Dissecting the IL‐6 pathway in cardiometabolic disease: A Mendelian randomization study on both <i>IL6</i> and <i>IL6R</i>

Asselbergs, Folkert W.; Natarajan, Pradeep; Ridker, Paul M.; Hovingh, G. Kees; Schmidt, Amand F.

doi:10.1111/bcp.15191

Cited by 45 publications

(33 citation statements)

References 85 publications

(108 reference statements)

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“…The mixed reliability of eQTL instruments in predicting direction of effect on the outcome could be due to a number of factors such as: less than perfect correlation between mRNA and protein levels 145 , hidden pleiotropy in single instruments used in the MR analysis (directly observed for IL2RA) 146 , presence of negative feedback loop involved in the drug mechanism 147 , translation into protein isoforms with distinct biological effects 148 and differential cell-type specific drug effect 149 .…”

Section: Combining Rct and Mr Results Can Offer Complimentary Evidenc...mentioning

confidence: 99%

Systematic comparison of Mendelian randomization studies and randomized controlled trials using electronic databases

Sobczyk

Smith

Gaunt

2022

Preprint

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Mendelian Randomization (MR) uses genetic instrumental variables to make causal inferences. Whilst sometimes referred to as "nature's randomized trial", it has distinct assumptions that make comparisons between the results of MR studies with those of actual randomized controlled trials (RCTs) invaluable. To scope the potential for (semi-)-automated triangulation of MR and RCT evidence, we mined ClinicalTrials.Gov, PubMed and EpigraphDB databases and carried out a series of 26 manual literature comparisons among 54 MR and 77 RCT publications. We found that only 11% of completed RCTs identified in ClinicalTrials.Gov submitted their results to the database. Similarly low coverage was revealed for Semantic Medline (SemMedDB) semantic triples derived from MR and RCT publications - 25% and 12%, respectively. Among intervention types that can be mimicked by MR, only trials of pharmaceutical interventions could be automatically matched to MR results due to insufficient annotation with MeSH ontology. A manual survey of the literature highlighted the potential for triangulation across a number of exposure/outcome pairs if these challenges can be addressed. We conclude that careful triangulation of MR with RCT evidence should involve consideration of similarity of phenotypes across study designs, intervention intensity and duration, study population demography and health status, comparator group, intervention goal and quality of evidence.

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Section: Combining Rct and Mr Results Can Offer Complimentary Evidenc...mentioning

confidence: 99%

Systematic comparison of Mendelian randomization studies and randomized controlled trials using electronic databases

Sobczyk

Smith

Gaunt

2022

Preprint

View full text Add to dashboard Cite

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Section: Methodsmentioning

confidence: 99%

“…Our IL6R instruments were selected based on a recent Mendelian randomisation study which performed a meta-analysis of a high sensitivity CRP Genome wide association study (GWAS) of 522 681 European individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium and UK Biobank. 30 Conceptually our genetic instrument is similar to the action of anti-IL6R monoclonal antibodies (e.g. tocilizumab) that lead to complete inhibition of IL6R signalling by blocking both IL6 classical and trans signalling.…”

Section: Mendelian Randomisation -Definition Of Instrumentsmentioning

confidence: 99%

“…Previous literature has not identified an association between variants proxying IL6R blockade and sepsis, although multiple studies have identified associations (in line with our estimates), suggesting these IL6R variants increases the risk of infection, which match randomised trial data. 30,41 . One trial was considering the use of IL6RA in paediatric sepsis (NCT04850443), but this was halted due to lack of funding.…”

Section: Sensitivity Analysesmentioning

confidence: 99%

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

Hamilton

Thomas

Arnold

et al. 2022

Preprint

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Introduction Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin-6 (IL-6). Genetic variants in IL6R known to downregulate IL-6 signalling are associated with improved COVID-19 outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RA). We hypothesised that blockade of IL6R could also improve outcomes in sepsis. Methods We performed a Mendelian randomisation analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis, sepsis severity, other infections, and COVID-19. We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP in a similar analysis. Results In the UK Biobank cohort (N=485,825, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of sepsis (OR=0.80; 95% CI 0.66-0.96, per unit of natural log transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR=0.74; 95% CI 0.38-0.70); critical care admission with sepsis (OR=0.48, 95% CI 0.30-0.78) and critical care death with sepsis (OR=0.37, 95% CI 0.14 - 0.98) Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 - 0.97) and for sepsis survival in critical care (OR=0.22; 95% CI 0.04- 1.31) in the GainS and GenOSept consortium. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR=0.69, 95% 0.57 - 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. Conclusions IL6R blockade is causally associated with reduced incidence of sepsis, sepsis related critical care admission, and sepsis related mortality. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. This data suggests a randomised trial of IL-6 receptor antagonists in sepsis should be considered.

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“…IL-6 is an important cytokine in myocardial lipid accumulation [ 29 ]. Blocking the expression of IL-6 or its receptor to the perturb IL-6 signaling pathway results in a reduction in the risk of coronary artery disease and atrial fibrillation, as well as T2D [ 31 ].…”

Section: Obesity Its Comorbidities and Associated Factorsmentioning

confidence: 99%

The Related Metabolic Diseases and Treatments of Obesity

2022

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Obesity is a chronic disease characterized by the abnormal or excessive accumulation of body fat, affecting more than 1 billion people worldwide. Obesity is commonly associated with other metabolic disorders, such as type 2 diabetes, non-alcoholic fatty liver disease, cardiovascular diseases, chronic kidney disease, and cancers. Factors such as a sedentary lifestyle, overnutrition, socioeconomic status, and other environmental and genetic conditions can cause obesity. Many molecules and signaling pathways are involved in the pathogenesis of obesity, such as nuclear factor (NF)-κB, Toll-like receptors (TLRs), adhesion molecules, G protein-coupled receptors (GPCRs), programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1), and sirtuin 1 (SIRT1). Commonly used strategies of obesity management and treatment include exercise and dietary change or restriction for the early stage of obesity, bariatric surgery for server obesity, and Food and Drug Administration (FDA)-approved medicines such as semaglutide and liraglutide that can be used as monotherapy or as a synergistic treatment. In addition, psychological management, especially for patients with obesity and distress, is a good option. Gut microbiota plays an important role in obesity and its comorbidities, and gut microbial reprogramming by fecal microbiota transplantation (FMT), probiotics, prebiotics, or synbiotics shows promising potential in obesity and metabolic syndrome. Many clinical trials are ongoing to evaluate the therapeutic effects of different treatments. Currently, prevention and early treatment of obesity are the best options to prevent its progression to many comorbidities.

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Dissecting the IL‐6 pathway in cardiometabolic disease: A Mendelian randomization study on both IL6 and IL6R

Cited by 45 publications

References 85 publications

Systematic comparison of Mendelian randomization studies and randomized controlled trials using electronic databases

Systematic comparison of Mendelian randomization studies and randomized controlled trials using electronic databases

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

The Related Metabolic Diseases and Treatments of Obesity

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