The effect of interleukin-6 signaling on severe malaria: A Mendelian randomization analysis

Objectives: Severe malaria remains a deadly disease for many young children in low-and middle-income countries. Levels of interleukin (IL)-6 have been shown to identify cases of severe malaria and associate with severity, but it is unknown if this association is causal. Methods: A single nucleotide polymorphism (SNP; rs2228145) in the IL-6 receptor was chosen as a ge-netic variant that is known to alter IL-6 signaling. We tested this, then took this forward as an instrument to perform Mendelian randomization (MR) in MalariaGEN, a large cohort study of patients with severe malaria at 11 worldwide sites. Results: In MR analyses using rs2228145, we did not identify an effect of decreased IL-6 signaling on severe malaria (odds ratio 1.14, 95% confidence interval 0.56-2.34, P = 0.713). The estimates of the as-sociation with any severe malaria subphenotype were similarly null, although with some imprecision. Further analyses using other MR approaches had similar results. Conclusion: These analyses do not support a causal role for IL-6 signaling in the development of severe malaria. This result suggests IL-6 may not be causal for severe outcomes in malaria, and that therapeutic manipulation of IL-6 is unlikely to be a suitable treatment for severe malaria. (c) 2023 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )

Automated summary

Through Mendelian Randomization (MR) analysis using the genetic variant rs2228145, it was found that decreasing IL-6 signaling does not have an effect on the development of severe malaria. This suggests that IL-6 may not be causal for severe outcomes in malaria, and therapeutic manipulation of IL-6 is unlikely to be a suitable treatment for severe malaria.