Gout is caused by the response of the innate immune system to monosodium urate (MSU) crystals. A recent gout GWAS identified a signal of genetic association at a locus encompassing IL1RN-IL1F10. Colocalisation analysis using Genotype Tissue Expression Database (GTEx) eQTL data showed that the signal overlaps with genetic control of IL1RN/IL1F10 gene expression. We assess the functional implications of IL1RN rs9973741, the lead gout-associated variant. We conducted functional validation of IL1RN rs9973741 in patients with gout and controls. The transcription level of IL1RN/IL1F10 was investigated in unstimulated or MSU-crystal co-stimulated PBMCs. Ex vivo functional assays were performed in PBMCs stimulated with C16 + MSU crystals or LPS for 24 h. Cytokine levels were assessed by ELISA. In unstimulated PBMCs, no association of IL1RN rs9973741 (gout risk allele G) to IL1RN expression was observed while IL-1F10 was hindered by low expression at both transcriptional and protein levels. However, G allele carriers showed lower IL1RN expression in PBMCs stimulated with C16/MSU crystal and lower concentrations of circulating IL-1Ra in both controls and gout patients. PBMCs depicted less spontaneous IL-1Ra release in GG homozygous controls and lower IL-1Ra production in response to C16 + MSU crystal costimulation in patients with gout. The G allele was associated with elevated IL-1β cytokine production in response to C16 + MSU crystal stimulation in controls. The gout risk allele G associates with lower circulating IL-1Ra, lower IL-1Ra production in PBMC assays and elevated IL-1β production in PBMCs challenged with C16 + MSU crystals but not in unchallenged cells. Our data indicate that the genetic signal that associates with gout at IL1RN-IL1F10 region functions to alter expression of IL-1Ra when stimulated by MSU crystals.

中文翻译：

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IL1RN-IL1F10 区的痛风相关 SNP 与痛风患者和对照 PBMC 中细胞因子产生的改变有关


痛风是由先天免疫系统对尿酸单钠 （MSU） 晶体的反应引起的。最近的痛风 GWAS 在包含 IL1RN-IL1F10 的基因座上发现了遗传关联的信号。使用基因型组织表达数据库 （GTEx） eQTL 数据的共定位分析显示，该信号与 IL1RN/IL1F10 基因表达的遗传控制重叠。我们评估了 IL1RN rs9973741 的功能意义，IL1RN rs9973741 是领先的痛风相关变体。我们在痛风患者和对照患者中对 IL1RN rs9973741 进行了功能验证。在未刺激或 MSU 晶体共刺激的 PBMC 中研究 IL1RN/IL1F10 的转录水平。在用 C16 + MSU 晶体或 LPS 刺激 24 小时的 PBMC 中进行离体功能测定。通过 ELISA 评估细胞因子水平。在未刺激的 PBMC 中，未观察到 IL1RN rs9973741 （痛风风险等位基因 G） 与 IL1RN 表达的关联，而 IL-1F10 在转录和蛋白质水平上均受到低表达的阻碍。然而，G 等位基因携带者在对照和痛风患者用 C16/MSU 晶体刺激的 PBMC 中显示出较低的 IL1RN 表达和较低的循环 IL-1Ra 浓度。PBMC 在 GG 纯合对照中描述较少的自发 IL-1Ra 释放，并且痛风患者响应 C16 + MSU 晶体共刺激而产生较低的 IL-1Ra。G 等位基因与对照组响应 C16 + MSU 晶体刺激的 IL-1β 细胞因子产生升高有关。痛风风险等位基因 G 与较低的循环 IL-1Ra、PBMC 测定中较低的 IL-1Ra 产生以及 PBMC 中 IL-1β 产生的增加有关，但与未攻击细胞无关。 我们的数据表明，当受到 MSU 晶体刺激时，IL1RN-IL1F10 区域与痛风相关的遗传信号会改变 IL-1Ra 的表达。