美国阿拉巴马大学Tony R. Merriman研究小组发现，全基因组关联分析揭示痛风的新致病通路。2024年10月15日，《自然—遗传学》杂志在线发表了这项成果。

据了解，痛风是一种慢性疾病，由于在高尿酸血症的情况下，单钠尿酸盐结晶的沉积引发先天免疫反应所致。

研究人员通过对260万人（包括120295名痛风患者）进行的全基因组关联研究（GWAS），提供了对痛风炎症成分分子机制的深入了解。研究人员检测到了377个基因座和410个遗传独立信号（149个尿酸和痛风中未报告的基因座）。

研究人员还发现了额外65个在尿酸中具有信号（来自630,117个个体的GWAS），痛风中没有信号的基因座。优先排序方案确定了痛风炎症过程中候选基因，包括与表观遗传重塑、细胞渗透压及NOD样受体蛋白3（NLRP3）炎症小体活性调节相关的基因。孟德尔随机化分析提供了，不确定潜能克隆性造血在痛风中具有因果作用的证据。

该研究识别了痛风炎症发病机制中适合后续研究的候选基因和分子过程。

附：英文原文

Title: A genome-wide association analysis reveals new pathogenic pathways in gout*

Author: Major, Tanya J., Takei, Riku, Matsuo, Hirotaka, Leask, Megan P., Sumpter, Nicholas A., Topless, Ruth K., Shirai, Yuya, Wang, Wei, Cadzow, Murray J., Phipps-Green, Amanda J., Li, Zhiqiang, Ji, Aichang, Merriman, Marilyn E., Morice, Emily, Kelley, Eric E., Wei, Wen-Hua, McCormick, Sally P. A., Bixley, Matthew J., Reynolds, Richard J., Saag, Kenneth G., Fadason, Tayaza, Golovina, Evgenia, OSullivan, Justin M., Stamp, Lisa K., Dalbeth, Nicola, Abhishek, Abhishek, Doherty, Michael, Roddy, Edward, Jacobsson, Lennart T. H., Kapetanovic, Meliha C., Melander, Olle, Andrs, Mariano, Prez-Ruiz, Fernando, Torres, Rosa J., Radstake, Timothy, Jansen, Timothy L., Janssen, Matthijs, Joosten, Leo A. B., Liu, Ruiqi, Gaal, Orsolya I., Crian, Tania O., Rednic, Simona, Kurreeman, Fina, Huizinga, Tom W. J., Toes, Ren, Liot, Frdric, Richette, Pascal, Bardin, Thomas, Ea, Hang Korng, Pascart, Tristan, McCarthy, Geraldine M., Helbert, Laura, Stibrkov, Blanka, Tausche, Anne-K., Uhlig, Till, Vitart, Vronique, Boutin, Thibaud S., Hayward, Caroline, Riches, Philip L., Ralston, Stuart H., Campbell, Archie, MacDonald, Thomas M., Nakayama, Akiyoshi, Takada, Tappei, Nakatochi, Masahiro, Shimizu, Seiko, Kawamura, Yusuke, Toyoda, Yu

Issue&Volume: 2024-10-15

Abstract: 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.

DOI: 10.1038/s41588-024-01921-5

Source: https://www.nature.com/articles/s41588-024-01921-5