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.
- gene polymorphism
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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.