Whether or not a person becomes seriously ill with Covid-19 depends, among other things, on genetic factors, and European researchers recently not only confirmed the central and already known role of the TLR7 gene in severe cases of the disease in men, but were also able to find evidence for a contribution of the gene in women.
In addition, they were able to show that genetic changes in three other genes of the innate immune system contribute to severe Covid-19, they said.
The investigation into a particularly large group of infected individuals was led by the University Hospital Bonn (UKB) and the University of Bonn, in co-operation with other research teams from Germany, the Netherlands, Spain and Italy, reports News-Medical.net
Their findings were published in the journal Human Genetics and Genomics Advances.
Even though the number of severe cases after infection with the SARS-CoV-2 virus has decreased, there is still great interest in understanding why, at the height of the pandemic, the infection was severe in some people but not in others.
In addition to many possible reasons such as increased age or pre-existing conditions, some people’s own genetic make-up can cause a severe course of the disease. Early work in the pandemic had already identified affected genes, most of which are involved in the innate immune response.
The gene with the strongest evidence to date is the TLR7 gene, which was identified as the cause of the disease in two pairs of Dutch brothers with severe cases back in 2020.
However, it was not yet known to what extent the effect of genetic changes in TLR7 is independent of other non-genetic risk factors, like increased age or previous illnesses, and whether there are other genes in which so-called mutations significantly increase the risk of severe Covid.
Increased risk in three other genes
In the study, the international research group led by Profesor Kerstin Ludwig, Institute of Human Genetics, University Hospital Bonn, looked at the gene sequences of 52 candidate genes, including TLR7, in a comparatively large patient sample.
Through collaborations with various European groups, the Bonn researchers gained access to DNA material from 1 772 people with severe Covid-19 and 5 347 control individuals with unknown SARS-CoV-2 status from Spain and Italy, i.e, from regions where a very high incidence and high mortality rate was observed, especially at the beginning of the pandemic.
All of those affected were infected at a time when vaccinations were not yet available, therefore they had no immune protection and were exposed to the virus virtually “unprepared”. In this large group of people, mutations that render the TLR7 gene non-functional were actually observed significantly more frequently in severely affected patients than in the control group.
“This ‘enrichment’ was even stronger when only those affected people were considered who, due to their age and state of health, would not actually have had a high risk of a severe course. This means that certain mutations in this gene significantly increase the risk of severe progression,” said first author and doctoral student at the Bonn Institute of Human Genetics Jannik Boos, who was in charge of the project.
In addition to TLR7, the Bonn researchers were also able to identify mutations in the three other genes: TBK1, INFAR1 and IFIH1, in the group of severely affected individuals.
Gender-specific differences due to hereditary factors?
The Bonn researchers then took a closer look at TLR7 and found the TLR7 gene is located on the X chromosome, of which men only have one copy, but women have two.
“So if there is a loss of function of TLR7 on one copy, men no longer have a functioning gene. Women, on the other hand, still have a healthy copy, so at least a little bit of functioning TLR7. It was therefore surprising for us that we also found TLR7 mutations more frequently in women with severe Covid-19 courses,” said Dr Axel Schmidt, a resident at the Institute of Human Genetics and in the Department of Neuropaediatrics at the UKB and who led the study with Ludwig.
With Professor Alexander Hoischen’s team from Radboudumc University Hospital in The Netherlands, the Bonn researchers found initial indications that the type of genetic changes is different in women: while in men the mutations led to the absence of TLR7, in women the “broken” TLR7 versions appeared to interact with the “healthy” copies and thus also influence their function.
“We assume that TLR7 can also be impaired in women with severe Covid, but presumably via a different biological mechanism,” said Ludwig, who is now working with groups from the Immunosensation2 cluster to clarify whether this hypothesis is correct and, if so, what the effects of this mechanism are on the immune system.
“This is important because it gives us information about the function and reaction of the immune system when it first comes into contact with a pathogen,” Ludwig added.
“If we have a better understanding of how severe courses of the disease develop, we can identify people at risk and protect them better or develop targeted therapies. We assume that the findings can be transferred at least in part to future pandemics.”
Study details
Stratified analyses refine association between TLR7 rare variants and severe Covid-19
Jannik Boos, Caspar van der Made, Gayatri Ramakrishnan et al.
Published in Human Genetics and Genomics Advances on 28 June 2024
Summary
Despite extensive global research into genetic predisposition for severe Covid-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1 772 severe Covid-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (<60 years) cases with no reported clinical risk factors (n = 378), compared to 0.24% of controls (odds ratio [OR] = 12.3, p = 1.27 × 10−10). Incorporation of the results of either functional assays or protein modelling led to a pronounced increase in effect size (ORmax = 46.5, p = 1.74 × 10−15). Association signals for the X-chromosomal gene TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe Covid-19 of the previously implicated genes IFNAR2, IFIH1, and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe Covid-19 and strengthen evidence for the etiological relevance of genes in the interferon signalling pathway.
News-Nedical.net article – Study identifies genes increasing risk of severe Covid-19 (Open access)
See more from MedicalBrief archives:
Decoding some of Covid’s mysteries, four years on
COVID-19 severity may link to weak spots in immune system — Genome study
And why the sex differences in Covid-19 susceptibility?