期刊
ANNALS OF THE RHEUMATIC DISEASES
卷 79, 期 4, 页码 536-544出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/annrheumdis-2019-216233
关键词
gout; gene polymorphism; cytokines; treatment; inflammation
类别
资金
- Health Research Council of New Zealand
- Interleukin Foundation
- Dutch Arthritis Foundation [12-02-303]
- Competitiveness Operational Programme grant of the Romanian Ministry of European Funds [P_37_762, MySMIS 103587]
- Spinoza grant of the Netherlands Organisation for Scientific Research
- AIRC under MFAG 2018 [22 136]
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=5.71x10(-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.
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