Researchers in Germany have conducted a study showing that between 2 and 8% of people in Eurasia carry a genetic variant inherited from Neanderthals that significantly increases the risk of becoming critically ill with coronavirus disease 2019 (COVID-19).
The variant occurs in the promoter region of a gene called DPP4. This gene codes for the host cell receptor for Middle East respiratory syndrome coronavirus (MERS-CoV) – the agent responsible for various outbreaks of respiratory illness in several countries since its discovery in 2012.
Scientists are currently uncertain whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the agent that causes COVID-19 – can also bind to DPP4.
However, Hugo Zeberg and Svante Pääbo from the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, have now found that the Neanderthal DPP4 variant doubles the risk of becoming critically ill with COVID-19.
The interaction between SARS-CoV-2 and DPP4, therefore, deserves further investigation, says the team.
A pre-print version of the paper is available on the bioRxiv* server while the article undergoes peer review.
*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Links between Neanderthal haplotypes and COVID-19 severity
Zeberg and Pääbo recently showed that a significant genetic risk factor for becoming severely ill with COVID-19 is inherited from Neanderthals.
The team identified an association between the presence of a Neanderthal haplotype on chromosome 3 and severe COVID-19. They also identified a protective Neanderthal haplotype on chromosome 12 that reduces the risk of severe COVID-9.
“In light of these findings, Neanderthals haplotypes might be of particular importance in attempts to reveal the genetic factors that predispose individuals to severe COVID-19,” write the researchers.
SARS-CoV-2 and the host cell receptor ACE2
Since the first cases of SARS-CoV-2 were identified in Wuhan, China, late last year (2019), researchers have established that the virus gains access to host cells by attaching to the human receptor angiotensin-converting enzyme 2 (ACE2).
ACE2 has also previously been identified as the receptor for other coronaviruses, including SARS-CoV-1 – the agent responsible for SARS outbreaks in 2002 to 2003.
Furthermore, the fact that males are at a greater risk for severe disease than females and the fact that the ACE2 gene is located on chromosome X would suggest that ACE2 may be a risk locus for severe COVID-19, say Zeberg and Pääbo.
However, the researchers say they are not yet aware of any association between ACE2 and COVID-19 severity having been described.
The MERS-CoV virus is known to gain viral entry using the host cell receptor DPP4 – a membrane-bound enzyme involved in various physiological processes, including glucose metabolism regulation.
Interestingly, preliminary studies have suggested that inhibitors of DPP4, which are used to treat diabetes mellitus, impact COVID-19 outcomes.
What did the researchers do?
The team used data from the 1000 Genomes Project to search for single nucleotide polymorphisms (SNPs) that carry Neanderthal-like alleles at the ACE2 and DPP4 loci.
In a region spanning the whole of the ACE2 gene, as well as 50,000 base pairs up-and down-stream of the gene, two such SNPs were identified.
The researchers also identified 39 SNPs at the DPP4 loci that form several haplotypes in and around the gene.
Next, the team used the latest release of the COVID-19 Host Genetics Initiative to investigate whether the Neanderthal DPP4 haplotypes are associated with severe illness in COVID-19.
The researchers found that under the rare disease assumption (where a disease is assumed to be rare in the population of interest), the Neanderthal-like alleles were associated with an approximately 80% increased risk per allele of being hospitalized following infection with SARS-CoV-2.
The strongest association was observed for the SNP rs117888248, which increased the risk of hospitalization by 84% and the risk of requiring mechanical ventilation by approximately 109%.
The researchers say the risk of severe COVID-19 when carrying the Neanderthal haplotype at the DPP4 locus is of a similar magnitude to that associated with the Neanderthal haplotype on chromosome 3 that they previously identified.
“Both these risk haplotypes have stronger effect sizes than the protective Neanderthal haplotype on chromosome 12, which decreases the risk of becoming severely ill by around 23%,” they write.
How many people carry the variant?
The team says the prevalence of the Neanderthal DPP4 haplotype is around 1% among Europeans, 2.5% among South Asians, 4% among East Asians, and 0.7% among admixed Americans.
The haplotype is not found among African individuals in the south of the Sahara.
Next, the researchers calculated the statistical significance of the association between the Neanderthal DPP4 haplotype and severe COVID-19 under the null-hypothesis that Neanderthal haplotypes have no impact on COVID-19. This revealed that the association between the DPP4 haplotype and severe disease is indeed statistically significant.
What are the study implications?
The researchers say studies have previously shown that SARS-CoV-2 binds to DPP4 and that a DPP4 homolog called DPP9 is associated with severe COVID-19.
However, one study indicated that that SARS-CoV-2 does not use DPP4 as a receptor to gain viral entry.
“The current findings suggest that the interaction of SARS-CoV-2 with membrane-bound and secreted forms of DPP4 deserves further investigation,” say Zeberg and Pääbo.
“Inhibitors of DPP4, which can be administered orally and are used in the treatment of diabetes mellitus, may also deserve attention with respect to possible effects on viral interactions with its host cells,” concludes the team.
*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
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