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Rare genetic variants in interleukin-37 link this anti-inflammatory cytokine to the pathogenesis and treatment of gout
  1. Viola Klück1,2,
  2. Rosanne C van Deuren1,3,
  3. Giulio Cavalli4,5,
  4. Amara Shaukat6,
  5. Peer Arts3,7,
  6. Maartje C Cleophas1,2,
  7. Tania O Crișan8,
  8. Anne-Kathrin Tausche9,
  9. Philip Riches10,
  10. Nicola Dalbeth11,
  11. Lisa K Stamp12,
  12. Jennie Harré Hindmarsh13,
  13. Tim L Th A Jansen14,
  14. Matthijs Janssen14,
  15. Marloes Steehouwer2,3,
  16. Stefan Lelieveld2,3,
  17. Maartje van de Vorst2,3,
  18. Christian Gilissen2,3,
  19. Lorenzo Dagna4,
  20. Frank L Van de Veerdonk1,2,
  21. Elan Z Eisenmesser15,
  22. SooHyun Kim16,
  23. Tony R Merriman6,
  24. Alexander Hoischen1,3,
  25. Mihai G Netea1,17,
  26. Charles A Dinarello1,5,
  27. Leo AB Joosten1,8
  1. 1 Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
  2. 2 Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
  3. 3 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
  4. 4 Internal Medicine and Clinical Immunology, Vita-Salute San Raffaele University, Milan, Italy
  5. 5 Department of Medicine, University of Colorado Denver, Denver, Colorado, USA
  6. 6 Department of Biochemistry, University of Otago, Dunedin, New Zealand
  7. 7 Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia, Australia
  8. 8 Department of Medical Genetics, Universitatea de Medicina si Farmacie Iuliu Hatieganu, Cluj-Napoca, Romania
  9. 9 Department of Internal Medicine, Section of Rheumatology, University Clinic Carl Gustav Carus, Dresden, Saxonia, Germany
  10. 10 Rheumatology and Bone Disease, University of Edinburgh, Edinburgh, UK
  11. 11 Department of Medicine, University of Auckland, Auckland, New Zealand
  12. 12 Department of Medicine, Otago University, Christchurch, Canterbury, New Zealand
  13. 13 Te Rangawairua o Paratene Ngata Research Centre, Ngāti Porou Hauora Charitable Trust, Te Puia Springs, Tairāwhiti, New Zealand
  14. 14 Department of Rheumatology, VieCuri Medical Center, Venlo, The Netherlands
  15. 15 Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Denver, Colorado, USA
  16. 16 Laboratory of Cytokine Immunology, Konkuk University, Seoul, Korea (the Republic of)
  17. 17 Department of Genomics and Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
  1. Correspondence to Leo AB Joosten, Department of Internal Medicine, RadboudUMC, Nijmegen 6525 GA, The Netherlands; Leo.Joosten{at}radboudumc.nl

Abstract

Objective Gout is characterised by severe interleukin (IL)-1-mediated joint inflammation induced by monosodium urate crystals. Since IL-37 is a pivotal anti-inflammatory cytokine suppressing the activity of IL-1, we conducted genetic and functional studies aimed at elucidating the role of IL-37 in the pathogenesis and treatment of gout.

Methods Variant identification was performed by DNA sequencing of all coding bases of IL37 using molecular inversion probe-based resequencing (discovery cohort: gout n=675, controls n=520) and TaqMan genotyping (validation cohort: gout n=2202, controls n=2295). Predictive modelling of the effects of rare variants on protein structure was followed by in vitro experiments evaluating the impact on protein function. Treatment with recombinant IL-37 was evaluated in vitro and in vivo in a mouse model of gout.

Results We identified four rare variants in IL37 in six of the discovery gout patients; p.(A144P), p.(G174Dfs*16), p.(C181*) and p.(N182S), whereas none emerged in healthy controls (Fisher’s exact p-value=0.043). All variants clustered in the functional domain of IL-37 in exon 5 (p-value=5.71×10−5). Predictive modelling and functional studies confirmed loss of anti-inflammatory functions and we substantiated the therapeutic potential of recombinant IL-37 in the treatment of gouty inflammation. Furthermore, the carrier status of p.(N182S)(rs752113534) was associated with increased risk (OR=1.81, p-value=0.031) of developing gout in hyperuricaemic individuals of Polynesian ancestry.

Conclusion Here, we provide genetic as well as mechanistic evidence for the role of IL-37 in the pathogenesis of gout, and highlight the therapeutic potential of recombinant IL-37 for the treatment of gouty arthritis.

  • gout
  • gene polymorphism
  • cytokines
  • treatment
  • inflammation
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Footnotes

  • Handling editor Josef S Smolen

  • VK, RCvD and GC contributed equally.

  • Contributors First authorship is shared by Viola Klück, Rosanne C. van Deuren and Giulio Cavalli as they contributed equally to this study.

  • Funding The New Zealand-based work was supported by the Health Research Council of New Zealand. MIP-based resequencing of IL37 was supported by the Interleukin Foundation. MCC was supported by a grant of the Dutch Arthritis Foundation (No. 12-02-303). LABJ and TOC were supported by a Competitiveness Operational Programme grant of the Romanian Ministry of European Funds (P_37_762, MySMIS 103587). MGN was supported by a Spinoza grant of the Netherlands Organisation for Scientific Research. GC was supported by AIRC under MFAG 2018-ID. 22 136 project.

  • Competing interests ND reports grants from Health Research Council of New Zealand, during the conduct of the study; grants and personal fees from AstraZeneca, grants from Amgen, personal fees from Horizon, personal fees from Selecta, personal fees from Janssen, personal fees from Abbvie, personal fees from Kowa, personal fees from Dyve BioSciences, personal fees from Arthrosi, outside the submitted work. LABJ reports to be Scientific Advisory Board member of Olatec Therapeutics LLC. A-KT reports personal fees from Speakers fees for Novartis Pharma, Ardea Biosience, Astra Zeneca, Gruenenthal, Berlin Chemie Menarini, outside the submitted work.

  • Patient and public involvement With the exception of clinical sample contribution, patients were not involved in this investigation as it revolves around basic and translational science. However, patient associations will be instrumental to the dissemination of the present research findings following publication.

  • Patient consent for publication Not required.

  • Ethics approval For animal experiments in this manuscript Institutional Animal Care and Use Committees of the University of Colorado Denver, Aurora, CO, USA. For human participants, ethical approval was obtained at the following institutes: Ethical Committee of the Radboud University Medical Centre (no. 42561.091.12; registration number 2012/482), New Zealand Multi-Region Ethics Committee (MEC/105/10/130), South East Scotland Research Ethics Committee (04/S1102/41), Ethikkommission, Technische Universität Dresden (EK 8012012), Northern Y Region Health Research Ethics Committee (NTY07/07/074), Lower South Ethics Committee (OTA/99/11/098), New Zealand Multi-region Ethics Committee (MEC/05/10/130), Ethical Committee of the Radboud University Medical Centre (no. NL32357.091.10; registration number 2010/104).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Data sets from the cohort of healthy volunteers are available on https://hfgp.bbmri.nl/. Data sets from gout cohorts and code are available upon reasonable request.

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