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Clin Pharmacol Ther. 2019 Mar 28. doi: 10.1002/cpt.1439. [Epub ahead of print]

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

Author information

1
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA.
2
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
3
Kaiser Permanente Northern California Division of Research, Oakland, California, USA.
4
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
5
RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Japan.
6
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
7
institute of Human Genetics, University of California San Francisco, California, USA.

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 BCRP, associated with worse response to allopurinol. However, for the first time this association reached genome-wide level significance (p=8.06 x 10-11 ). Additionally, we identified a novel association with a variant in GREM2 (rs1934341, p=3.2 x 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. This article is protected by copyright. All rights reserved.

KEYWORDS:

EHR ; GWAS ; SLC2A9; pharmacodynamics; pharmacogenomics; rheumatology

PMID:
30924126
DOI:
10.1002/cpt.1439

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