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

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.

SUBMITTER: Tin A

PROVIDER: S-EPMC6858555 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Tin Adrienne A Marten Jonathan J Halperin Kuhns Victoria L VL Li Yong Y Wuttke Matthias M Kirsten Holger H Sieber Karsten B KB Qiu Chengxiang C Gorski Mathias M Yu Zhi Z Giri Ayush A Sveinbjornsson Gardar G Li Man M Chu Audrey Y AY Hoppmann Anselm A O'Connor Luke J LJ Prins Bram B Nutile Teresa T Noce Damia D Akiyama Masato M Cocca Massimiliano M Ghasemi Sahar S van der Most Peter J PJ Horn Katrin K Xu Yizhe Y Fuchsberger Christian C Sedaghat Sanaz S Afaq Saima S Amin Najaf N Ärnlöv Johan J Bakker Stephan J L SJL Bansal Nisha N Baptista Daniela D Bergmann Sven S Biggs Mary L ML Biino Ginevra G Boerwinkle Eric E Bottinger Erwin P EP Boutin Thibaud S TS Brumat Marco M Burkhardt Ralph R Campana Eric E Campbell Archie A Campbell Harry H Carroll Robert J RJ Catamo Eulalia E Chambers John C JC Ciullo Marina M Concas Maria Pina MP Coresh Josef J Corre Tanguy T Cusi Daniele D Felicita Sala Cinzia SC de Borst Martin H MH De Grandi Alessandro A de Mutsert Renée R de Vries Aiko P J APJ Delgado Graciela G Demirkan Ayşe A Devuyst Olivier O Dittrich Katalin K Eckardt Kai-Uwe KU Ehret Georg G Endlich Karlhans K Evans Michele K MK Gansevoort Ron T RT Gasparini Paolo P Giedraitis Vilmantas V Gieger Christian C Girotto Giorgia G Gögele Martin M Gordon Scott D SD Gudbjartsson Daniel F DF Gudnason Vilmundur V Haller Toomas T Hamet Pavel P Harris Tamara B TB Hayward Caroline C Hicks Andrew A AA Hofer Edith E Holm Hilma H Huang Wei W Hutri-Kähönen Nina N Hwang Shih-Jen SJ Ikram M Arfan MA Lewis Raychel M RM Ingelsson Erik E Jakobsdottir Johanna J Jonsdottir Ingileif I Jonsson Helgi H Joshi Peter K PK Josyula Navya Shilpa NS Jung Bettina B Kähönen Mika M Kamatani Yoichiro Y Kanai Masahiro M Kerr Shona M SM Kiess Wieland W Kleber Marcus E ME Koenig Wolfgang W Kooner Jaspal S JS Körner Antje A Kovacs Peter P Krämer Bernhard K BK Kronenberg Florian F Kubo Michiaki M Kühnel Brigitte B La Bianca Martina M Lange Leslie A LA Lehne Benjamin B Lehtimäki Terho T Liu Jun J Loeffler Markus M Loos Ruth J F RJF Lyytikäinen Leo-Pekka LP Magi Reedik R Mahajan Anubha A Martin Nicholas G NG März Winfried W Mascalzoni Deborah D Matsuda Koichi K Meisinger Christa C Meitinger Thomas T Metspalu Andres A Milaneschi Yuri Y O'Donnell Christopher J CJ Wilson Otis D OD Gaziano J Michael JM Mishra Pashupati P PP Mohlke Karen L KL Mononen Nina N Montgomery Grant W GW Mook-Kanamori Dennis O DO Müller-Nurasyid Martina M Nadkarni Girish N GN Nalls Mike A MA Nauck Matthias M Nikus Kjell K Ning Boting B Nolte Ilja M IM Noordam Raymond R O'Connell Jeffrey R JR Olafsson Isleifur I Padmanabhan Sandosh S Penninx Brenda W J H BWJH Perls Thomas T Peters Annette A Pirastu Mario M Pirastu Nicola N Pistis Giorgio G Polasek Ozren O Ponte Belen B Porteous David J DJ Poulain Tanja T Preuss Michael H MH Rabelink Ton J TJ Raffield Laura M LM Raitakari Olli T OT Rettig Rainer R Rheinberger Myriam M Rice Kenneth M KM Rizzi Federica F Robino Antonietta A Rudan Igor I Krajcoviechova Alena A Cifkova Renata R Rueedi Rico R Ruggiero Daniela D Ryan Kathleen A KA Saba Yasaman Y Salvi Erika E Schmidt Helena H Schmidt Reinhold R Shaffer Christian M CM Smith Albert V AV Smith Blair H BH Spracklen Cassandra N CN Strauch Konstantin K Stumvoll Michael M Sulem Patrick P Tajuddin Salman M SM Teren Andrej A Thiery Joachim J Thio Chris H L CHL Thorsteinsdottir Unnur U Toniolo Daniela D Tönjes Anke A Tremblay Johanne J Uitterlinden André G AG Vaccargiu Simona S van der Harst Pim P van Duijn Cornelia M CM Verweij Niek N Völker Uwe U Vollenweider Peter P Waeber Gerard G Waldenberger Melanie M Whitfield John B JB Wild Sarah H SH Wilson James F JF Yang Qiong Q Zhang Weihua W Zonderman Alan B AB Bochud Murielle M Wilson James G JG Pendergrass Sarah A SA Ho Kevin K Parsa Afshin A Pramstaller Peter P PP Psaty Bruce M BM Böger Carsten A CA Snieder Harold H Butterworth Adam S AS Okada Yukinori Y Edwards Todd L TL Stefansson Kari K Susztak Katalin K Scholz Markus M Heid Iris M IM Hung Adriana M AM Teumer Alexander A Pattaro Cristian C Woodward Owen M OM Vitart Veronique V Köttgen Anna A

