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[Preprint]. 2023 Feb 8:2023.02.07.23285472.

doi: 10.1101/2023.02.07.23285472.

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

Fergus Hamilton¹, Haiko Schurz², Tom A Yates³, James J Gilchrist^{4

5}, Marlo Möller², Vivek Naranbhai^{4

6

7

8

9}, Peter Ghazal¹⁰, Nicholas J Timpson¹; International Host TB Genetics Consortium; Tom Parks^{4

35}, Gabriele Pollara³

Collaborators, Affiliations

Collaborators

International Host TB Genetics Consortium:
Peter J Dodd¹¹, Eileen G Hoal², Andrew P Morris¹², Adrian Vs Hill^{4

13}, Reinout van Crevel^{14

15}, Arjan van Laarhoven¹⁴, Tom Ottenhoff¹⁶, Andres Metspalu¹⁷, Reedik Magi¹⁷, Christian G Meyer¹⁸, Magda Ellis¹⁹, Thorsten Thye²⁰, Surakameth Mahasirimongkol²¹, Ekawat Pasomsub²², Katsushi Tokunaga²³, Yosuke Omae²³, Hideki Yanai²⁴, Taisei Mushiroda²⁵, Michiaki Kubo²⁵, Atsushi Takahashi^{26

27}, Yoichiro Kamatani²⁶, Bachti Alisjahbana²⁸, Wei Liu^{29

30}, A-Dong Sheng^{31

32

33

34}, Yurong Yang¹⁰

Affiliations

¹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
² 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.
³ Division of Infection and Immunity, University College London, London, UK.
⁴ Wellcome Trust Centre for Human Genetics, Oxford, UK.
⁵ Department of Paediatrics, University of Oxford, UK.
⁶ Massachusetts General Hospital, Boston, USA.
⁷ Dana-Farber Cancer Institute, Boston, USA.
⁸ Centre for the AIDS Programme of Research in South Africa, Durban, South Africa.
⁹ Harvard Medical School, Boston, USA.
¹⁰ Cardiff University, Cardiff, UK.
¹¹ School of Health and Related Research, University of Sheffield, Sheffield, UK.
¹² Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK.
¹³ Jenner Institute, University of Oxford, UK.
¹⁴ 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.
¹⁵ 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.
¹⁶ Estonian Genome Center, Institute of Genomics, University of Tartu, Estonia.
¹⁷ Institute of Tropical Medicine, Eberhard-Karls University Tübingen, Germany and Faculty of Medicine, Duy Tan University, Da Nang, Vietnam.
¹⁸ Tuberculosis Research Group, Centenary Institute, Sydney, Australia.
¹⁹ Department of Infectious Disease Epidemiology, Bernhard Nocht Institute for Tropical Medicine Hamburg, 20359 Hamburg, Germany.
²⁰ Department of Medical Sciences, Ministry of Public Health, Nonthaburi, 11000, Thailand.
²¹ Virology Laboratory, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand.
²² Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan.
²³ Fukujuji Hospital and Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Kiyose, 204-0022, Japan.
²⁴ RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan.
²⁵ Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan.
²⁶ Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Suita, Osaka, 564-8565, Japan.
²⁷ Faculty of Medicine, Universitas Padjdjaran - Hasan Sadikin Hospital, Bandung Indonesia.
²⁸ 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.
²⁹ National Tissue engineering center of China, shanghai, People's republic of China.
³⁰ National Clinical Research Center for Respiratory Diseases, National Key Discipline of Pediatrics, Capital Medical University, No. 56 Nanlishi Road, Xicheng District, Beijing, 100045, China.
³¹ 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.
³² Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Beijing Pediatric Research Institute, No. 56 Nanlishi Road, Xicheng District, Beijing, 100045, China.
³³ 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.
³⁵ Department of Infectious Diseases Imperial College London, London, UK.

PMID: 36798349
PMCID: PMC9934798
DOI: 10.1101/2023.02.07.23285472

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

Fergus Hamilton et al. medRxiv. 2023.

[Preprint]. 2023 Feb 8:2023.02.07.23285472.

doi: 10.1101/2023.02.07.23285472.

