Temporary loss of smell and taste is a common feature of Covid-19. Researchers have now investigated why this does not occur in all patients infected with the coronavirus and whether there may be genetic factors behind it. When comparing the genomes of almost 70,000 people infected with Sars-CoV-2, they came across variants in the environment of two genes that at least partially determine the risk of loss of smell. Both genes contain building instructions for enzymes that are closely linked to the olfactory process and could explain the loss of smell in the event of a malfunction.
The nasal mucosa is one of the tissues that are the first to be affected when infected with the Sars-CoV-2 coronavirus. The virus primarily attacks the supporting cells and the ciliated cells of the nasal mucosa, which are covered with cilia. These cell types have a particularly large number of ACE2 receptors on their surface and thus offer the pathogen a suitable docking point. However, it remained unclear for a long time whether the olfactory sensory cells themselves are also infected and damaged by the virus. The impairment of the sense of smell and taste that occurs in many Covid 19 patients indicates an attack on the olfactory cells. However, recent studies suggest that these sensory failures are not due to a direct effect of the virus on the olfactory cells or the olfactory bulb, but rather represent a kind of collateral damage. The exact mechanisms behind the olfactory disorders and the question of why not all infected people show these symptoms are still unclear.
Genome comparison in almost 70,000 infected people
To get to the bottom of this question, Janie Shelton and her colleagues at the US genetic analysis company 23andMe looked for possible genetic risk factors for the loss of smell. To do this, they evaluated the genetic data of 69,841 test persons from the USA and Great Britain who had tested positive for Sars-CoV-2. “Of these individuals, 68 percent reported experiencing smell and taste deficits during their infection,” the team said. This symptom was significantly more common in people of European descent than in those of Asian or African ancestry. Using data from all participants, Shelton and her colleagues performed a genome-wide comparative analysis (GWAS), looking for gene variants that are more common in people with coronavirus-related olfactory disorders than in those who are not affected.
In these comparative analyses, one gene locus was noticed that was altered significantly more frequently in those affected by olfactory disorders. “Although this genetic association is clearest in the European population, the effect sizes are consistent across populations,” report Shelton and her colleagues. From the genetic data and the frequency of the loss of smell in their test subjects, the scientists conclude that the variants in this gene locus increase the risk of losing the sense of smell by around eleven percent. More detailed analyzes revealed that the variants in question are close to the two genes UGT2A1 and UGT2A2. “These two genes are not only the closest, but also biologically plausible candidates,” say the team.
Enzymes important for “cleaning” odor perception
The two genes are mainly active in the mucous membrane cells of the nose and contain the building instructions for enzymes that play an important role in smell perception. As the research team explains, these enzymes are primarily responsible for binding to odorous substances that have already been detected and thus neutralizing them. As a result, these odorous substances become invisible to the olfactory receptors, so to speak, and these can prepare themselves to perceive new, additional scents. This is important so that scent stimuli do not get caught in the nose and block further perception of smells. The enzymes ensure that the odor impression disappears as soon as the triggering odor is no longer present in the environment.
How the gene variants that have now been identified influence this process is still just as unclear as the question of what effect a Sars-CoV-2 infection has on the activity of these genes. Nevertheless, Shelton and her colleagues see in their find the first indications that genetic factors also play a role in determining whether the coronavirus infection affects the sense of smell of an affected person. The results could also help to elucidate the biological mechanisms behind the infection-related olfactory disorders.
Source: Janie Shelton (23andMe Inc., Sunnyvale) et al., Nature Genetics, doi: 10.1038/s41588-021-00986-w