Nature genetics 20191002 10

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 p ...[more]

PMID: 31578528

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Project description:BackgroundPrevious studies have noted significant variation in serum urate (sUA) levels, and it is unknown how this influences the accuracy of hyperuricemia classification based on single data points. Despite this known variability, hyperuricemic patients are often used as a control group in gout studies. Our objective was to determine the accuracy of hyperuricemia classifications based on single data points versus multiple data points given the degree of variability observed with serial measurements of sUA.MethodsData was analyzed from a cross-over clinical trial of urate-lowering therapy in young adults without a gout diagnosis. In the control phase, sUA levels used for this analysis were collected at 2-4 week intervals. Mean coefficient of variation for sUA was determined, as were rates of conversion between normouricemia (sUA ≤6.8 mg/dL) and hyperuricemia (sUA > 6.8 mg/dL).ResultsMean study participant (n = 85) age was 27.8 ± 7.0 years, with 39% female participants and 41% African-American participants. Mean sUA coefficient of variation was 8.5% ± 4.9% (1 to 23%). There was no significant difference in variation between men and women, or between participants initially normouricemic and those who were initially hyperuricemic. Among those initially normouricemic (n = 72), 21% converted to hyperuricemia during at least one subsequent measurement. The subgroup with initial sUA < 6.0 (n = 54) was much less likely to have future values in the range of hyperuricemia compared to the group with screening sUA values between 6.0-6.8 (n = 18) (7% vs 39%, p = 0.0037). Of the participants initially hyperuricemic (n = 13), 46% were later normouricemic during at least one measurement.ConclusionSingle sUA measurements were unreliable in hyperuricemia classification due to spontaneous variation. Knowing this, if a single measurement must be used in classification, it is worth noting that those with an sUA of < 6.0 mg/dL were less likely to demonstrate future hyperuricemic measurements and this could be considered a safer threshold to rule out intermittent hyperuricemia based on a single measurement point.Trial registrationData from parent study ClinicalTrials.gov Identifier: NCT02038179 .

Dataset Information

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

Publications

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

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