What is the genetic link with the severity of the COVID-19 disease?


Two pairs of brothers in the Netherlands, all hospitalized by COVID-19[female[feminine, have led to a breakthrough in the understanding of our immune response to disease and indicate a genetic link with varying severity of COVID-19 disease.

The sharp thought of a conscientious physician in Radboud University Medical Center (RUMC; Nijmegen, The Netherlands) led researchers at the university to discover a link between the Toll-like receptor 7 (TLR7) and the severity of the patient’s response to COVID-19. The study opens a new avenue for investigating the treatment of COVID-19 while highlighting a potential genetic link to COVID-19.

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The doctor’s interest was first piqued when two younger brothers were both infected with SARS-CoV-2 and had to be ventilated due to the severity of their response to the infection. Sadly, one of the brothers died from the infection. The result for these brothers is against the norm, with the majority of young and healthy individuals being able to fight off infection without needing hospitalization. Noting this anomaly and the fact that the patients were brothers, she brought the case to the attention of colleagues at the university, who set up a multidisciplinary team to investigate the cases.

The gender of the patients also increased the risk of the severe response being more than a coincidence. Many genes linked to the immune response reside in the X chromosome, of which humans have only one. This means that any abnormality in the genes of the X chromosome is more likely to be expressed phenotypically, because the male Y chromosome contains far fewer genes than the X, making it less likely to contain a functional counterpart of the mutant gene. .

This suspected genetic component received additional credit when another pair of healthy brothers under 35 fell seriously ill with COVID-19 in hospital.

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Alexander Hoischen, geneticist at RUMC, used a rapid clinical exome method to sequence each sibling’s exomes. Cas van der Made (RUMC) described how the resulting sequences were then analyzed: “We mainly looked at genes that play a role in the immune system. We know that several of these genes are located on the X chromosome, and with two pairs of brothers, the genes on the affected X chromosome were the most suspect. “

The study found a deletion mutation in the TLR7 gene from the first two siblings and a single base substitution in the same gene from the second pair of siblings. In both cases, this led to a significant reduction in the production of the TLR7 protein.

van der Made and the team worked to establish the function of TLR7 and the impact when it is not functional. They found that “TLR7 triggers the production of so-called interferons, signaling proteins essential for the defense against viral infections. This immune response is perhaps all the more important in the fight against the SARS-CoV-2 virus because we know from the literature that the virus has tricks to reduce the production of interferons by immune cells.

The team tested this genetic link to the severity of the COVID-19 disease by mimicking a SARS-CoV-2 infection in patients with malfunction TLR7 genes in their immune cells, the team found that very few interferons are produced and that immune cell response is weak.

Discussing the significance of this finding, Hoischen said that “TLR7 function has so far never been associated with an innate error in immunity. But unexpectedly, we now have an indication that TLR7 is essential for protection against this coronavirus. Thus, it appears that the virus can replicate without being disturbed because the immune system does not receive a message that the virus has invaded. Because TLR7, which must identify the intruder and then activate the defense, is barely present, which could be the reason for the severity of the disease in these brothers.

This study highlights a new avenue for exploring potential treatments for COVID-19 and could also provide an explanation for the observed trend of higher deaths from COVID-19 in men than in women.

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