Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of proinflammatory cytokines, including interleukin-1β (IL-1β). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated with elevated IL-1β, thus we investigated CHIP as a risk factor for gout. To test the clinical association between CHIP and gout, we analyzed whole exome sequencing data from 177 824 individuals in the MGB Biobank (MGBB) and UK Biobank (UKB). In both cohorts, the frequency of gout was higher among individuals with CHIP than without CHIP (MGBB, CHIP with variant allele fraction [VAF] ≥2%: odds ratio [OR], 1.69; 95% CI, 1.09-2.61; P = .0189; UKB, CHIP with VAF ≥10%: OR, 1.25; 95% CI, 1.05-1.50; P = .0133). Moreover, individuals with CHIP and a VAF ≥10% had an increased risk of incident gout (UKB: hazard ratio [HR], 1.28; 95% CI, 1.06-1.55; P = .0107). In murine models of gout pathogenesis, animals with Tet2 knockout hematopoietic cells had exaggerated IL-1β secretion and paw edema upon administration of MSU crystals. Tet2 knockout macrophages elaborated higher levels of IL-1β in response to MSU crystals in vitro, which was ameliorated through genetic and pharmacologic Nlrp3 inflammasome inhibition. These studies show that TET2-mutant CHIP is associated with an increased risk of gout in humans and that MSU crystals lead to elevated IL-1β levels in Tet2 knockout murine models. We identify CHIP as an amplifier of NLRP3-dependent inflammatory responses to MSU crystals in patients with gout.

中文翻译：

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TET2 突变克隆造血和痛风风险。

痛风是一种常见的炎症性关节炎，由高尿酸血症患者体内尿酸钠 (MSU) 晶体沉淀引起。急性发作伴随着促炎细胞因子的分泌，包括白细胞介素-1β (IL-1β)。不确定潜能克隆造血 (CHIP) 是一种与年龄相关的疾病，易患血液癌症和心血管疾病。CHIP 与 IL-1β 升高相关，因此我们将 CHIP 作为痛风的危险因素进行研究。为了测试 CHIP 与痛风之间的临床关联，我们分析了 MGB 生物库 (MGBB) 和英国生物库 (UKB) 中 177,824 名个体的全外显子组测序数据。在这两个队列中，患有 CHIP 的个体痛风发生频率高于未患有 CHIP 的个体（MGBB、变异等位基因分数 [VAF] ≥2% 的 CHIP：比值比 [OR]，1.69；95% CI，1.09-2.61；P = .0189；UKB，VAF ≥10% 的 CHIP：OR，1.25；95% CI，1.05-1.50；P = .0133）。此外，患有 CHIP 且 VAF ≥10% 的个体发生痛风的风险增加（UKB：风险比 [HR]，1.28；95% CI，1.06-1.55；P = .0107）。在痛风发病机制的小鼠模型中，Tet2 敲除造血细胞的动物在给予 MSU 晶体后出现了 IL-1β 分泌过多和爪水肿。Tet2 敲除巨噬细胞在体外对 MSU 晶体产生更高水平的 IL-1β 反应，通过遗传和药理 Nlrp3 炎性体抑制可以改善这种情况。这些研究表明，TET2 突变体 CHIP 与人类痛风风险增加有关，并且 MSU 晶体会导致 Tet2 敲除小鼠模型中 IL-1β 水平升高。我们确定 CHIP 是痛风患者对 MSU 晶体的 NLRP3 依赖性炎症反应的放大器。