Genome‐wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response. Issue 5 (6th April 2015)

• Record Type: Journal Article
• Authors: Wen, CC; Yee, SW; Liang, X; Hoffmann, TJ; Kvale, MN; Banda, Y; Jorgenson, E; Schaefer, C; Risch, N; Giacomini, KM
• Is Part Of: Clinical pharmacology & therapeutics. Volume 97:Issue 5(2015:May)
• Page Start: 518
• Page End: 525
• Publication Date: 2015-04-06
• Subjects: Pharmacology -- Periodicals; Therapeutics -- Periodicals; 615.5
• DOI: 10.1002/cpt.89
• Languages: English
• ISSNs: 0009-9236

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>The first‐line treatment of hyperuricemia, which causes gout, is allopurinol. The allopurinol response is highly variable, with many users failing to achieve target serum uric acid (SUA) levels. No genome‐wide association study (GWAS) has examined the genetic factors affecting allopurinol effectiveness. Using 2, 027 subjects in Kaiser Permanente's Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort, we conducted a GWAS of allopurinol‐related SUA reduction, first in the largest ethnic group, non‐Hispanic white (NHW) subjects, and then in a stratified transethnic meta‐analysis. <italic>ABCG2</italic>, encoding the efflux pump BCRP, was associated with SUA reduction in NHW subjects (<italic>P =</italic> 2 × 10⁻⁸), and a missense allele (rs2231142) was associated with a reduced response (<italic>P =</italic> 3 × 10⁻⁷) in the meta‐analysis. Isotopic uptake studies in cells demonstrated that BCRP transports allopurinol and genetic variants in <italic>ABCG2</italic> affect this transport. Collectively, this first GWAS of allopurinol response demonstrates that <italic>ABCG2</italic> is a key determinant of response to the drug.</p> </abstract>