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.

中文翻译：

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白细胞介素 37 中的罕见遗传变异将这种抗炎细胞因子与痛风的发病机制和治疗联系起来

目的痛风以尿酸钠结晶诱发的白细胞介素(IL)-1介导的严重关节炎症为特征。由于 IL-37 是抑制 IL-1 活性的关键抗炎细胞因子，我们进行了遗传和功能研究，旨在阐明 IL-37 在痛风发病机制和治疗中的作用。方法 通过使用基于分子倒置探针的重测序（发现队列：痛风 n=675，对照 n=520）和 TaqMan 基因分型（验证队列：痛风 n=2202，对照 n= 2295）。对稀有变异对蛋白质结构的影响进行预测建模，然后进行体外实验评估对蛋白质功能的影响。在痛风小鼠模型中对重组 IL-37 的治疗进行了体外和体内评估。结果 我们在 6 名新发现的痛风患者中发现了 IL37 的 4 种罕见变异；p.(A144P)、p.(G174Dfs*16)、p.(C181*) 和 p.(N182S)，而健康对照中均未出现（Fisher 精确 p 值 = 0.043）。所有变体都聚集在外显子 5 中 IL-37 的功能域中（p 值 = 5.71×10-5）。预测模型和功能研究证实了抗炎功能的丧失，我们证实了重组 IL-37 在治疗痛风炎症方面的治疗潜力。此外，p.(N182S)(rs752113534) 的携带者状态与波利尼西亚血统的高尿酸血症个体患痛风的风险增加（OR=1.81，p 值=0.031）相关。结论 在这里，我们提供了 IL-37 在痛风发病机制中的作用的遗传和机制证据，