Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels
PublisherNature Publishing Group
MetadataShow full item record
AbstractElevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10−56) and SLC2A9 (p = 4.5 × 10−7). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10−3). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout. Copyright 2018, The Author(s).
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85054895100&doi=10.1038%2fs41467-018-06620-4&partnerID=40&md5=0306d8305dc551ed2e7a3715c2c3c337; http://hdl.handle.net/10713/9773
- Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele.
- Authors: Tin A, Woodward OM, Kao WH, Liu CT, Lu X, Nalls MA, Shriner D, Semmo M, Akylbekova EL, Wyatt SB, Hwang SJ, Yang Q, Zonderman AB, Adeyemo AA, Palmer C, Meng Y, Reilly M, Shlipak MG, Siscovick D, Evans MK, Rotimi CN, Flessner MF, Köttgen M, Cupples LA, Fox CS, Köttgen A, CARe and CHARGE Consortia.
- Issue date: 2011 Oct 15
- Contribution of Rare Variants of the <i>SLC22A12</i> Gene to the Missing Heritability of Serum Urate Levels.
- Authors: Misawa K, Hasegawa T, Mishima E, Jutabha P, Ouchi M, Kojima K, Kawai Y, Matsuo M, Anzai N, Nagasaki M
- Issue date: 2020 Apr
- Complex analysis of urate transporters SLC2A9, SLC22A12 and functional characterization of non-synonymous allelic variants of GLUT9 in the Czech population: no evidence of effect on hyperuricemia and gout.
- Authors: Hurba O, Mancikova A, Krylov V, Pavlikova M, Pavelka K, Stibůrková B
- Issue date: 2014
- Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans.
- Authors: Anzai N, Ichida K, Jutabha P, Kimura T, Babu E, Jin CJ, Srivastava S, Kitamura K, Hisatome I, Endou H, Sakurai H
- Issue date: 2008 Oct 3
- SLC2A9 is a high-capacity urate transporter in humans.
- Authors: Caulfield MJ, Munroe PB, O'Neill D, Witkowska K, Charchar FJ, Doblado M, Evans S, Eyheramendy S, Onipinla A, Howard P, Shaw-Hawkins S, Dobson RJ, Wallace C, Newhouse SJ, Brown M, Connell JM, Dominiczak A, Farrall M, Lathrop GM, Samani NJ, Kumari M, Marmot M, Brunner E, Chambers J, Elliott P, Kooner J, Laan M, Org E, Veldre G, Viigimaa M, Cappuccio FP, Ji C, Iacone R, Strazzullo P, Moley KH, Cheeseman C
- Issue date: 2008 Oct 7