant near the gene ABO—glycosyltransferase enzyme that determines an individual’s ABO blood type by modifying the oligosaccharides on cell surface glycoproteins—showed an inverse relationship between the respiratory diseases, linked to an increase in the risk of influenza infection and a decreased risk for COVID-19. Of note, a recent 23andMe study also reported a similar pattern of opposing associations with COVID-19 and influenza at the ABO locus.
The researchers conclude that the lack of significant and directionally consistent associations between reported influenza infection and COVID-19 loci suggests that the two diseases share few—if any—genetic risk factors. Consistent with these findings, the two risk variants for reported influenza identified in the AncestryDNA GWAS (in or near B3GALT5 and ST6GAL1) did not have a directionally consistent association with COVID-19 in the HGI analysis.
It is important to note that the study’s influenza-infected population was categorized using self-reporting and does not represent true susceptibility to infection. The control group includes an undetermined number of individuals not exposed to influenza in either season or who were infected but not tested (for example, asymptomatic).
This study, led by the Regeneron Genetics Center and published in Nature Genetics, involved researchers from several academic institutes, including the University of Pennsylvania’s Perelman School of Medicine, the Colorado Center for Precision Medicine, the Mayo Clinic Project Generation, and the University of California Los Angeles ATLAS Collaboration.
