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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.

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Publisher Full Text
ncbi.nlm.nih.gov
doi.org
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Authors+Show Affiliations

Wen CC
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
Yee SW
No affiliation info available
Liang X
No affiliation info available
Hoffmann TJ
No affiliation info available
Kvale MN
No affiliation info available
Banda Y
No affiliation info available
Jorgenson E
No affiliation info available
Schaefer C
No affiliation info available
Risch N
No affiliation info available
Giacomini KM
No affiliation info available

MeSH

ATP Binding Cassette Transporter, Subfamily G, Member 2ATP-Binding Cassette TransportersAgedAllopurinolBiomarkersCaliforniaCell SurvivalDose-Response Relationship, DrugFemaleGene FrequencyGenome-Wide Association StudyGenotypeGout SuppressantsHEK293 CellsHumansHyperuricemiaMaleMiddle AgedMitoxantroneNeoplasm ProteinsPharmacogeneticsPhenotypePolymorphism, Single NucleotideTransfectionTreatment OutcomeUric Acid

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 -