Constantinescu, Andrei-Emil W

Cunnington, Aubrey

Ghazal, Peter

Hamilton, Fergus W

Hughes, David A

Mitchell, Ruth E

Timpson, Nicholas J

Introduction: Severe malaria remains a deadly disease for many young children in low -- and middle--income countries. Levels of Interleukin--6 (IL--6) have been shown to identify cases of severe malaria and associate with severity, but it is unknown if this association is causal, or whether manipulation of IL--6 might alter outcomes in severe malaria. Methods: A single nucleotide polymorphism (SNP, rs2228145) in the IL--6 receptor (IL6R) was chosen as a genetic variant that is known to alter IL--6 signalling. We measured the association between the minor allele of this SNP (C) and C--reactive protein (CRP) levels, a marker of IL--6 signalling in the non--European ancestry population recruited to UK Biobank. We then took this forward as an instrument to perform Mendelian randomisation (MR) in MalariaGEN, a large cohort study of patients with severe malaria at eleven worldwide sites. As a secondary approach, we identified cis protein quantitative trait loci (cis--pQTL) for IL6R itself and other markers of IL--6 signalling in a recently published GWAS of the plasma proteome performed in African Americans. We then performed MR using these instruments in the African MalariaGEN sites (9/11). Analyses were performed at each site, and meta--analysed using inverse variance weighting. Additional analyses were performed for specific sub--phenotypes of severe malaria: cerebral malaria and severe malarial anaemia. Results: The minor allele (C) of rs2228145 was associated with decreased CRP across all tested continental ancestries in UK Biobank. There was no evidence of heterogeneity of effect and a large overall effect (beta -0.11 per standard deviation of normalised CRP per C allele, p = 7.55 x 10-255) In Mendelian randomisation studies using this SNP, we did not identify an effect of decreased IL--6 signalling on severe malaria case status (Odds ratio 1.14, 95.56 -- 2.34, p = 0.713). Estimates of the association with any severe malaria sub--phenotype were similarly null although there was significant imprecision in all estimates. Using an alternative instrument (cis--pQTLs for IL6R), which included 3 SNPS (including rs2228145), we identified the same null effect, but with greater precision (Odds ratio 1.02, 95.95 1.10), and no effect on any severe malaria subtypes. Conclusions: Mendelian randomisation analyses using a SNP in the IL--6 receptor known to alter IL--6 signalling do not support a causal role for IL--6 signalling in the development of severe malaria, or any severe malaria sub--phenotype. This result suggests IL--6 may not be causal for severe outcomes in malaria, and that therapeutic manipulation of IL--6 may not be a suitable treatment for severe malaria. Competing Interest Statement The authors have declared no competing interest. Funding Statement FHs time was funded by the GW4-CAT Wellcome Doctoral Fellowship Scheme. PGs time was funded by the Ser Cymru programme, the Welsh Government, and the EU-ERDF. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215-2001), the MRC Integrative Epidemiology Unit (MCtextbackslashUUtextbackslash00011/1) and works within the CRUK 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. 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. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study only used publicly available summary genetic association data. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes This study was performed using publicly available data. MalariaGEN summary statistics are available at the MalariaGEN website 27 while Pan-UKBB GWAS are available via the Pan-UKBB website 21 and via the MRC-IEU OpenGWAS website.2

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The effect of genetically proxied IL-6 signalling on severe malaria: A Mendelian randomisation analysis

https://research-information.bris.ac.uk/en/publications/32b6fb31-9e20-4739-9b24-3391b5317078

The effect of genetically proxied IL-6 signalling on severe malaria: A Mendelian randomisation analysis

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