Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels
Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels
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DOI：
10.1038/s41588-019-0504-x
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发表时间：
2019-10-01
期刊：
影响因子：
30.8
通讯作者：
Koettgen, Anna
中科院分区：
文献类型：
--
作者：
Tin, Adrienne;Marten, Jonathan;Koettgen, Anna
血清尿酸水平升高引起痛风，并通过尚不清楚的机制与心脏代谢疾病相关。我们对457,690名个体进行了血清尿酸的跨祖先全基因组关联研究，在334,880名个体的独立队列中确定了183个位点（147个以前未知），这些位点可以改善痛风的预测。血清尿酸与许多心脏代谢特征具有显著的遗传相关性，遗传因果分析支持多效性的重要作用。富集分析、尿酸盐相关位点的精细定位以及47个组织中基因表达的共定位表明，肾脏和肝脏是主要靶器官，并优先考虑潜在的致病基因和变异，包括肝脏和肾脏中的转录主调控因子HNF1A和HNF4A。实验验证表明，HNF4A反激活了肾细胞中编码主要尿酸转运体ABCG2的启动子，并且HNF4A p.s thr139ile是一个功能性变体。器官内部和跨器官的转录协同调节可能是在尿酸和心脏代谢性状之间观察到的多效性的一般机制。
Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.