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.

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels

Noce D.;Horn K.;Brumat M.;Campana E.;Catamo E.;Ciullo M.;Concas M. P.;Gasparini P.;Girotto G.;La Bianca M.;Liu J.;Magi R.;Martin N. G.;Pirastu N.;Pistis G.;Robino A.;Ruggiero D.;Salvi E.;Schmidt H.;Teren A.;
2019

Abstract

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.
Pubblicato
https://www.nature.com/articles/s41588-019-0504-x#Sec1
File in questo prodotto:
File Dimensione Formato  
41467_2019_Article_12283.pdf

accesso aperto

Descrizione: Supplementary information is available for this paper at https://doi.org/10.1038/s41467-019-12283-6
Tipologia: Documento in Versione Editoriale
Licenza: Creative commons
Dimensione 5.39 MB
Formato Adobe PDF
5.39 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11368/2958750
Citazioni
  • ???jsp.display-item.citation.pmc??? 89
  • Scopus 135
  • ???jsp.display-item.citation.isi??? 136
social impact