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

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    Author
    Tin, A.
    Li, Y.
    Brody, J.A.
    Date
    2018
    Journal
    Nature Communications
    Publisher
    Nature Publishing Group
    Type
    Article
    
    Metadata
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    See at
    https://dx.doi.org/10.1038/s41467-018-06620-4
    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 × 10−56) 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).
    Keyword
    Uric Acid
    Gout
    renal urate
    xome
    Genetic Predisposition to Disease
    Kidney Function Tests
    Identifier to cite or link to this item
    https://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
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41467-018-06620-4
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