Association of polymorphisms of IL-6 pathway genes (IL6, IL6R and IL6ST) with COVID-19 severity in an Amazonian population

Interleukin-6 have been recognized as a major role player in COVID-19 severity, being an important regulator of cytokine storm. Hence, the evaluation of the influence of polymorphisms in key genes of IL-6 pathway, namely IL6, IL6R and IL6ST, may provide valuable prognostic/predictive biomarkers on COVID-19. The present cross-sectional study genotyped three Single Nucleotide Polymorphisms - SNPs (rs1800795, rs2228145 and rs7730934) at IL6, IL6R and IL6ST genes, respectively, in 227 COVID-19 patients (132 hospitalized and 95 non-hospitalized). Genotype frequencies were compared between these groups. As control group, published data on gene and genotype frequencies was gathered from published studies from before the pandemic started. Our major results point to an association of IL6 C allele with COVID-19 severity. Moreover, IL-6 plasmatic levels were higher among IL6 CC genotype carriers. Additionally, the frequency of symptoms was higher at IL6 CC and IL6R CC genotypes. In conclusion the data suggest an important role of IL6 C allele and IL6R CC genotype on COVID-19 severity, in agreement with indirect evidences from literature about association of these genotypes with mortality rates, pneumonia, heightening of protein plasmatic levels proinflammatory driven effects.


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Interleukin-6 have been recognized as a major role player in COVID-19 severity, 49 being an important regulator of cytokine storm. Hence, the evaluation of the influence of 50 polymorphisms in key genes of IL-6 pathway, namely IL6, IL6R and IL6ST, may provide 51 valuable prognostic/predictive biomarkers on COVID-19. The present cross-sectional 52 study genotyped three Single Nucleotide Polymorphisms -SNPs (rs1800795, rs2228145 53 and rs7730934) at IL6, IL6R and IL6ST genes, respectively, in 227 COVID-19 patients 54 (132 hospitalized and 95 non-hospitalized). Genotype frequencies were compared 55 between these groups. As control group, published data on gene and genotype frequencies 56 was gathered from published studies from before the pandemic started. Our major results 57 point to an association of IL6 C allele with COVID-19 severity. Moreover, IL-6 plasmatic 58 levels were higher among IL6 CC genotype carriers. Additionally, the frequency of 59 symptoms was higher at IL6 CC and IL6R CC genotypes. In conclusion the data suggest 60 an important role of IL6 C allele and IL6R CC genotype on COVID-19 severity, in 61 agreement with indirect evidences from literature about association of these genotypes . CC-BY 4.0 International license perpetuity. It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in    In this context polymorphisms at IL6, IL6R and IL6ST genes become interesting 84 candidates to be prognostic and predictive markers on COVID-19 severity. IL-6 pathways 85 have been reported to modulate the expression of IL6 and IL6R genes, respectively [5] 86 and to be associated to several inflammatory, autoimmune and infectious diseases [6 -8].
. CC-BY 4.0 International license perpetuity. It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in   Demographic and clinical data were collected from patients, including gender, 103 age, and COVID-19-specific data (date of onset of symptoms, symptoms at diagnosis of 104 COVID-19, hospitalization, need for oxygen and comorbidities). Patients were grouped 105 according hospitalization.

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Genomic DNA was isolated from blood samples using commercial kit (Wizard® respectively, was performed by customized TaqMan® assays, commercially provided by . CC-BY 4.0 International license perpetuity. It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in

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Clinical and demographic characteristics of the sample is presented in Table 1, 134 while the Table 2 presents the genotype and allele frequencies in the sample and 135 subsamples.
. CC-BY 4.0 International license perpetuity. It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in . CC-BY 4.0 International license perpetuity. It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The

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The retrieving of data on IL-6 plasmatic levels from our previous published study 158 [10] showed that among 95 patients with active COVID-19 the levels of plasmatic IL-6 159 was higher among IL6 CC genotype carriers (seven patients; average 40,11 pg/ml) than   The association of the IL6 genotype CC is also corroborated by the higher 172 frequency of COVID-19 symptoms among CC carriers (Table 3), as well as by the slight 173 increase of IL-6 levels in CC in comparison to GG genotypes, during the active disease. conclusive, there are a trend toward higher IL-6 production among the allele C carriers as 177 well as an association of this allele with more sever forms of pneumonia in general, as 178 previously suggested in a recent meta-analysis [16]. In this context an additional 179 association of the IL6R genotype CC with higher frequencies of symptoms could be also 180 observed in our results.

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While the association of IL6 genotypes with serum IL-6 levels is still not 182 completely understood, the IL6R genotype CC is more consistently associated with higher