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    ABCG2 polymorphisms in gout: Insights into disease susceptibility and treatment approaches

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    Author
    Cleophas, M.C.
    Joosten, L.A.
    Stamp, L.K.
    Date
    2017
    Journal
    Pharmacogenomics and Personalized Medicine
    Publisher
    Dove Medical Press Ltd
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://www.doi.org/10.2147/PGPM.S105854
    Abstract
    As a result of the association of a common polymorphism (rs2231142, Q141K) in the ATP-binding cassette G2 (ABCG2) transporter with serum urate concentration in a genome-wide association study, it was revealed that ABCG2 is an important uric acid transporter. This review discusses the relevance of ABCG2 polymorphisms in gout, possible etiological mechanisms, and treatment approaches. The 141K ABCG2 urate-increasing variant causes instability in the nucleotide-binding domain, leading to decreased surface expression and function. Trafficking of the protein to the cell membrane is altered, and instead, there is an increased ubiquitin-mediated proteasomal degradation of the variant protein as well as sequestration into aggresomes. In humans, this leads to decreased uric acid excretion through both the kidney and the gut with the potential for a subsequent compensatory increase in renal urinary excretion. Not only does the 141K polymorphism in ABCG2 lead to hyperuricemia through renal overload and renal underexcretion, but emerging evidence indicates that it also increases the risk of acute gout in the presence of hyperuricemia, early onset of gout, tophi formation, and a poor response to allopurinol. In addition, there is some evidence that ABCG2 dysfunction may promote renal dysfunction in chronic kidney disease patients, increase systemic inflammatory responses, and decrease cellular autophagic responses to stress. These results suggest multiple benefits in restoring ABCG2 function. It has been shown that decreased ABCG2 141K surface expression and function can be restored with colchicine and other small molecule correctors. However, caution should be exercised in any application of these approaches given the role of surface ABCG2 in drug resistance. Copyright 2017 Cleophas et al.
    Sponsors
    MC is supported by a grant of the Dutch Arthritis Foundation (nr. 12-02-303). LJ is supported by a Competitiveness Operational Programme grant of the Romanian Ministry of European Funds (P_37_762). TRM is supported by the Health Research Council of New Zealand.
    Keyword
    ABCG2
    Allopurinol
    BCRP
    Gout
    Polymorphism
    Urate
    Uric acid
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85020016823&doi=10.2147%2fPGPM.S105854&partnerID=40&md5=0a2d96f1848a370e7c5c364001a090aa; http://hdl.handle.net/10713/9884
    ae974a485f413a2113503eed53cd6c53
    10.2147/PGPM.S105854
    Scopus Count
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    UMB Open Access Articles 2017

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