In the present study, AG and GG genotypes of rs2275913 locus in IL-17A gene were found to confer COVID-19 susceptibility to the populations of Spain and Brazil. TT genotype of rs763780 locus in IL-17F gene was not found to confer any susceptibility to any populations due to the high frequencies in all populations of selected countries (China, Japan, Iran, Spain, Mexico, Netherlands, Turkey, Finland, Brazil, Czechia). However, the polymorphisms in IL-6, IL-6R and IL-10 genes appear not to be correlated with the prevalence (per million) of COVID-19 infection and mortality rates (per million) due to this infection. The variations in the prevalence of COVID-19 and its mortality rates among countries may be explained by cytokine storm differed by the polymorphisms of rs2275913 locus in IL-17A gene.
IL-6 is an important member of the cytokine network and plays a central role in acute inflammation and cytokine storm.53 During the classical signal transduction of IL-6, IL-6 binds to its receptor IL-6R to form a complex and then binds to the transmembrane glycoprotein 130 to initiate intracellular signal transduction triggering biological functions such as proliferation, differentiation, oxidative stress, immune regulation, etc.54 IL-6 can promote T-cell population expansion and activation and B-cell differentiation, regulate the acute phase response and release of a large number of cytokines. SARS-CoV-2 activates the innate and adaptive immune systems, resulting in the release of a large number of cytokines, including IL-6. This results in a systemic inflammatory response called cytokine release syndrome (CRS) in a large number of patients with severe COVID-19, which is an important reason of death.55 On the other hand, polymorphisms in the IL6 was linked to certain viral infections like hepatitis C (HCV), influenza virus, and hepatitis B virus (HBV).56 Mao et al. revealed that IL6 rs1800795 G allele could act as a protective factor while IL10 rs1800896 A allele could act as a risk indicator in pneumonia-induced sepsis in Chinese Han patients. Furthermore, these IL6 polymorphisms were associated with clinical stage of sepsis and affected the secretion of IL-6 and IL-10.14 A very recent meta-analysis reported a relation between the IL6 gene polymorphism and predisposition as well as disease severity of pneumonia, suggested the carrier status of IL6 allele with higher IL-6 production and pneumonia severity.57 However, in the present study, we could not find a significant correlation between the frequencies of rs1800796/rs1800795 and rs2228145 polymorphisms in IL-6 and IL-6R genes, probably due to the variations among the genetic immune profiling of populations.
IL-10 is one of the complex group of mediators participating in the pathogenesis of COVID-19. In influenza infection, IL-10 is highly abundant, especially during the adaptive immune response.58 Serum IL-10 levels with IL-6 were found to be significantly higher in critical COVID-19 patients, than in moderate and severe patients. The levels of IL-10 were also reported to be positively correlated with CRP amount, and IL-6 and IL-10 were found to be predictive of disease severity.59 The first study for IL-10 polymorphism in SARS did not show any significant association of this SNP with SARS.60 A case-control study for cytokine genotyped the SNP IL-10 also did not find a significant association between the genotype and allele frequencies of IL-10 polymorphisms among the SARS patients in terms the death and survival ratio.61 This result is consistent with our present finding showing no significant correlation between two polymorphisms of IL-10 gene (rs1800896 and rs1800871 loci) and the prevalence of SARS-CoV-2 and mortality rates due to its infection. However, we cannot exclude the role of IL-10, IL-6 and IL-6R as the susceptibility genes for COVID-19, since other SNPs in these genes may also be involved in gene expression regulation. Further association studies on other SNPs, which could alter the gene expression level are required to ascertain the relationship of IL-6, IL-6R and IL-10 in COVID-19 infection.
IL-17 is the most well-known and multifunctional cytokine of a cytokine family. Its predominant either based on the gene expression or the trigger of precipitation. These two phenomena seem to affect the dominant effect of its expression as a protective cytokine or lead to a damaging hyper-inflammatory state.62 IL-17 and other T helper 17 cell-related pro-inflammatory cytokines, such as IL-1, IL-6, IL-15, TNF and IFNγ were found to be positively correlate with the severity of MERS-CoV, SARS-CoV and SARS-CoV-2.63,64 A retrospective analysis of IL-17 gene polymorphisms in patients with acute respiratory distress syndrome (ARDS) revealed that patients with a polymorphism that resulted in attenuated IL-17 production had an increased 30-day survival, whereas a genetic polymorphism that resulted in producing more IL-17 correlated with decreased survival.65 Mikacenic et al. measured circulating IL-17A in ARDS and showed that elevated circulating and alveolar levels of IL-17A are associated with increased percentage of alveolar neutrophils, alveolar permeability and organ dysfunction in ARDS.66 However, there is no detailed information about the association between frequency of polymorphisms of IL-17A and IL-17F genes of COVID patients among the populations. This is the first study showing the positive significant correlation between the prevalence and mortality rates in COVID-19 and GG genotype of rs2275913 SNP in IL-17A gene, additionally, a negative correlation between those prevalence and mortality rates and AG genotype. AA genotype also gave a significant negative correlation with the prevalence of disease among countries. We found another negative significant correlation between the prevalence and mortality rates, and the frequencies of CC genotype for rs763780 SNP in IL-17F gene, suggesting that the genetic variations in IL-17 gene may be linked to the distribution of COVID-19 infection among nations.
The pathology of COVID-19 involves a complex interaction between the SARS-CoV2 and the body immune system. Vitamin D plays a major role regulating the immune system, including immune responses to viral infection.67 Vitamin D has been reported to modulate macrophages’ response, preventing them from releasing too many inflammatory cytokines and chemokines, which are frequently observed in COVID-19 cases.68 Recently, we reported the genetic polymorphism especially in the gene of vitamin D binding protein is associated with the increased risk of COVID-19 infection and its mortality among populations with white race.69 Therefore, the correlation of the variations in interleukin gene polymorphisms and the prevalence of COVID-19 with its mortality rate may depend on the modulatory effect of Vitamin D metabolism in individuals which is determined by the genetic background. However, the prevalence of SARS COV-2 infection differs from the severity of COVID-19, by association with many factors such as public awareness, behaviors and antiviral policy of each country except the host genetic factors. On the contrary, the severity of the disease induced by viral infection might be associated with the genetic host factors including immune profiling. More detailed and large sampled studies about the genetic variations in infected patients with different degrees of severity are needed to explain the underlying mechanism of cytokine storm in COVID-19 patients.