Altered IL-6 signalling and risk of tuberculosis: a multi-ancestry mendelian randomisation study

Fergus Hamilton; Haiko Schurz; Tom A Yates; James J Gilchrist; Marlo Möller; Vivek Naranbhai; Peter Ghazal; Nicholas J Timpson; Genes & Health Research Team; International Tuberculosis Host Genetics Consortium; Tom Parks; Gabriele Pollara

doi:10.1016/S2666-5247(24)00162-9

Altered IL-6 signalling and risk of tuberculosis: a multi-ancestry mendelian randomisation study

Lancet Microbe. 2024 Nov 20:100922. doi: 10.1016/S2666-5247(24)00162-9. Online ahead of print.

Collaborators

Shaheen Akhtar, Mohammad Anwar, Omar Asgar, Samina Ashraf, Saeed Bidi, Gerome Breen, James Broster, Raymond Chung, David Collier, Charles J Curtis, Shabana Chaudhary, Grainne Colligan, Panos Deloukas, Ceri Durham, Faiza Durrani, Fabiola Eto, Sarah Finer, Joseph Gafton, Ana Angel, Chris Griffiths, Joanne Harvey, Teng Heng, Sam Hodgson, Qin Qin Huang, Matt Hurles, Karen A Hunt, Shapna Hussain, Kamrul Islam, Vivek Iyer, Benjamin M Jacobs, Georgios Kalantzis, Ahsan Khan, Claudia Langenberg, Cath Lavery, Sang Hyuck Lee, Daniel MacArthur, Sidra Malik, Daniel Malawsky, Hilary Martin, Dan Mason, Rohini Mathur, Mohammed Bodrul Mazid, John McDermott, Caroline Morton, Bill Newman, Elizabeth Owor, Asma Qureshi, Shwetha Ramachandrappa, Mehru Raza, Jessry Russell, Nishat Safa, Miriam Samuel, Moneeza Siddiqui, Michael Simpson, John Solly, Marie Spreckley, Daniel Stow, Michael Taylor, Richard C Trembath, Karen Tricker, David A van Heel, Klaudia Walter, Caroline Winckley, Suzanne Wood, John Wright, Ishevanhu Zengeya, Julia Zöllner, Haiko Schurz¹⁰, Vivek Naranbhai¹¹, Tom A Yates¹², James J Gilchrist¹³, Tom Parks⁸, Peter J Dodd¹⁴, Marlo Möller¹⁰, Eileen G Hoal¹⁰, Andrew P Morris¹⁵, Adrian V S Hill¹⁶, Reinout van Crevel¹⁷, Arjan van Laarhoven¹⁸, Tom H M Ottenhoff¹⁹, Andres Metspalu²⁰, Reedik Magi²⁰, Christian G Meyer²¹, Magda Ellis²², Thorsten Thye²³, Surakameth Mahasirimongkol²⁴, Ekawat Pasomsub²⁵, Katsushi Tokunaga²⁶, Yosuke Omae²⁶, Hideki Yanai²⁷, Taisei Mushiroda²⁸, Michiaki Kubo²⁸, Atsushi Takahashi²⁹, Yoichiro Kamatani³⁰, Bachti Alisjahbana³¹, Wei Liu³², A-Dong Sheng³³, Yurong Yang³⁴

Affiliations

¹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. Electronic address: fh6520@bristol.ac.uk.
² South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
³ Division of Infection and Immunity, University College London, London, UK; Institute of Health Informatics, University College London, London, UK.
⁴ Centre for Human Genetics, University of Oxford, Oxford, UK; Department of Paediatrics, University of Oxford, Oxford, UK.
⁵ Centre for Human Genetics, University of Oxford, Oxford, UK; Massachusetts General Hospital, Boston, USA; Dana-Farber Cancer Institute, Boston, USA; Centre for the AIDS Programme of Research in South Africa, Durban, South Africa; Harvard Medical School, Boston, USA.
⁶ Cardiff University, Cardiff, UK.
⁷ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁸ Centre for Human Genetics, University of Oxford, Oxford, UK; Department of Infectious Diseases Imperial College London, London, UK.
⁹ Division of Infection and Immunity, University College London, London, UK. Electronic address: g.pollara@ucl.ac.uk.
¹⁰ DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
¹¹ Centre for Human Genetics, University of Oxford, Oxford, UK; MasRSAhusetts General Hospital, Boston, USA; Dana-Farber Cancer Institute, Boston, USA; Centre for the AIDS Programme of Research in South Africa, Durban, South Africa; Harvard Medical School, Boston, USA.
¹² Division of Infection and Immunity, Faculty of Medical Sciences, University College London, London, UK.
¹³ Centre for Human Genetics, University of Oxford, Oxford, UK; Department of Paediatrics, University of Oxford, UK.
¹⁴ School of Health and Related Research, University of Sheffield, Sheffield, UK.
¹⁵ Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK.
¹⁶ Centre for Human Genetics, University of Oxford, Oxford, UK; Jenner Institute, University of Oxford, UK.
¹⁷ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹⁸ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
¹⁹ Head Lab Dept of Infectious Diseases; Head Group Immunology and Immunogenetics of Bacterial Infectious Diseases Leiden University Medical Center, PO Box 9600, 2300RC Leiden, the Netherlands.
²⁰ Estonian Genome Center, Institute of Genomics, University of Tartu, Estonia.
²¹ Institute of Tropical Medicine, Eberhard-Karls University Tübingen, Germany and Faculty of Medicine, Duy Tan University, Da Nang, Vietnam.
²² Tuberculosis Research Group, Centenary Institute, Sydney, Australia.
²³ Department of Infectious Disease Epidemiology, Bernhard Nocht Institute for Tropical Medicine Hamburg, 20359 Hamburg, Germany.
²⁴ Department of Medical Sciences, Ministry of Public Health, Nonthaburi, 11000, Thailand.
²⁵ Virology Laboratory, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand.
²⁶ Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan.
²⁷ Fukujuji Hospital and Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Kiyose, 204-0022, Japan.
²⁸ RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan.
²⁹ Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan; Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Suita, Osaka, 564-8565, Japan.
³⁰ Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan.
³¹ Faculty of Medicine, Universitas Padjdjaran - Hasan Sadikin Hospital, Bandung Indonesia.
³² Department of Plastic and reconstructive surgery, shanghai Key laboratory of Tissue engineering, shanghai Ninth People's hospital, shanghai Jiao Tong University - school of Medicine, shanghai, People's republic of China; National Tissue engineering center of China, shanghai, People's republic of China.
³³ National Clinical Research Center for Respiratory Diseases, National Key Discipline of Pediatrics, Capital Medical University, No 56 Nanlishi Road, Xicheng District, Beijing, 100045, China; Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, No 56 Nanlishi Road, Xicheng District, Beijing, 100045, China; Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Beijing Pediatric Research Institute, No 56 Nanlishi Road, Xicheng District, Beijing, 100045, China; Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou, China.
³⁴ Ningxia Medical University, Ningxia Hui Autonomous Region, the People's Republic of China.

