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

Deanna J. Brackman, Sook Wah Yee, Osatohanmwen J. Enogieru, Christian Shaffer, Dilrini Ranatunga, Joshua C. Denny, Wei Qi Wei, Yoichiro Kamatani, Michiaki Kubo, Dan M. Roden, Eric Jorgenson, Kathleen M. Giacomini

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4 Citations (Scopus)

Abstract

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 × 10−11). Additionally, we identified a novel association with a variant in GREM2 (rs1934341, P = 3.22 × 10−6). 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.

Original languageEnglish
Pages (from-to)623-631
Number of pages9
JournalClinical Pharmacology and Therapeutics
Volume106
Issue number3
DOIs
Publication statusPublished - 01-01-2019

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

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    Brackman, D. J., Yee, S. W., Enogieru, O. J., Shaffer, C., Ranatunga, D., Denny, J. C., Wei, W. Q., Kamatani, Y., Kubo, M., Roden, D. M., Jorgenson, E., & Giacomini, K. M. (2019). Genome-Wide Association and Functional Studies Reveal Novel Pharmacological Mechanisms for Allopurinol. Clinical Pharmacology and Therapeutics, 106(3), 623-631. https://doi.org/10.1002/cpt.1439