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

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

Nature genetics (2019-10-04)

Adrienne Tin, Jonathan Marten, Victoria L Halperin Kuhns, Yong Li, Matthias Wuttke, Holger Kirsten, Karsten B Sieber, Chengxiang Qiu, Mathias Gorski, Zhi Yu, Ayush Giri, Gardar Sveinbjornsson, Man Li, Audrey Y Chu, Anselm Hoppmann, Luke J O'Connor, Bram Prins, Teresa Nutile, Damia Noce, Masato Akiyama, Massimiliano Cocca, Sahar Ghasemi, Peter J van der Most, Katrin Horn, Yizhe Xu, Christian Fuchsberger, Sanaz Sedaghat, Saima Afaq, Najaf Amin, Johan Ärnlöv, Stephan J L Bakker, Nisha Bansal, Daniela Baptista, Sven Bergmann, Mary L Biggs, Ginevra Biino, Eric Boerwinkle, Erwin P Bottinger, Thibaud S Boutin, Marco Brumat, Ralph Burkhardt, Eric Campana, Archie Campbell, Harry Campbell, Robert J Carroll, Eulalia Catamo, John C Chambers, Marina Ciullo, Maria Pina Concas, Josef Coresh, Tanguy Corre, Daniele Cusi, Sala Cinzia Felicita, Martin H de Borst, Alessandro De Grandi, Renée de Mutsert, Aiko P J de Vries, Graciela Delgado, Ayşe Demirkan, Olivier Devuyst, Katalin Dittrich, Kai-Uwe Eckardt, Georg Ehret, Karlhans Endlich, Michele K Evans, Ron T Gansevoort, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Martin Gögele, Scott D Gordon, Daniel F Gudbjartsson, Vilmundur Gudnason, Toomas Haller, Pavel Hamet, Tamara B Harris, Caroline Hayward, Andrew A Hicks, Edith Hofer, Hilma Holm, Wei Huang, Nina Hutri-Kähönen, Shih-Jen Hwang, M Arfan Ikram, Raychel M Lewis, Erik Ingelsson, Johanna Jakobsdottir, Ingileif Jonsdottir, Helgi Jonsson, Peter K Joshi, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Yoichiro Kamatani, Masahiro Kanai, Shona M Kerr, Wieland Kiess, Marcus E Kleber, Wolfgang Koenig

PMID31578528

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.

MATERIALS

Product Number

Brand

Product Description

P1274

Sigma-Aldrich

Poly-L-lysine hydrobromide, mol wt 70,000-150,000 by viscosity