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

Fergus Hamilton; Ruth E Mitchell; Andrei Constantinescu; David Hughes; Aubrey Cunnington; Peter Ghazal; Nicholas J Timpson

doi:10.1016/j.ijid.2023.02.008

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

Fergus Hamilton, Ruth E Mitchell, Andrei Constantinescu, David Hughes, Aubrey Cunnington, Peter Ghazal, Nicholas J Timpson

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Abstract

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.

Original language	English
Pages (from-to)	251-259
Number of pages	9
Journal	International Journal of Infectious Diseases
Volume	129
Early online date	16 Feb 2023
DOIs	https://doi.org/10.1016/j.ijid.2023.02.008
Publication status	Published - 1 Apr 2023

Bibliographical note

Funding Information:
FH's time was funded by the GW4-CAT Wellcome Doctoral Fellowship Scheme (222894/Z/21/Z). PG's time was funded by the Ser Cymru program, the Welsh Government, and the EU-ERDF. NJT is a Wellcome Trust investigator (202802/Z/16/Z), is the princial investigator of the Avon Longitudinal Study of Parents and Children (Medical Research Council, MRC & Wellcome Trust, WT 217065/Z/19/Z), is supported by the University of Bristol National Institute for Health Research Biomedical Research Centre (BRC-1215-2001), the MRC Integrative Epidemiology Unit (MC_UU_00011/1), and works within the Cancer Research UK Integrative Cancer Epidemiology Programme (C18281/A29019). This study makes use of data generated by MalariaGEN. A full list of the investigators who contributed to the generation of the data is available from www.malariagen.net . The funding for this project was provided by Wellcome Trust (WT077383/Z/05/Z) and the Bill & Melinda Gates Foundation through the Foundation of the National Institutes of Health (566) as part of the Grand Challenges in Global Health Initiative. The funder had no role in the design, analysis, or reporting of this study.

Publisher Copyright:
© 2023 The Author(s)

Keywords

Child
Humans
Child, Preschool
Interleukin-6/genetics
Mendelian Randomization Analysis
Cohort Studies
Malaria/genetics
Polymorphism, Single Nucleotide
Genome-Wide Association Study

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "The effect of interleukin-6 signaling on severe malaria: A Mendelian randomization analysis",

abstract = "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.",

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author = "Fergus Hamilton and Mitchell, {Ruth E} and Andrei Constantinescu and David Hughes and Aubrey Cunnington and Peter Ghazal and Timpson, {Nicholas J}",

note = "Funding Information: FH's time was funded by the GW4-CAT Wellcome Doctoral Fellowship Scheme (222894/Z/21/Z). PG's time was funded by the Ser Cymru program, the Welsh Government, and the EU-ERDF. NJT is a Wellcome Trust investigator (202802/Z/16/Z), is the princial investigator of the Avon Longitudinal Study of Parents and Children (Medical Research Council, MRC & Wellcome Trust, WT 217065/Z/19/Z), is supported by the University of Bristol National Institute for Health Research Biomedical Research Centre (BRC-1215-2001), the MRC Integrative Epidemiology Unit (MC_UU_00011/1), and works within the Cancer Research UK Integrative Cancer Epidemiology Programme (C18281/A29019). This study makes use of data generated by MalariaGEN. A full list of the investigators who contributed to the generation of the data is available from www.malariagen.net . The funding for this project was provided by Wellcome Trust (WT077383/Z/05/Z) and the Bill & Melinda Gates Foundation through the Foundation of the National Institutes of Health (566) as part of the Grand Challenges in Global Health Initiative. The funder had no role in the design, analysis, or reporting of this study. Publisher Copyright: {\textcopyright} 2023 The Author(s)",

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TY - JOUR

T1 - The effect of interleukin-6 signaling on severe malaria

T2 - A Mendelian randomization analysis

AU - Hamilton, Fergus

AU - Mitchell, Ruth E

AU - Constantinescu, Andrei

AU - Hughes, David

AU - Cunnington, Aubrey

AU - Ghazal, Peter

AU - Timpson, Nicholas J

N1 - Funding Information: FH's time was funded by the GW4-CAT Wellcome Doctoral Fellowship Scheme (222894/Z/21/Z). PG's time was funded by the Ser Cymru program, the Welsh Government, and the EU-ERDF. NJT is a Wellcome Trust investigator (202802/Z/16/Z), is the princial investigator of the Avon Longitudinal Study of Parents and Children (Medical Research Council, MRC & Wellcome Trust, WT 217065/Z/19/Z), is supported by the University of Bristol National Institute for Health Research Biomedical Research Centre (BRC-1215-2001), the MRC Integrative Epidemiology Unit (MC_UU_00011/1), and works within the Cancer Research UK Integrative Cancer Epidemiology Programme (C18281/A29019). This study makes use of data generated by MalariaGEN. A full list of the investigators who contributed to the generation of the data is available from www.malariagen.net . The funding for this project was provided by Wellcome Trust (WT077383/Z/05/Z) and the Bill & Melinda Gates Foundation through the Foundation of the National Institutes of Health (566) as part of the Grand Challenges in Global Health Initiative. The funder had no role in the design, analysis, or reporting of this study. Publisher Copyright: © 2023 The Author(s)

PY - 2023/4/1

Y1 - 2023/4/1

N2 - 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.

AB - 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.

KW - Child

KW - Humans

KW - Child, Preschool

KW - Interleukin-6/genetics

KW - Mendelian Randomization Analysis

KW - Cohort Studies

KW - Malaria/genetics

KW - Polymorphism, Single Nucleotide

KW - Genome-Wide Association Study

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DO - 10.1016/j.ijid.2023.02.008

M3 - Article (Academic Journal)

C2 - 36801374

SN - 1201-9712

VL - 129

SP - 251

EP - 259

JO - International Journal of Infectious Diseases

JF - International Journal of Infectious Diseases

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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