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The effect of interleukin-6 signaling on severe malaria: A Mendelian randomization analysis
Fergus Hamilton1, Ruth E Mitchell2, Andrei Constantinescu2
1MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Infection Sciences, North Bristol NHS Trust, Bristol, UK.
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.
Insights
Interleukin-6 (IL-6) signaling is not causally linked to severe malaria development. This study suggests IL-6 may not be a suitable therapeutic target for treating severe malaria outcomes.
Area of Science:
- Genetics
- Immunology
- Infectious Diseases
Background:
- Severe malaria is a significant cause of mortality in children in low- and middle-income countries.
- Elevated interleukin-6 (IL-6) levels correlate with severe malaria, but a causal link remains unproven.
Purpose of the Study:
- To investigate the causal role of interleukin-6 (IL-6) signaling in the pathogenesis of severe malaria using a genetic approach.
Main Methods:
- Utilized Mendelian randomization (MR) analysis with a single nucleotide polymorphism (SNP; rs2228145) in the IL-6 receptor as a genetic instrument.
- The study involved a large cohort of severe malaria patients from the MalariaGEN study across 11 global sites.
Main Results:
- Mendelian randomization analyses did not reveal a causal effect of reduced IL-6 signaling on the risk of severe malaria (OR 1.14, P=0.713).
- Associations with specific severe malaria subphenotypes were also null, albeit with some statistical imprecision.
- Alternative MR approaches yielded consistent, non-significant results.
Conclusions:
- The findings do not support a causal role for IL-6 signaling in the development of severe malaria.
- Interleukin-6 (IL-6) is unlikely to be a direct cause of severe malaria outcomes.
- Targeting IL-6 therapeutically for severe malaria is not supported by this genetic evidence.
