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Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response.
Clin Pharmacol Ther. 2015 May; 97(5):518-25.CP

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+Show Affiliations

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25676789

Citation

Wen, C C., et al. "Genome-wide Association Study Identifies ABCG2 (BCRP) as an Allopurinol Transporter and a Determinant of Drug Response." Clinical Pharmacology and Therapeutics, vol. 97, no. 5, 2015, pp. 518-25.
Wen CC, Yee SW, Liang X, et al. Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response. Clin Pharmacol Ther. 2015;97(5):518-25.
Wen, C. C., Yee, S. W., Liang, X., Hoffmann, T. J., Kvale, M. N., Banda, Y., Jorgenson, E., Schaefer, C., Risch, N., & Giacomini, K. M. (2015). Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response. Clinical Pharmacology and Therapeutics, 97(5), 518-25. https://doi.org/10.1002/cpt.89
Wen CC, et al. Genome-wide Association Study Identifies ABCG2 (BCRP) as an Allopurinol Transporter and a Determinant of Drug Response. Clin Pharmacol Ther. 2015;97(5):518-25. PubMed PMID: 25676789.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response. AU - Wen,C C, AU - Yee,S W, AU - Liang,X, AU - Hoffmann,T J, AU - Kvale,M N, AU - Banda,Y, AU - Jorgenson,E, AU - Schaefer,C, AU - Risch,N, AU - Giacomini,K M, Y1 - 2015/04/06/ PY - 2014/10/03/received PY - 2015/02/03/accepted PY - 2015/2/14/entrez PY - 2015/2/14/pubmed PY - 2015/6/26/medline SP - 518 EP - 25 JF - Clinical pharmacology and therapeutics JO - Clin Pharmacol Ther VL - 97 IS - 5 N2 - 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. SN - 1532-6535 UR - https://www.unboundmedicine.com/medline/citation/25676789/Genome_wide_association_study_identifies_ABCG2__BCRP__as_an_allopurinol_transporter_and_a_determinant_of_drug_response_ L2 - https://doi.org/10.1002/cpt.89 DB - PRIME DP - Unbound Medicine ER -