Some people may be genetically predisposed for severe forms of Covid-19

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Two point mutations in the patient’s genome are associated with worsening SARS-CoV-2 infection.

But why such a disparity of symptoms in SARS-CoV-2 infection? Why, for the majority of affected individuals, the disease remains mild or even asymptomatic, while for others, it degenerates into a severe form, resulting in acute respiratory failure, sometimes fatal? These questions, among many others related to Covid-19, have plagued doctors and biologists since the appearance of the new coronavirus in late 2019. David Ellinghaus, of Christian-Albrechts University, in Kiel, Germany, and his colleagues, provide elements of response.

It has long been suspected that genetic predispositions would explain, at least in part, the severity of the disease. To explore this avenue, virologists have carried out a large genetic study in nearly 2,000 patients suffering from a severe form distributed in various hospitals in Italy and Spain, in areas particularly affected by the pandemic. Their genomes were compared to those of a control group.

In all, almost nine million point mutations, varying from one individual to another, have been detected. Such mutations, called SNP for “Single nucleotid polymorphism”, consists in replacing one nucleotide (A, T, C or G) in the DNA sequence by another, which sometimes leads to a change in the composition of the encoded protein. Such changes, which affect about one in every 1,000 nucleotides in the human genome, sometimes have significant repercussions. For example, sickle cell disease, or sickle cell anemia, results from a unique SNP in the hemoglobin gene.

Among the SNPs identified by David Ellinghaus, two are significantly correlated with the severity of the Covid-19: noted rs11385942 and rs657152 (these are references from the NCBI dbSNP database, where “rs” means “SNP reference”), they are respectively located on locus 3p21.31 and 9q34.2. This code indicates the chromosome number (3 and 9), the arm (p and q), and the region indicated according to the dark and light bands which appear on a chromosome after coloring.

What genes are affected by these loci? The 3p21.31 locus is associated with the SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1 genes. What is their role ? Three of them (CCR9, CXCR6 and XCR1) encode receptors for cytokines, these molecules that mediate immunity. The CXCR6 receptor is involved more particularly in defense against pathogens in the airways by influencing CD8 T lymphocytes in the lungs. The SLC6A20 gene codes for a transporter that interacts with the angiotensin 2 converting enzyme (ACE2), the receptor to which SARS-CoV-2 binds to infect a cell. As for the LZTFL1 gene, coding for an actor in the circulation of proteins in cells, it is particularly expressed in the lungs. These functions can easily be linked to the progress of the infection with the new coronavirus.

Another observation, the frequency of SNP rs11385942 at locus 3p21.31 was notably higher in patients on mechanical ventilation. Finally, the patients with the two variants (they are homozygous) of the gene carrying the SNP rs11385942 were younger than the others.

The second locus identified, locus 9q34.2, is that of the genes responsible for the ABO blood groups. Analysis has shown that group A is associated with a higher risk of developing a severe form of the disease, while group O, on the other hand, provides some kind of protection. These results confirm what previous studies, not based on genetics, had highlighted.

The numerous links of the genes of the locus 3p21.31 with what is known of Covid-19 plead for a real effect of SNP rs11385942 in the severity of the disease. This is to a lesser extent the case of SNP rs657152 at locus 9q34.2. However, the authors warn that these are still only correlations, associations. The cause and effect link needs to be demonstrated. In such a case, doctors would have a precious indicator of clinical progress.