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Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels
Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA;Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA.ORCID iD: 0000-0002-4207-5866
Univ Edinburgh, Inst Genet & Mol Med, MRC, Human Genet Unit, Edinburgh, Midlothian, Scotland.
Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA.
Univ Freiburg, Inst Genet Epidemiol, Dept Biometry Epidemiol & Med Bioinformat, Fac Med, Freiburg, Germany;Univ Freiburg, Med Ctr, Freiburg, Germany.
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 10, p. 1459-1474Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2019. Vol. 51, no 10, p. 1459-1474
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Medical Genetics
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URN: urn:nbn:se:uu:diva-396652DOI: 10.1038/s41588-019-0504-xISI: 000489016400010PubMedID: 31578528OAI: oai:DiVA.org:uu-396652DiVA, id: diva2:1370226
Available from: 2019-11-14 Created: 2019-11-14 Last updated: 2019-11-14Bibliographically approved

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Giedraitis, VilmantasIngelsson, Erik

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