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Correlation between interleukin gene polymorphisms and current prevalence and mortality rates due to novel coronavirus disease 2019 (COVID‐2019) in 23 countries

Abstract Background The novel coronavirus disease 2019 (COVID‐19) infection may rely on a potential genetic background for the variations in the inflammatory response. We aimed to investigate the possible correlation between polymorphisms in the IL‐6 gene at rs1800796/rs1800795, in IL‐6R at rs2228145, in IL‐10 at rs1800896 and rs1800871, in IL‐17 at rs2275913 and rs763780 loci, and COVID‐19 prevalence and mortality rates among populations of 23 countries. Methods We searched the literature for polymorphisms in China, Japan, India, Spain, Mexico, Sweden, Turkey, Brazil, Russia, Poland, Italy, South Africa, Netherlands, Greece, Germany, UK, Iran, Finland, Czechia, Tunisia, Norway, Egypt, Croatia. We recorded the prevalence and mortality rates (per million) caused by the Coronavirus infection recorded on 7th September 2020 and 6th December 2020. Results There was a significant positive correlation between the frequency of AG genotype of rs1800896 and prevalence recorded on 6th December 2020 (r: 0.53, r 2: 0.28, p < .05). There was a significant negative correlation between the mortality rates recorded on 7th September, and the AG genotype of rs2275913 (r: −0.51, r 2: 0.26, p < .05). There was a significant positive correlation between the prevalence recorded on 6th December, and TT genotype at rs763780 (r: 0.65, r2:0.42, p < .05) while a negative correlation between prevalence and TC genotype at rs763780 (r: −0.66, r 2: 0.43, p < .05). Also, a significant negative correlation was found between mortality rates recorded on 6th December 2020 and CC genotype at rs763780 (r: −0.56, r 2: 0.31, p < .05). Conclusion The variations in prevalence of COVID‐19 and its mortality rates among countries may be explained by the polymorphisms at rs1800896 in IL‐10, rs2275913 in IL‐17A, and rs763780 loci in the IL‐17F gene.


| INTRODUCTION
Beginning from December 2019, the coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has evolved into a pandemic and has given rise to challenging health concerns worldwide. 1  The pathogenesis of COVID-19 harbors an effective inflammatory response, triggering a complex group of mediators including interleukins. 3 In the course of the disease, excessive production of pro-inflammatory cytokines results in a cytokine storm which is responsible for the severe progression of the disease and the acute organ injuries. 1 The underlying mechanism is that SARS-CoV-2 can rapidly activate pathogenic T helper cell type 1 (Th1) cells to secrete pro-inflammatory cytokines including interleukin-6 (IL-6), IL-10, and IL-17. 4 COVID-19 patients were reported to have high IL-6 and IL-10 levels and low CD4 + T and CD8 + T cell levels associated with the disease severity. 5 Some studies have also reported that the patients with severe COVID-19 have higher levels of IL-2, IL-6, IL-7, IL-10 than patients with mild and moderate infections. [3][4][5] IL-17 levels were found to be increased in COVID-19 patients hospitalized in the intensive-care unit compared to the control patients. 6 Therefore, these key inflammatory factors in COVID- 19 have paramount importance in understanding the cytokine storm-related mortality in severe cases. 3 Genetic polymorphisms implicated in understanding the basis of diseases also allow for the prevention of the spread of infections, and for the development of potentially effective treatments against the diseases. One common type of these polymorphisms, the single nucleotide polymorphisms (SNPs) are known to be effective in the pathways that play an important role in the attachment of the microbiological agent to the host cell, in the host's resistance to the diseases, in the susceptibility to disease and the severity of diseases. 1 There are growing numbers of reports stating that severe symptoms of COVID-19 might be attributed to the human genetic variants in genes related to immune deficiency, pneumonia, sepsis, and/or cytokine storm. 7 Recently, it was reported that the G allele of the rs1800795 locus in the IL6 gene could act as a protective factor while the A allele of rs1800896 in IL10 gene could act as a risk indicator in pneumonia-induced sepsis in Chinese Han patients. In addition, these polymorphisms in IL6 gene were associated with the clinical stage of sepsis and have crucial effects on the secretion of IL-6 and IL-10 in the patients. 8 On the other hand, a report of IL-17 gene polymorphisms in patients with an acute respiratory distress syndrome (ARDS) revealed that 30-day survival rate increased in the patients with a genetic polymorphism that resulted in an attenuated IL-17 production, whereas a polymorphism that resulted in the production of more IL-17 correlated with the decreased survival rate. 9 Therefore, we hypothesized that SNPs in IL-6, IL-6R, IL-10,   IL-17A, and IL-17F genes may participate in the clinical course of   COVID-19 infection and the survival/mortality rates due to this infection.
The main goal of this study was to evaluate a possible correlation between the common polymorphisms at rs1800796/rs1800795 locus of IL-6 gene, at rs2228145 locus of IL-6R gene, at rs1800896 and rs1800871 loci of IL-10 gene, at rs2275913 locus of IL-17A gene and rs763780 locus of IL-17F gene, and the prevalence of COVID-19 and the mortality rates among populations of 23 countries including Turkey.

