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

Clin Pharmacol Ther. 2019 Sep;106(3):623-631. doi: 10.1002/cpt.1439. Epub 2019 May 23.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics*
  • Aged
  • Aged, 80 and over
  • Allopurinol / pharmacology*
  • Cytokines / genetics
  • Ethnic Groups
  • Female
  • Genome-Wide Association Study
  • Glucose Transport Proteins, Facilitative / antagonists & inhibitors
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Proteins / genetics*
  • Oxypurinol / pharmacology
  • Prognosis
  • Uric Acid / metabolism*

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Cytokines
  • GREM2 protein, human
  • Glucose Transport Proteins, Facilitative
  • Neoplasm Proteins
  • SLC2A9 protein, human
  • Uric Acid
  • Allopurinol
  • Oxypurinol