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Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.
Wednesday,2019-12-04 16:01 America/Los_Angeles — ecterry
| Title | Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels. |
| Publication Type | Journal Article |
| Year of Publication | 2019 |
| Authors | Tin, A, Marten, J, Kuhns, VLHalperin, Li, Y, Wuttke, M, Kirsten, H, Sieber, KB, Qiu, C, Gorski, M, Yu, Z, Giri, A, Sveinbjornsson, G, Li, M, Chu, AY, Hoppmann, A, O'Connor, LJ, Prins, B, Nutile, T, Noce, D, Akiyama, M, Cocca, M, Ghasemi, S, van der Most, PJ, Horn, K, Xu, Y, Fuchsberger, C, Sedaghat, S, Afaq, S, Amin, N, Arnlöv, J, Bakker, SJL, Bansal, N, Baptista, D, Bergmann, S, Biggs, ML, Biino, G, Boerwinkle, E, Bottinger, EP, Boutin, TS, Brumat, M, Burkhardt, R, Campana, E, Campbell, A, Campbell, H, Carroll, RJ, Catamo, E, Chambers, JC, Ciullo, M, Concas, MPina, Coresh, J, Corre, T, Cusi, D, Felicita, SCinzia, de Borst, MH, 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, MK, Gansevoort, RT, Gasparini, P, Giedraitis, V, Gieger, C, Girotto, G, Gögele, M, Gordon, SD, Gudbjartsson, DF, Gudnason, V, Haller, T, Hamet, P, Harris, TB, Hayward, C, Hicks, AA, Hofer, E, Holm, H, Huang, W, Hutri-Kähönen, N, Hwang, S-J, Ikram, AM, Lewis, RM, Ingelsson, E, Jakobsdottir, J, Jonsdottir, I, Jonsson, H, Joshi, PK, Josyula, NShilpa, Jung, B, Kähönen, M, Kamatani, Y, Kanai, M, Kerr, SM, Kiess, W, Kleber, ME, Koenig, W, Kooner, JS, Körner, A, Kovacs, P, Krämer, BK, Kronenberg, F, Kubo, M, Kuhnel, B, La Bianca, M, Lange, LA, Lehne, B, Lehtimäki, T, Liu, J, Loeffler, M, Loos, RJF, Lyytikäinen, L-P, Mägi, R, Mahajan, A, Martin, NG, März, W, Mascalzoni, D, Matsuda, K, Meisinger, C, Meitinger, T, Metspalu, A, Milaneschi, Y, O'Donnell, CJ, Wilson, OD, J Gaziano, M, Mishra, PP, Mohlke, KL, Mononen, N, Montgomery, GW, Mook-Kanamori, DO, Müller-Nurasyid, M, Nadkarni, GN, Nalls, MA, Nauck, M, Nikus, K, Ning, B, Nolte, IM, Noordam, R, O'Connell, JR, Olafsson, I, Padmanabhan, S, Penninx, BWJH, Perls, T, Peters, A, Pirastu, M, Pirastu, N, Pistis, G, Polasek, O, Ponte, B, Porteous, DJ, Poulain, T, Preuss, MH, Rabelink, TJ, Raffield, LM, Raitakari, OT, Rettig, R, Rheinberger, M, Rice, KM, Rizzi, F, Robino, A, Rudan, I, Krajcoviechova, A, Cifkova, R, Rueedi, R, Ruggiero, D, Ryan, KA, Saba, Y, Salvi, E, Schmidt, H, Schmidt, R, Shaffer, CM, Smith, AV, Smith, BH, Spracklen, CN, Strauch, K, Stumvoll, M, Sulem, P, Tajuddin, SM, Teren, A, Thiery, J, Thio, CHL, Thorsteinsdottir, U, Toniolo, D, Tönjes, A, Tremblay, J, Uitterlinden, AG, Vaccargiu, S, van der Harst, P, van Duijn, CM, Verweij, N, Völker, U, Vollenweider, P, Waeber, G, Waldenberger, M, Whitfield, JB, Wild, SH, Wilson, JF, Yang, Q, Zhang, W, Zonderman, AB, Bochud, M, Wilson, JG, Pendergrass, SA, Ho, K, Parsa, A, Pramstaller, PP, Psaty, BM, Böger, CA, Snieder, H, Butterworth, AS, Okada, Y, Edwards, TL, Stefansson, K, Susztak, K, Scholz, M, Heid, IM, Hung, AM, Teumer, A, Pattaro, C, Woodward, OM, Vitart, V, Köttgen, A |
| Corporate/Institutional Authors | German Chronic Kidney Disease Study, LifeLines Cohort Study,, V. A. Million Veteran Program |
| Journal | Nat Genet |
| Volume | 51 |
| Issue | 10 |
| Pagination | 1459-1474 |
| Date Published | 2019 Oct |
| ISSN | 1546-1718 |
| Abstract | <p>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.</p> |
| DOI | 10.1038/s41588-019-0504-x |
| Alternate Journal | Nat. Genet. |
| PubMed ID | 31578528 |
| PubMed Central ID | PMC6858555 |
| Grant List | R01AR073178-01A1 / / U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) / Postdoctoral Fellowship (17POST3650016) / / American Heart Association (American Heart Association, Inc.) / P30 DK090868 / DK / NIDDK NIH HHS / United States R01 DK114091 / DK / NIDDK NIH HHS / United States KO 3598/4-1 / / Deutsche Forschungsgemeinschaft (German Research Foundation) / R01 AR073178 / AR / NIAMS NIH HHS / United States U54GM115428 / / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) / 016.186.125 / / Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research) / CRC 1140, project number 246781735 / / Deutsche Forschungsgemeinschaft (German Research Foundation) / |
ePub date:
19/10