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

Research output: Contribution to journalArticle

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
JournalClinical Pharmacology and Therapeutics
DOIs
Publication statusPublished - 01-01-2019

Fingerprint

Allopurinol
Genome-Wide Association Study
Pharmacology
Oxypurinol
Uric Acid
Breast Neoplasms
Xanthine Oxidase
Proteins
Cardiovascular Diseases
Genome
Kidney

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Brackman, D. J., Yee, S. W., Enogieru, O. J., Shaffer, C., Ranatunga, D., Denny, J. C., ... Giacomini, K. M. (2019). Genome-Wide Association and Functional Studies Reveal Novel Pharmacological Mechanisms for Allopurinol. Clinical Pharmacology and Therapeutics. https://doi.org/10.1002/cpt.1439
Brackman, Deanna J. ; Yee, Sook Wah ; Enogieru, Osatohanmwen J. ; Shaffer, Christian ; Ranatunga, Dilrini ; Denny, Joshua C. ; Wei, Wei Qi ; Kamatani, Yoichiro ; Kubo, Michiaki ; Roden, Dan M. ; Jorgenson, Eric ; Giacomini, Kathleen M. / Genome-Wide Association and Functional Studies Reveal Novel Pharmacological Mechanisms for Allopurinol. In: Clinical Pharmacology and Therapeutics. 2019.
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Brackman, DJ, Yee, SW, Enogieru, OJ, Shaffer, C, Ranatunga, D, Denny, JC, Wei, WQ, Kamatani, Y, Kubo, M, Roden, DM, Jorgenson, E & Giacomini, KM 2019, 'Genome-Wide Association and Functional Studies Reveal Novel Pharmacological Mechanisms for Allopurinol', Clinical Pharmacology and Therapeutics. https://doi.org/10.1002/cpt.1439

Genome-Wide Association and Functional Studies Reveal Novel Pharmacological Mechanisms for Allopurinol. / Brackman, Deanna J.; Yee, Sook Wah; Enogieru, Osatohanmwen J.; Shaffer, Christian; Ranatunga, Dilrini; Denny, Joshua C.; Wei, Wei Qi; Kamatani, Yoichiro; Kubo, Michiaki; Roden, Dan M.; Jorgenson, Eric; Giacomini, Kathleen M.

In: Clinical Pharmacology and Therapeutics, 01.01.2019.

Research output: Contribution to journalArticle

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AU - Ranatunga, Dilrini

AU - Denny, Joshua C.

AU - Wei, Wei Qi

AU - Kamatani, Yoichiro

AU - Kubo, Michiaki

AU - Roden, Dan M.

AU - Jorgenson, Eric

AU - Giacomini, Kathleen M.

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