title: Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response.
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.
authors: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
authors: C C
authors: CC
authors: Wen
authors: S W
authors: SW
authors: Yee
authors: X
authors: X
authors: Liang
authors: T J
authors: TJ
authors: Hoffmann
authors: M N
authors: MN
authors: Kvale
authors: Y
authors: Y
authors: Banda
authors: E
authors: E
authors: Jorgenson
authors: C
authors: C
authors: Schaefer
authors: N
authors: N
authors: Risch
authors: K M
authors: KM
authors: Giacomini
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D000493:Allopurinol / Q000378:metabolism / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002140:California / Q000453:epidemiology; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005838:Genotype; D006074:Gout Suppressants / Q000378:metabolism / Q000627:therapeutic use*; D057809:HEK293 Cells; D006801:Humans; D033461:Hyperuricemia / Q000097:blood / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000378:metabolism / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D014162:Transfection; D016896:Treatment Outcome; D014527:Uric Acid / Q000097:blood
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D015415:Biomarkers; D006074:Gout Suppressants; D009363:Neoplasm Proteins; D014527:Uric Acid; D000493:Allopurinol; D008942:Mitoxantrone