A genome-wide association analysis of 2,622,830 individuals reveals new pathogenic pathways in gout.-猫眼课题宝

DOI：

10.1101/2022.11.26.22281768

发表时间：

2022-11

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Tanya J. Major;R. Takei;H. Matsuo;M. Leask;K. Ruth;Topless;Y. Shirai;Zhiqiang Li;A. Ji;M. Cadzow;A. Nicholas;Sumpter;M. Merriman;A. Phipps-Green;Mariana Urquiaga;E. Eric;Kelley;Rachel D. King;S. Lewis;Brooke A. Maxwell;Wen-Hua Wei;Sally;P. McCormick;R. Reynolds;K. Saag;M. Bixley;Tayaza;Fadason;J. O’Sullivan;L. Stamp;N. Dalbeth;Abhishek;M. Doherty;E. Roddy;L. Jacobsson;Meliha;C. Kapetanovic;O. Melander;M. Andrés;F. Pérez-Ruiz;Rosa;J. Torres;T. Radstake;T. Jansen;M. Janssen;B. LeoA.;Joosten;Ruiqi Liu;O. Gaal;S. Rednic;Fina;Kurreeman;T. Huizinga;R. Toes;F. Lioté;P. Richette;T. Bardin;Hang‐Korng Ea;T. Pascart;G. McCarthy;Laura;Helbert;Blanka Stib;rková;A. Tausche;T. Uhlig;V. Vitart;Thibaud S. Boutin;C. Hayward;P. Riches;S. Ralston;Archie;Campbell;A. Nakayama;Tappei Takada;M. Nakatochi;Seiko Shimizu;Y. Kawamura;Yu;Toyoda;Hirofumi;Nakaoka;Ken;Yamamoto;Keitaro;Matsuo;Nariyoshi;Shinomiya;K. Ichida;Chaeyoung Lee;L. Bradbury;Matthew A. Brown;P. Robinson;C. RussellR.;Buchanan;Catherine L. Hill;S. Lester;M. Smith;Maureen;Rischmueller;Hyon K. Choi;E. Stahl;J. Miner;D. Solomon;Jing;Cui;K. Giacomini;Deanna Brackman;E. Jorgenson;Wen Wang;S. Shringarpure;A. So;Yukinori;Okada;Changgui Li;Yongyong Shi;T. Merriman

痛风是高尿酸血症背景下的尿酸盐晶体沉积的慢性疾病，通常表现为急性炎性关节炎的复发性发作，其由于对沉积晶体的先天免疫反应而发生。从高尿酸血症发展到临床痛风的分子机制知之甚少。在这里，我们从一项对260万人的遗传研究中了解了这一进展，其中包括120，282名痛风患者。我们检测到376个位点和410个遗传独立的信号（148个新的位点在尿酸盐和痛风）。我们确定了1,768个候选基因，随后的通路分析揭示了尿酸盐代谢、2型糖尿病、染色质修饰和结构是痛风的主要通路。位于显著GWAS位点内或与显著GWAS位点统计学上相关的基因因其控制从高尿酸血症到痛风的进展的潜力而被优先考虑。这确定了参与表观遗传重塑、细胞渗透压和NLRP 3-炎性体活性调节的强候选免疫基因。在XDH的遗传关联信号，编码尿酸产生酶黄嘌呤氧化还原酶（XOR），共定位与XDH表达的遗传控制，但仅在前列腺。我们证明了小鼠前列腺中的XOR活性和尿酸盐产生，并使用单细胞RNA序列数据提出了前列腺尿酸盐再摄取、合成和分泌的模型。痛风相关基因座在不确定潜能的克隆造血（CHIP）中表现过度，孟德尔随机化分析为CHIP在痛风中的因果作用提供了证据。与表观基因组调节剂的含义一致，这为表观基因组重塑作为痛风的病因提供了支持。我们为痛风的分子发病机制提供了新的见解，并确定了一系列在痛风炎症过程中发挥作用的候选基因。

Gout is a chronic disease of monosodium urate crystal deposition in the setting of hyperuricemia that typically presents with recurrent flares of acute inflammatory arthritis that occur due to innate immune response to deposited crystals. The molecular mechanism of the progression from hyperuricemia to clinical gout is poorly understood. Here we provide insights into this progression from a genetic study of 2.6 million people, including 120,282 people with gout. We detected 376 loci and 410 genetically independent signals (148 new loci in urate and gout). We identified 1,768 candidate genes with subsequent pathway analysis revealing urate metabolism, type 2 diabetes, and chromatin modification and structure as top pathways in gout. Genes located within or statistically linked to significant GWAS loci were prioitized for their potential to control the progression from hyperuricemia to gout. This identified strong candidate immune genes involved in epigenetic remodelling, cell osmolarity, and regulation of NLRP3-inflammasome activity. The genetic association signal at XDH, encoding the urate-producing enzyme xanthine oxidoreductase (XOR), co-localizes with genetic control of XDH expression, but only in the prostate. We demonstrate XOR activity and urate production in the mouse prostate, and use single-cell RNA sequence data to propose a model of urate reuptake, synthesis, and secretion by the prostate. The gout-associated loci were over-represented for genes implicated in clonal hematopoeiesis of indeterminate potential (CHIP) and Mendelian randomization analysis provided evidence for a causal role of CHIP in gout. In concert with implication of epigenomic regulators, this provides support for epigenomic remodelling as causal in gout. We provide new insights into the molecular pathogenesis of gout and identify an array of candidate genes for a role in the inflammatory process of gout.

A genome-wide association analysis of 2,622,830 individuals reveals new pathogenic pathways in gout.

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