Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: Findings from a Mendelian randomisation study

Mitchell

Constantinescu

et al. 2022

Preprint

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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% CI 0.56 – 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% CI 0.95 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.

Section: Introductionmentioning

confidence: 68%

Section: Limitationsmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Identification Of Exposuresmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Mitchell

Constantinescu

et al. 2022

Preprint

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Variation inERAP2has opposing effects on severe respiratory infection and autoimmune disease

Mentzer

Parks

et al. 2022

Preprint

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Introduction: ERAP2 is an aminopeptidase involved in immunological antigen presentation. Genotype data in human samples from before and after the Black Death, an epidemic due to Yersinia pestis, have marked changes in population allele frequency of the common single nucleotide polymorphism (SNP) rs2549794. This SNP in strong linkage disequilibrium with a key splicing SNP in ERAP2 (rs2248374) and this suggests that variation at ERAP2 may be relevant for protection from infection. rs2549794 is also associated with Crohn's disease and findings imply balancing selection between infection and autoimmune disease at this locus. There have been no large-scale prospective case-control studies of variation at ERAP2 and infection. Methods: This study aimed to explore the association between variation at ERAP2 and a) infection, b) autoimmune disease, and c) parental longevity as a proxy for lifespan. Genome Wide Association Studies (GWAS) of these outcomes were identified in contemporary cohorts (UK Biobank, FinnGen, and GenOMICC). Effect estimates were extracted for rs2549794 and rs2248374. Additionally, cis expression and protein quantitative trait loci (QTLs) for ERAP2 were used in Mendelian randomisation analyses. Results: Across all cohorts, the T allele (minor allele frequency of 0.4-0.5) of rs2549794 showed evidence of association with respiratory infection (odds ratio; OR for pneumonia 1.03; 95% CI 1.01-1.05; p = 0.014). Effect estimates were larger in bacterial rather than viral infection and larger for more severe phenotypes (OR for critical care admission with pneumonia 1.08; 95% CI 1.02-1.14, p = 0.008, OR for death from pneumonia 1.07; 95% CI 1.01-1.12; p = 0.014). In contrast, opposing effects were identified for Crohn's disease (OR 0.86; 95% CI 0.82-0.90, p = 8.6 x 10-9) and type 1 diabetes (OR 0.95; 95% CI 0.90-0.99, p = 0.02). No strong evidence for association was identified for sepsis. Carriage of the T allele was associated with increased age of parental death (beta in Z-scored years across both parents age at death 0.01, 95% CI 0.004- 0.017, p = 0.002). Similar results were identified for rs2248374. In Mendelian randomisation analyses, increasing transcription or protein levels of ERAP2 were strongly associated with protection from respiratory infection, with opposing effects identified on Crohn's disease and type 1 diabetes. Increased expression of ERAP2 was associated with reduced parental longevity. Conclusions: Variation at ERAP2 is associated with severe respiratory infection in modern societies, with an opposing association with Crohn's disease and type 1 diabetes. These data support the hypothesis that changes in allele frequencies in ERAP2 observed at the time of the Black Death reflect protection from infection, and suggest ongoing balancing selection at this locus driven by autoimmune and infectious disease

Altered IL-6 signalling and risk of tuberculosis disease: a meta-analysis and Mendelian randomisation study

Schurz

Yates

et al. 2023

Preprint

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IL-6 responses are ubiquitous in Mycobacterium tuberculosis (Mtb) infections, but their role in determining human tuberculosis (TB) disease risk is unknown. We used single nucleotide polymorphisms (SNPs) in and near the IL-6 receptor (IL6R) gene, focusing on the non-synonymous variant, rs2228145 associated with reduced classical IL-6 signalling, to assess the effect of altered IL-6 activity on TB disease risk. We identified 16 genome wide association studies (GWAS) of TB disease collating 17,982 cases of TB disease and 972,389 controls across 4 continents. Meta-analyses and Mendelian randomisation analyses revealed that reduced classical IL-6 signalling was associated with lower odds of TB disease, a finding replicated using multiple, independent SNP instruments and 2 separate exposure variables. Our findings establish a causal relationship between IL-6 signalling and the outcome of Mtb infection, suggesting IL-6 antagonists do not increase the risk of TB disease and should be investigated as adjuncts in treatment.