Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels.

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State: Public
Version: Final published version
Serval ID
serval:BIB_EC5F1BA0E000
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels.
Journal
Nature communications
Author(s)
Tin A., Li Y., Brody J.A., Nutile T., Chu A.Y., Huffman J.E., Yang Q., Chen M.H., Robinson-Cohen C., Macé A., Liu J., Demirkan A., Sorice R., Sedaghat S., Swen M., Yu B., Ghasemi S., Teumer A., Vollenweider P., Ciullo M., Li M., Uitterlinden A.G., Kraaij R., Amin N., van Rooij J., Kutalik Z., Dehghan A., McKnight B., van Duijn C.M., Morrison A., Psaty B.M., Boerwinkle E., Fox C.S., Woodward O.M., Köttgen A.
ISSN
2041-1723 (Electronic)
ISSN-L
2041-1723
Publication state
Published
Issued date
12/10/2018
Peer-reviewed
Oui
Volume
9
Number
1
Pages
4228
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
Elevated 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 <sup>-56</sup> ) and SLC2A9 (p = 4.5 × 10 <sup>-7</sup> ). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10 <sup>-3</sup> ). 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.
Keywords
Exome/genetics, Genetic Predisposition to Disease, Glucose Transport Proteins, Facilitative/chemistry, Glucose Transport Proteins, Facilitative/genetics, Glucose Transport Proteins, Facilitative/metabolism, Humans, Kidney Function Tests, Meta-Analysis as Topic, Organic Anion Transporters/chemistry, Organic Anion Transporters/genetics, Organic Anion Transporters/metabolism, Organic Cation Transport Proteins/chemistry, Organic Cation Transport Proteins/genetics, Organic Cation Transport Proteins/metabolism, Protein Structure, Secondary, Uric Acid/blood
Pubmed
Web of science
Open Access
Yes
Create date
25/10/2018 13:29
Last modification date
20/08/2019 17:14
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