Authors

Collaborators

International Host TB Genetics Consortium:
Peter J Dodd¹¹, Eileen G Hoal², Andrew P Morris¹², Adrian Vs Hill^{4

13}, Reinout van Crevel^{14

15}, Arjan van Laarhoven¹⁴, Tom Ottenhoff¹⁶, Andres Metspalu¹⁷, Reedik Magi¹⁷, Christian G Meyer¹⁸, Magda Ellis¹⁹, Thorsten Thye²⁰, Surakameth Mahasirimongkol²¹, Ekawat Pasomsub²², Katsushi Tokunaga²³, Yosuke Omae²³, Hideki Yanai²⁴, Taisei Mushiroda²⁵, Michiaki Kubo²⁵, Atsushi Takahashi^{26

27}, Yoichiro Kamatani²⁶, Bachti Alisjahbana²⁸, Wei Liu^{29

30}, A-Dong Sheng^{31

32

33

34}, Yurong Yang¹⁰

Affiliations

¹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
² 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.
³ Division of Infection and Immunity, University College London, London, UK.
⁴ Wellcome Trust Centre for Human Genetics, Oxford, UK.
⁵ Department of Paediatrics, University of Oxford, UK.
⁶ Massachusetts General Hospital, Boston, USA.
⁷ Dana-Farber Cancer Institute, Boston, USA.
⁸ Centre for the AIDS Programme of Research in South Africa, Durban, South Africa.
⁹ Harvard Medical School, Boston, USA.
¹⁰ Cardiff University, Cardiff, UK.
¹¹ School of Health and Related Research, University of Sheffield, Sheffield, UK.
¹² Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK.
¹³ Jenner Institute, University of Oxford, UK.
¹⁴ 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.
¹⁵ 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.
¹⁶ Estonian Genome Center, Institute of Genomics, University of Tartu, Estonia.
¹⁷ Institute of Tropical Medicine, Eberhard-Karls University Tübingen, Germany and Faculty of Medicine, Duy Tan University, Da Nang, Vietnam.
¹⁸ Tuberculosis Research Group, Centenary Institute, Sydney, Australia.
¹⁹ Department of Infectious Disease Epidemiology, Bernhard Nocht Institute for Tropical Medicine Hamburg, 20359 Hamburg, Germany.
²⁰ Department of Medical Sciences, Ministry of Public Health, Nonthaburi, 11000, Thailand.
²¹ Virology Laboratory, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand.
²² Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan.
²³ Fukujuji Hospital and Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Kiyose, 204-0022, Japan.
²⁴ RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan.
²⁵ Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan.
²⁶ Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Suita, Osaka, 564-8565, Japan.
²⁷ Faculty of Medicine, Universitas Padjdjaran - Hasan Sadikin Hospital, Bandung Indonesia.
²⁸ 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.
²⁹ National Tissue engineering center of China, shanghai, People's republic of China.
³⁰ National Clinical Research Center for Respiratory Diseases, National Key Discipline of Pediatrics, Capital Medical University, No. 56 Nanlishi Road, Xicheng District, Beijing, 100045, China.
³¹ 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.
³² Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Beijing Pediatric Research Institute, No. 56 Nanlishi Road, Xicheng District, Beijing, 100045, China.
³³ 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.
³⁵ Department of Infectious Diseases Imperial College London, London, UK.

PMID: 36798349
PMCID: PMC9934798
DOI: 10.1101/2023.02.07.23285472

Abstract

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.

Keywords: IL-6 receptor; Mendelian randomisation; Tuberculosis; meta-analysis.

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Figures

**Figure 1:**
Effect of altered IL-6 signalling activty on TB disease risk using Mendelian randomisation analyses. Odds ratios for the effect of reduced IL-6 signalling (on the scale of log CRP decrease) on TB disease Estimates generated by the Wald ratio and use rs2228145 as a single instrumental variable. Odds ratios less than one suggest lower risk of TB disease.

See this image and copyright information in PMC

References

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This is a preprint.

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

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Affiliations

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

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Abstract

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