The single nucleotide polymorphism rs4986790 (c.896A>G) in the gene TLR4 as a protective factor in corona virus disease 2019 (COVID-19)

Abstract

Background and aims: Several factors, such as hypertension and diabetes mellitus, are known to influence the course of coronavirus disease 2019 (COVID-19). However, there is currently little information on genetic markers that influence the severity of COVID-19. In this study, we specifically investigated the single nucleotide polymorphism (SNP) rs4986790 in the TLR4 gene to identify a universal marker for preclinical prediction of COVID-19 disease progression.

Methods: We analyzed the influence of demographics, pre-existing conditions, inflammatory parameters at the time of hospitalization, and TLR4 rs4986790 genotype on the outcome of COVID-19 in a comprehensive cohort (N = 1570). We performed multivariable analysis to investigate the impact of each factor.

Results: We confirmed that younger patient age and absence of pre-existing conditions were protective factors against disease progression. Furthermore, when comparing patients with mild SARS-CoV-2 infection with patients who required hospitalization or intensive care or even died due to COVID-19, the AG/GG genotype of TLR4 rs4986790 was found to be a protective factor against COVID-19 disease progression (OR: 0.51, 95% CI: 0.34 - 0.77, p = 0.001). In addition, we demonstrated that low levels of interleukin-6 (IL-6) and procalcitonin (PCT) had a favorable effect on COVID-19 disease severity. In the subsequent multivariable analysis, we confirmed the absence of cardiovascular disease, low levels of IL-6 and PCT, and TLR4 rs4986790 AG/GG genotypes as independent predictors of potential hospitalization and reduction of severe or fatal disease course.

Conclusion: In this study, we identified an additional genetic factor that may serve as an invariant predictor of COVID-19 outcome. The TLR4 rs4986790 AG/GG genotype reduced by half the risk of COVID-19 patients requiring hospitalization, intensive care or to have a fatal outcome. In addition, we were able to confirm the influence of previously known factors such as pre-existing conditions and inflammatory markers upon the onset of disease on the course of COVID-19. Based on these observations, we hereby provide another prognostic biomarker that could be used in routine diagnostics as a predictive factor for the severity of COVID-19 prior to SARS-CoV-2 infection.

Keywords: COVID-19; IL-6; SARS-CoV-2; TLR4; disease severity; polymorphism; prognostic marker; rs4986790.

Figure 1

(A) Distribution of interleukin-6 (IL-6) levels (pg/mL) at the time of hospital admission among all patients with SARS-CoV-2 infection according to COVID-19 severity. There was a significant increase in IL-6 levels with COVID-19 severity (p < 0.0001): ‘mild’ (N = 93, median = 8.4, IQR = 3.7 - 21.2); ‘hospitalized’ (N = 483, median = 26.2, IQR = 10.6 - 53.8); ‘severe’ (N = 241, median = 62.4, IQR = 27.7 - 119.5); and ‘fatal’ (N = 243, median = 102.0, IQR = 38.1 - 226.0). (B) Distribution of procalcitonin (PCT) levels (ng/mL) at the time of hospital admission among all patients with SARS-CoV-2 infection according to COVID-19 severity. There was a significant increase in PCT levels with COVID-19 severity (p < 0.0001): ‘mild’ (N = 102, median = 0.03, IQR = 0.02 - 0.05); ‘hospitalized’ (N = 679, median = 0.06, IQR = 0.03 - 0.13); ‘severe’ (N = 280, median = 0.13, IQR = 0.07 - 0.40); and ‘fatal’ (N = 304, median = 0.36, IQR = 0.12 - 1.37). IL-6, interleukin-6; PCT, procalcitonin; IQR, interquartile range.