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- Title
Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response.
- Authors
Wen, CC; Yee, SW; Liang, X; Hoffmann, TJ; Kvale, MN; Banda, Y; Jorgenson, E; Schaefer, C; Risch, N; Giacomini, KM
- 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.
- Subjects
HYPERURICEMIA; ALLOPURINOL; URIC acid; ARTHRITIS; GOUT; CARDIOVASCULAR diseases; GOUT suppressants; PATIENTS; THERAPEUTICS; DISEASE risk factors
- Publication
Clinical Pharmacology & Therapeutics, 2015, Vol 97, Issue 5, p518
- ISSN
0009-9236
- Publication type
Article
- DOI
10.1002/cpt.89