Mutations in TLR7 and other genes increase risk of severe Covid

Mutations in the TLR7 gene increase the risk of severe Covid in men. German research, conducted with Radboudumc and Spanish and Italian researchers, shows that those mutations also increase the risk of severe Covid in women. In addition, three other genes of the innate immune system were found to contribute to severe Covid. The study was published in Human Genetics and Genomics Advances.

Whether a person becomes seriously ill from COVID-19 depends on genetic factors, among others. Although the number of severe cases after infection with SARS-CoV-2 virus has decreased, it is still being investigated why during the corona pandemic the infection was severe in some people and not in others. This is important because it provides information about the function and response of the immune system when it first comes into contact with a pathogen. If we better understand how such severe disease develops, we can identify people at increased risk and better protect them or develop targeted therapies. "We assume that the findings can be at least partially used in future pandemics," says Kerstin Ludwig of the Institute of Human Genetics at the University Hospital Bonn (UKB).

Genetically vulnerable

So far, mutations in the TLR7 gene are the most obvious example of 'genetic vulnerability' to Covid. This was shown in work by Alexander Hoischen and Cas van der Made of the Radboudumc, published in JAMA in summer 2020. That paper identified TLR7 as the cause of the disease in two pairs of Dutch brothers with severe Covid. In the study now published, the international research group looked at 52 candidate genes in a relatively large patient file containing DNA material from 1,772 people with severe COVID-19 and 5,347 control subjects with unknown SARS-CoV-2 status coming from Spain and Italy. In these countries, many people became ill and many died, especially at the beginning of the pandemic. All affected people were infected when vaccinations were not yet available and they were immunologically exposed to the virus almost "unprepared".

Three additional risk genes

In this large group of people, mutations in the TLR7 gene were observed much more often in severely affected COVID-19 patients than in the control group. This difference was even greater when only affected people who would not actually be at high risk of a severe course due to their age and health status were considered. This means that certain mutations in this gene significantly increase the risk of a severe course and confirms the role of TLR7 in Covid. In addition, in the group of severely affected individuals, the researchers also identified mutations in three other genes: TBK1, INFAR1 and IFIH1.

Gender-specific differences

The TLR7 gene is located on the X chromosome. Of this, men (XY) have one copy and women (XX) have two. If TLR does not work, it no longer functions in men, who have only one copy of it. In such a case, women still have at least one good, functioning copy. Remarkably, the researchers saw that in women with one mutated TLR7, a severe course of Covid nevertheless occurred more often. With Hoischen's Nijmegen team, the Bonn researchers found the first indications that the type of genetic changes are different in women. Hoischen: "In men, the mutations lead to absence of TLR7. In women, the mutated TLR7 versions react with the healthy copies, reducing their function. As a result, women are also at higher risk."

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Source: Universiteit Bonn

Publicatin in Human Genetics and Genomics Advances: Stratified analyses refine association between TLR7 rare variants and severe COVID-19 - Jannik Boos, Caspar I. van der Made, Gayatri Ramakrishnan, …… , Alexander Hoischen, Axel Schmidt, Kerstin U. Ludwig

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