Gout is a chronic disease that is caused by an innate immune response to deposited monosodium urate crystals in the setting of hyperuricemia. Here, we provide insights into the molecular mechanism of the poorly understood inflammatory component of gout from a genome-wide association study (GWAS) of 2.6 million people, including 120,295 people with prevalent gout. We detected 377 loci and 410 genetically independent signals (149 previously unreported loci in urate and gout). An additional 65 loci with signals in urate (from a GWAS of 630,117 individuals) but not gout were identified. A prioritization scheme identified candidate genes in the inflammatory process of gout, including genes involved in epigenetic remodeling, cell osmolarity and regulation of NOD-like receptor protein 3 (NLRP3) inflammasome activity. Mendelian randomization analysis provided evidence for a causal role of clonal hematopoiesis of indeterminate potential in gout. Our study identifies candidate genes and molecular processes in the inflammatory pathogenesis of gout suitable for follow-up studies.

痛风是一种慢性疾病，由高尿酸血症情况下对沉积的尿酸单钠晶体的先天免疫反应引起。在这里，我们从一项针对 260 万人（包括 120,295 名流行痛风患者）的全基因组关联研究 （GWAS） 中深入了解了痛风炎症成分知之甚少的分子机制。我们检测到 377 个基因座和 410 个遗传独立信号（149 个以前未报道的尿酸盐和痛风基因座）。另外 65 个信号在尿酸盐中 （来自 630,117 个体的 GWAS） 但未鉴定出痛风。优先方案确定了痛风炎症过程中的候选基因，包括参与表观遗传重塑、细胞渗透压和 NOD 样受体蛋白 3 （NLRP3） 炎性小体活性调节的基因。孟德尔随机化分析为不确定潜力的克隆造血在痛风中的因果作用提供了证据。我们的研究确定了适合随访研究的痛风炎症发病机制中的候选基因和分子过程。