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Genome‐wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response
Author(s) -
Wen CC,
Yee SW,
Liang X,
Hoffmann TJ,
Kvale MN,
Banda Y,
Jorgenson E,
Schaefer C,
Risch N,
Giacomini KM
Publication year - 2015
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.89
Subject(s) - allopurinol , genome wide association study , gout , hyperuricemia , abcg2 , pharmacogenomics , pharmacogenetics , medicine , pharmacology , genetic association , genotype , uric acid , genetics , transporter , single nucleotide polymorphism , biology , atp binding cassette transporter , gene
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.