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Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response.

Clinical pharmacology and therapeutics (2015-02-14)
C C Wen, S W Yee, X Liang, T J Hoffmann, M N Kvale, Y Banda, E Jorgenson, C Schaefer, N Risch, K M Giacomini
ABSTRACT

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. ABCG2, encoding the efflux pump BCRP, was associated with SUA reduction in NHW subjects (P = 2 × 10(-8) ), and a missense allele (rs2231142) was associated with a reduced response (P = 3 × 10(-7) ) in the meta-analysis. Isotopic uptake studies in cells demonstrated that BCRP transports allopurinol and genetic variants in ABCG2 affect this transport. Collectively, this first GWAS of allopurinol response demonstrates that ABCG2 is a key determinant of response to the drug.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Allopurinol, xanthine oxidase inhibitor
Supelco
Allopurinol, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Oxypurinol, ≥98% (HPLC)
Allopurinol, European Pharmacopoeia (EP) Reference Standard
USP
Allopurinol, United States Pharmacopeia (USP) Reference Standard
Supelco
Oxypurinol, analytical standard