A new study looks at the role of genetics in the leveling degrees of infection.
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Whereas, some people seem to be slightly affected with COVID-19 when they contract the virus, others get a more severe form of it. Although there is some information on disease severity and pathways, investigators wanted to see if they could uncover more from a genetic standpoint.
A new study points to specific genes and the potential role they play in virus severity in patients. Specifically, investigators looked at Toll-like receptor 7 (TLR7) and found mutations that render the TLR7 gene non-functional were found significantly more frequently in severely affected COVID-19 patients than in a control group.1
"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," says first author, Jannik Boos, doctoral student at the Bonn Institute of Human Genetics, who was in charge of the project.1
"The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity." 2 The TLR7 gene had previously been identified as the cause of the disease in 2 pairs of Dutch brothers with severe cases back in summer 2020, according to the investigators. Prior to this latest research, they pointed out they did not understand the extent of the effect of genetic changes in TLR7.
In addition to TLR7, the investigators identified mutations in the 3 other genes—TBK1, INFAR1 and IFIH1—in the group of severely affected COVID-19 patients.
Researchers identified that mutations in the TLR7 gene, which is crucial for innate immunity, are significantly more frequent in severely affected COVID-19 patients.
The TLR7 gene is located on the X chromosome. Since men have only one X chromosome, a non-functional TLR7 gene leaves them without a backup.
Beyond TLR7, mutations in genes such as TBK1, IFNAR1, and IFIH1 were also found to contribute to severe COVID-19 cases.
The investigators examined the gene sequences of 52 candidates, including TLR7. They had the DNA material from 1772 people with severe COVID-19 and 5347 control individuals with unknown SARS-CoV-2 status in Spain and Italy. And all those infected occurred prior to the approval of COVID-19 vaccines.
The investigators found the TLR7 gene is located on the X chromosome, of which men only have 1 copy, but women have 2 and this could have a detrimental effect on the former group. "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 Axel Schmidt, MD, a resident at the Institute of Human Genetics and in the Department of Neuropaediatrics at the University Hospital Bonn. Schmidt co-led the study with Kerstin Ludwig, PhD, professor, Institute of Human Genetics, University Hospital Bonn.1
Although gene mutations lead to the absence of TLR7 in men, for women the mutated TLR7 versions appear 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.1
The investigators said the findings confirm the initial hypothesis that TLR7 played a role in disease severity and point to other genes’ involvement. “The present findings reinforce prior genetic evidence for an etiological role of the X-chromosomal gene TLR7 in severe COVID-19 through the identification of a robust enrichment of deleterious rare variants. Notably, this enrichment was particularly pronounced in young individuals with severe COVID-19 with no reported demographic or clinical risk factors, and was also present in the female-only subgroup,” the investigators wrote. “Together with results from protein structural modeling, this suggests the existence of more complex pathomechanisms of TLR7 variants, beyond X-linked recessive loss of function. The analyses also generated statistical evidence that rare variants in three additional genes of the interferon signaling pathway, specifically IFNAR2, IFIH1, and TBK1, contribute to severe COVID-19, though these findings require further follow-up.”3