| MATERIALS AND METHODS
To test this hypothesis and to limit any confounding bias (latitude, etc.), we focused on the countries whose IL-6 gene polymorphisms at rs1800796 and rs1800795 loci, IL-6R gene polymorphism at rs2228145 locus, IL-10 gene polymorphism at rs1800896 and rs1800871 loci, IL-17A gene polymorphism at rs2275913 and IL-17F gene polymorphism at rs763780 loci were defined and the allele frequencies were reported in 54 studies. 10  Sweden, Poland, Germany, and the UK frequently have GC genotype.
Only the Japanese population frequently showed the CC genotype for rs1800796 polymorphism ( The analysis between the frequencies of rs1800796/rs1800795 polymorphism in IL-6 gene and rs2228145 polymorphism in IL-6R gene, and the prevalence of COVID-19 and mortality rates per country demonstrated that there was no significant correlation between the prevalence (per million), mortality rates (per million), and the frequencies of polymorphisms found in IL-6 and IL-6R genes (p > .05) ( Table 2).
Population diversities of IL-10 gene polymorphisms at rs1800896 locus showed that the populations of China, Mexico, Tunisia, and Japan frequently have the AA genotype while the populations of India, Iran, Spain, Netherland, Finland, Brazil, Czechia, Poland, Germany, Norway, and the UK frequently have the AG genotype. The frequency of GG genotype of rs1800896 polymorphism was the highest only among the Italian population (- Table 3). Population diversities of IL-10 gene polymorphisms at rs1800871 locus showed that the populations of Spain, Italy, Finland, Czechia, Japan, Norway, and the UK frequently have CC genotype while the populations of India, Iran, Mexico, Netherland, Brazil, and Tunisia frequently have CT genotype. Only Chinese and German populations frequently showed TT genotype for rs1800871 polymorphism ( Table 3).
The analysis between the frequencies of rs1800896 and rs1800871 polymorphisms of IL-10 gene, and the prevalence of COVID-19 and mortality rates recorded on 7th September and 6th December 2020 per country demonstrated that there was no significant correlation between the prevalence (per million), mortality rates (per million), and the frequencies of these polymorphisms found in IL-10 gene except the frequency of AG genotype at rs1800896 locus (Table 4). There was a statistically significant positive correlation between the frequency of AG genotype and the prevalence of COVID-19 cases recorded on 6th December 2020 (r: 0.53, r 2 : 0.28, p < .05). 28% of the variability among the number of cases may be explained by the frequency of AG genotype at rs1800896 among populations ( Figure S1).  Table 5).
The analysis between the frequencies of rs2275913 polymorphism in IL-17A gene and prevalence of COVID-19 and mortality rates per country demonstrated that there was a significant negative correlation between the mortality rates (per million) recorded on 7th September 2020, and AG genotype (r: −0.51, r 2 :0.26, p < .05) while there was no significant correlation between the prevalence and mortality rates recorded on 6th December 2020 and any genotype of the rs2275913 polymorphism ( Table 6). 26% of the variability among the mortality rates may be explained by the frequency of AG genotype at rs2275913 among the populations ( Figure S2).
The analysis between the frequencies of rs763780 polymorphism in IL-17F gene and the prevalence of COVID-19 cases and mortality rates per country demonstrated that there was a significant positive correlation between the prevalence (per million) recorded on 6th December 2020, and TT genotype (r: 0.65, r 2 : 0.42, p < .05) while a negative correlation was found between that prevalence and TC genotype (r: −0.66, r 2 : 0.43, p < .05). 42% and 43% of the variability among the number of cases may be explained by the frequency of TT and TC genotypes at rs763780, respectively ( Figure S3). Also, a significant negative correlation was found between the mortality rates (per million) recorded on 6th December T A B L E 2 Correlation between IL-6 (rs1800796/rs1800795) and IL-6R (rs2228145) polymorphisms and prevalence of COVID-19 and mortality rates for all countries  Table 6). Therefore, 31% of the variability among the mortality rates may be explained by the frequency of CC genotypes at rs763780 locus among populations ( Figure S4).

| DISCUSSION
In the present study, the AG genotype of rs1800896 locus in IL-10 which accounts for the high mortality rates. 64 In addition, the polymorphisms in the IL-6 gene were associated with specific viral infections including influenza virus, hepatitis C (HCV), and hepatitis B virus (HBV). 65 A very recent meta-analysis reported an association between a polymorphism in the IL-6 gene and predisposition and disease severity of pneumonia, suggested that the IL-6 allele carries a status of higher IL-6 production and pneumonia severity. 66    T A B L E 6 Correlation between IL-17A (rs2275913) and IL-17F (rs763780) polymorphisms and the prevalence of COVID-19 and mortality rates per country

AUTHOR CONTRIBUTIONS
All authors have contributed significantly to the work.