Genetic Susceptibility to SARS-CoV-2: From the Nehandertal Age to 2020

Since late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated coronavirus disease 2019 (COVID-19) have become a worldwide threat to public health [1,2]. SARS-CoV-2 is characterized by an extremely strong inflammatory response that can lead to severe manifestations such as adult respiratory syndrome, sepsis and potentially fatal coagulopathy [3]. These symptoms occur mainly in elderly subjects, males, and patients with preexisting serious comorbidities like cardiovascular, pulmonary, and renal diseases [4].

In addition to significant mortality, another key problem of COVID-19, is the exponential increase of infections and the very large number of patients admitted to hospitals. Even more confusing is that not all infected patients develop a severe respiratory illness. Currently, the reason for these large inter-individual variations in disease severity is not clear.

So, what makes some people more vulnerable than others to SARS-CoV-2? The answer to this question could be found in interpersonal genetic variability, which determines how the individual responds to the virus [5]. Currently, there is no proven effective therapy.

In this regard, Hugozeberg and Svante Pääbo had an article published in Nature [6] in which they considered a recent study about genetic susceptibility to COVID-19. In another recent work [7], the authors conducted a genome-wide association study involving 1980 patients with COVID-19 during which they highlighted two chromosomal regions associated with severe forms of the disease. The gene clusters under consideration are six genes present on chromosome 3 (3p21.31 position) and the region associated with AB0 blood groups on chromosome 9 (9q34. 2 position). In this study, it was understood that only the gene cluster present on chromosome 3 is associated with the more severe forms of COVID-19 at the genome-wide level. This gene cluster on chromosome 3 has a high linkage disequilibrium (LD). Furthermore, these genes are highly associated in the population (r2 > 0.98) and are 49.4 kb long. The haplotype appears to have been inherited from Neanderthals or the Denisovans [8,9]. The aim of the study, therefore, was to understand how these genes came down to us. Many of them have been found homozygous in the Vindija33.19 Neanderthal genome found in Croatia.

From the Neanderthals to the present day, there is probably an ancestry, but due to recombination in each generation, the haplotype gradually shrank into smaller and smaller fragments. All this has been confirmed by studies concerning the genetic flow from Neanderthals to modern mankind [10].

These studies compared the Neanderthal genome with the genome present in the 1000 Genomes Project data. The result was that 253 haplotypes of today’s people contain 450 variable positions and exhibit a different frequency among different populations. In fact, the 49.4 kb haplotypes are almost absent in African and East Asian populations, but have a 30% frequency in South Asian and about an 8% frequency in European populations. The population that has the highest frequency is in Bangladesh (63%), where subjects are carriers of at least one copy of the Neanderthal-risk haplotype, whereas 13% are homozygous for the haplotype [10].

From this it can be deduced that carriers of the Neanderthal haplotype could be a contributing factor to the dangerousness of COVID-19 in some populations, especially among those of an advanced age. To confirm this, individuals of Bangladeshi origin, present in the U.K., have about twice the risk of dying from COVID-19 compared to the general population (Hazzard ratio 95% CI:1.7–2.4) [11].

Similarly, in the study of A. Nguyen [12], gene susceptibility to the more severe form of COVID-19 was also analysed. He focused on the genetic variables of the major complex of histocompatibility (MCH) class I, in particular on Human Leukocyte Antigen (HLA) alleles. It is known that there is an association between the HLA genotype and the severity of some diseases including COVID-19. A comparison of the binding affinity between MHC class I and 145 different HLAs against SARS-CoV-2 revealed that HLA-B*46:01 had less affinity for the virus, suggesting that individuals with this allele may be particularly vulnerable to COVID-19. A similar result had previously been obtained for SARS [13]. Conversely, it was observed that HLA-B*15:03 has a greater compatibility with the peptides of the virus, thus giving greater protection to those who possess it. This shelter is tied to conserved and common peptides between SARS-CoV-2 and other common human coronaviruses. Who has the HLA-B*15:03 overexpression gains greater protection due to the T-cell based immunity obtained by past infections of less harmful coronaviruses [14].

In conclusion, knowing individual genetic variation can help explain different susceptibility to SARS-CoV-2. Such knowledge could therefore help to identify individuals who have a higher risk of contracting the disease. Of course, this would also help create a vaccine or make it possible to find adequate, if not preventive, therapy for those who have a greater chance of meeting the most serious form of the virus, thus preventing hospitalization or death. For this reason, it is very important to stimulate further exploration of current findings for their usefulness in clinical risk-profiling of patients with COVID-19 and toward a mechanistic understanding of the underlying pathophysiology.