Altered IL-6 signalling and risk of tuberculosis disease: a meta-analysis and Mendelian randomisation study
Year: 2023
Type: preprint
Abstract: Summary 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.
Source: medRxiv
Institutions: University of Bristol, MRC Integrative Epidemiology Unit, South African Medical Research Council, Stellenbosch University, University College London, Centre for Human Genetics, University of Oxford, Harvard University, Centre for the AIDS Programme of Research in South Africa, Massachusetts General Hospital, Dana-Farber Cancer Institute, Cardiff University, Imperial College London
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Wellcome Trust, Llywodraeth Cymru, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, European Commission, University of Bristol, Koninklijke Nederlandse Akademie van Wetenschappen, University College London Hospitals NHS Foundation Trust, National Institutes of Health, Medical Research Council, National Health and Medical Research Council, European Regional Development Fund, National Institute of Allergy and Infectious Diseases, European and Developing Countries Clinical Trials Partnership
Awards: G1131969086, G1777342200, G1888088267, G1953887145, G2347075150, Antibody gene variation and infectious disease susceptibility, G2975900969, G323433674, G324601231, G3288322216, G391091299, TOLLIP Deficiency, Immune Dysregulation, and Tuberculosis Susceptibility, G4499358239, What lies behind the causal impact of body mass index (BMI) level and change on human health? Added value from complementary study design and deep metabolomic phenotyping., Investigation of immune pathways and genetics underlying resistance and tolerance in severe infection, Investigation of immune pathways and genetics underlying resistance and tolerance in severe infection, G7063735130, What lies behind the causal impact of body mass index (BMI) level and change on human health? Added value from complementary study design and deep metabolomic phenotyping., A mathematical modeling framework for tuberculosis burden estimation and economic evaluation of pharmaceutical interventions
OpenAlex ID: W4319459798