Assessing the potential correlation of polymorphisms in the IL6R with relative IL6 elevation in severely ill COVID-19 patients'

Cytokine. 2021 Dec;148:155662. doi: 10.1016/j.cyto.2021.155662. Epub 2021 Jul 29.


Background: Elevated Interleukin-6 (IL-6) may play an important role in the pathophysiology of COVID-19 yet attenuated response is not seen across all severe patients. We aimed to determine the effect of IL-6 baseline levels and other clinical variables on mortality and outcomes in hospitalized COVID-19 patients as well as to explore genetic variants associated with attenuated IL-6 response.

Methods: Baseline IL-6 cytokine levels were measured in hospitalized patients participating in ongoing ODYSSEY phase 3 randomized study of tradipitant and placebo in hospitalized patients with severe COVID-19 who are receiving supplemental oxygen support. Furthermore blood samples for whole genome sequencing analysis were collected from 150 participants.

Results: We report significantly elevated IL-6 in COVID-19 infected hospitalized patients, n = 100 (p-value < 0.0001) when compared to controls n = 324. We also report a significantly increased level of IL-6 (p-value < 0.01) between the severe and mild COVID-19 patients with severity defined on a WHO scale. Excessive IL-6 plasma levels correlate with higher mortality (p-value 0.001). Additionally, based on our classification analysis, combination of IL-6 elevation and high levels of serum glucose can identify highest risk-group of COVID19 patients. Furthermore, we explore the role of genetic regulatory variants affecting baseline IL-6 levels specifically in COVID-19 patients. We have directly tested the association between variants in the IL6 and IL6R gene region and IL6 plasma levels. We provide results for a common IL-6 variant previously associated with pneumonia, rs1800795, and rs2228145 that was previously shown to affect IL-6 plasma levels, as well as report on novel variants associated with IL-6 plasma levels detected in our study patients.

Conclusions: While it is unlikely that "cytokine storm" is the norm in severe COVID19, baseline elevations above 150 pg/ml may be associated with worst outcomes and as such may warrant treatment considerations. So far no clinical studies used IL-6 baseline assessment to stratify the patient population participating in clinical studies. We believe that careful examination and interpretation of the IL-6 levels and genetic variants can help to determine a patient population with a potentially very robust clinical response to IL-6 inhibition.

Trial registration: NCT04326426.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • COVID-19 / blood*
  • COVID-19 / genetics*
  • COVID-19 / mortality
  • Heterozygote
  • Humans
  • Interleukin-6 / blood*
  • Interleukin-6 / genetics
  • Polymorphism, Single Nucleotide / genetics*
  • Receptors, Interleukin-6 / genetics*


  • IL6R protein, human
  • Interleukin-6
  • Receptors, Interleukin-6

Associated data