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

Details

Serval ID
serval:BIB_8527944B3CFF
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.
Journal
Nature genetics
Author(s)
Tin A., Marten J., Halperin Kuhns V.L., Li Y., Wuttke M., Kirsten H., Sieber K.B., Qiu C., Gorski M., Yu Z., Giri A., Sveinbjornsson G., Li M., Chu A.Y., Hoppmann A., O'Connor L.J., Prins B., Nutile T., Noce D., Akiyama M., Cocca M., Ghasemi S., van der Most P.J., Horn K., Xu Y., Fuchsberger C., Sedaghat S., Afaq S., Amin N., Ärnlöv J., Bakker SJL, Bansal N., Baptista D., Bergmann S., Biggs M.L., Biino G., Boerwinkle E., Bottinger E.P., Boutin T.S., Brumat M., Burkhardt R., Campana E., Campbell A., Campbell H., Carroll R.J., Catamo E., Chambers J.C., Ciullo M., Concas M.P., Coresh J., Corre T., Cusi D., Felicita S.C., de Borst M.H., De Grandi A., de Mutsert R., de Vries APJ, Delgado G., Demirkan A., Devuyst O., Dittrich K., Eckardt K.U., Ehret G., Endlich K., Evans M.K., Gansevoort R.T., Gasparini P., Giedraitis V., Gieger C., Girotto G., Gögele M., Gordon S.D., Gudbjartsson D.F., Gudnason V., Haller T., Hamet P., Harris T.B., Hayward C., Hicks A.A., Hofer E., Holm H., Huang W., Hutri-Kähönen N., Hwang S.J., Ikram M.A., Lewis R.M., Ingelsson E., Jakobsdottir J., Jonsdottir I., Jonsson H., Joshi P.K., Josyula N.S., Jung B., Kähönen M., Kamatani Y., Kanai M., Kerr S.M., Kiess W., Kleber M.E., Koenig W., Kooner J.S., Körner A., Kovacs P., Krämer B.K., Kronenberg F., Kubo M., Kühnel B., La Bianca M., Lange L.A., Lehne B., Lehtimäki T., Liu J., Loeffler M., Loos RJF, Lyytikäinen L.P., Magi R., Mahajan A., Martin N.G., März W., Mascalzoni D., Matsuda K., Meisinger C., Meitinger T., Metspalu A., Milaneschi Y., O'Donnell C.J., Wilson O.D., Gaziano J.M., Mishra P.P., Mohlke K.L., Mononen N., Montgomery G.W., Mook-Kanamori D.O., Müller-Nurasyid M., Nadkarni G.N., Nalls M.A., Nauck M., Nikus K., Ning B., Nolte I.M., Noordam R., O'Connell J.R., Olafsson I., Padmanabhan S., Penninx BWJH, Perls T., Peters A., Pirastu M., Pirastu N., Pistis G., Polasek O., Ponte B., Porteous D.J., Poulain T., Preuss M.H., Rabelink T.J., Raffield L.M., Raitakari O.T., Rettig R., Rheinberger M., Rice K.M., Rizzi F., Robino A., Rudan I., Krajcoviechova A., Cifkova R., Rueedi R., Ruggiero D., Ryan K.A., Saba Y., Salvi E., Schmidt H., Schmidt R., Shaffer C.M., Smith A.V., Smith B.H., Spracklen C.N., Strauch K., Stumvoll M., Sulem P., Tajuddin S.M., Teren A., Thiery J., Thio CHL, Thorsteinsdottir U., Toniolo D., Tönjes A., Tremblay J., Uitterlinden A.G., Vaccargiu S., van der Harst P., van Duijn C.M., Verweij N., Völker U., Vollenweider P., Waeber G., Waldenberger M., Whitfield J.B., Wild S.H., Wilson J.F., Yang Q., Zhang W., Zonderman A.B., Bochud M., Wilson J.G., Pendergrass S.A., Ho K., Parsa A., Pramstaller P.P., Psaty B.M., Böger C.A., Snieder H., Butterworth A.S., Okada Y., Edwards T.L., Stefansson K., Susztak K., Scholz M., Heid I.M., Hung A.M., Teumer A., Pattaro C., Woodward O.M., Vitart V., Köttgen A.
Working group(s)
German Chronic Kidney Disease Study, Lifelines Cohort Study, V. A. Million Veteran Program
ISSN
1546-1718 (Electronic)
ISSN-L
1061-4036
Publication state
Published
Issued date
10/2019
Peer-reviewed
Oui
Volume
51
Number
10
Pages
1459-1474
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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.
Keywords
ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics, Cardiovascular Diseases/blood, Cardiovascular Diseases/epidemiology, Cardiovascular Diseases/genetics, Cohort Studies, Genetic Loci, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Gout/blood, Gout/epidemiology, Gout/genetics, Hepatocyte Nuclear Factor 1-alpha/genetics, Hepatocyte Nuclear Factor 4/genetics, Humans, Kidney/metabolism, Kidney/pathology, Liver/metabolism, Liver/pathology, Metabolic Diseases/blood, Metabolic Diseases/epidemiology, Metabolic Diseases/genetics, Neoplasm Proteins/genetics, Organ Specificity, Polymorphism, Single Nucleotide, Signal Transduction, Uric Acid/blood
Pubmed
Web of science
Create date
07/10/2020 14:32
Last modification date
08/10/2020 5:27
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