PMID: 39579785
DOI: 10.1016/S2666-5247(24)00162-9

Abstract

Background: The role of IL-6 responses in human tuberculosis risk is unknown. IL-6 signalling inhibitors, such as tocilizumab, are thought to increase the risk of progression to tuberculosis, and screening for latent Mycobacterium tuberculosis infection before using these drugs is widely recommended. We used single nucleotide polymorphisms (SNPs) in and near the IL-6 receptor gene (IL6R), including the non-synonymous variant, rs2228145, for which the C allele contributes to reduced classic (cis) IL-6 signalling activity, to test the hypothesis that altered IL-6 signalling is causally associated with the risk of developing tuberculosis.

Methods: We performed a meta-analysis of genome-wide association studies (GWAS) published in English from database inception to Jan 1, 2024. GWAS were identified from the European Bioinformatics Institute, MRC Integrative Epidemiology Unit catalogues, and MEDLINE, selecting publicly available studies for which tuberculosis was an outcome and that included the IL6R rs2228145 SNP. Using each study's population-level summary statistics, effect estimates were extracted for each additional copy of the C allele of rs2228145. We used these estimates to perform multi-ancestry, two-sample mendelian randomisation analyses to estimate the causal effect of reduced IL-6 signalling on tuberculosis. Our primary analyses used rs2228145-C as a genetic instrument, weighted on C-reactive protein (CRP) reduction as a measure of the effect on IL-6 signalling. We also took an alternative, ancestry-specific, multiple SNP approach using IL-6 receptor plasma protein as an exposure. Additionally, we compared the effects of rs2228145 in tuberculosis with those in critical COVID-19, rheumatoid arthritis, Crohn's disease, and coronary artery disease using the summary statistics extracted from GWAS.

Findings: 17 GWAS were included, collating data for 19 302 individuals with tuberculosis (cases) and 1 019 821 population controls across multiple ancestries. For each additional rs2228145-C allele, the odds of tuberculosis reduced (odds ratio [OR] 0·94 [95% CI 0·92-0·97]; p=6·8 × 10^-6). Multi-ancestry mendelian randomisation analyses supported these findings, with decreased odds of tuberculosis associated with readouts of reduced IL-6 signalling (0·52 [0·39-0·69] for each natural log CRP decrease; p=6·8 × 10^-6), with weak evidence of heterogeneity (I²=0·315; p=0·11). Ancestry-specific, multiple SNP mendelian randomisation using increase in IL-6 receptor plasma protein as an exposure revealed a similar reduced risk of tuberculosis (OR 0·94 [95% CI 0·93-0·96]; p=2·4 × 10^-10). The protective effects on tuberculosis seen with rs2228145-C were similar in size and direction to those observed in critical COVID-19 (0·66 [0·50-0·86]), Crohn's disease (0·57 [0·44-0·74]), and rheumatoid arthritis (0·45 [0·36-0·58]), all of which benefit from the therapeutic effects of IL-6 antagonism.

Interpretation: Our findings propose a causal relationship between reduced IL-6 signalling and lower risk of tuberculosis, akin to the effect seen in other IL-6 mediated diseases. This study suggests that IL-6 antagonists do not increase the risk of tuberculosis but rather should be investigated as therapeutic adjuncts in its treatment.

Funding: UK National Institute for Health and Care Research, Wellcome Trust, EU European Regional Development Fund, the Welsh Government, and UK Research and Innovation.