Dan Roden
Faculty Member
Last active: 3/24/2020

Genome-Wide Association and Functional Studies Reveal Novel Pharmacological Mechanisms for Allopurinol.

Brackman DJ, Yee SW, Enogieru OJ, Shaffer C, Ranatunga D, Denny JC, Wei WQ, Kamatani Y, Kubo M, Roden DM, Jorgenson E, Giacomini KM
Clin Pharmacol Ther. 2019 106 (3): 623-631

PMID: 30924126 · PMCID: PMC6941886 · DOI:10.1002/cpt.1439

Allopurinol, which lowers uric acid (UA) concentration, is increasingly being recognized for its benefits in cardiovascular and renal disease. However, response to allopurinol is variable. We gathered samples from 4,446 multiethnic subjects for a genome-wide association study of allopurinol response. Consistent with previous studies, we observed that the Q141K variant in ABCG2 (rs2231142), which encodes the efflux pump breast cancer resistance protein (BCRP), associated with worse response to allopurinol. However, for the first time this association reached genome-wide level significance (P = 8.06 × 10 ). Additionally, we identified a novel association with a variant in GREM2 (rs1934341, P = 3.22 × 10 ). In vitro studies identified oxypurinol, the active metabolite of allopurinol, as an inhibitor of the UA transporter GLUT9, suggesting that oxypurinol may modulate UA reabsorption. These results provide strong evidence for a role of BCRP Q141K in allopurinol response, and suggest that allopurinol may have additional hypouricemic effects beyond xanthine oxidase inhibition.

© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.

MeSH Terms (16)

Aged Aged, 80 and over Allopurinol ATP Binding Cassette Transporter, Subfamily G, Member 2 Cytokines Ethnic Groups Female Genome-Wide Association Study Glucose Transport Proteins, Facilitative Humans Male Middle Aged Neoplasm Proteins Oxypurinol Prognosis Uric Acid

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