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

Hamilton, Fergus, Mitchell, Ruth E, Constantinescu, Andrei, Hughes, David, Cunnington, Aubrey, Ghazal, Peter ORCID: and Timpson, Nicholas J. 2023. The effect of interleukin-6 signaling on severe malaria: A Mendelian randomization analysis. International Journal of Infectious Diseases 129 , pp. 251-259. 10.1016/j.ijid.2023.02.008

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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 genetic 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 association 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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Publisher: Elsevier
ISSN: 1201-9712
Date of First Compliant Deposit: 22 March 2023
Date of Acceptance: 10 February 2023
Last Modified: 09 Nov 2023 02:05

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