TY - JOUR
T1 - Genome-Wide Association and Functional Studies Reveal Novel Pharmacological Mechanisms for Allopurinol
AU - Brackman, Deanna J.
AU - Yee, Sook Wah
AU - Enogieru, Osatohanmwen J.
AU - Shaffer, Christian
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.
N1 - Publisher Copyright:
© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics
PY - 2019/9
Y1 - 2019/9
N2 - 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.
AB - 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.
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U2 - 10.1002/cpt.1439
DO - 10.1002/cpt.1439
M3 - Article
C2 - 30924126
AN - SCOPUS:85066828642
SN - 0009-9236
VL - 106
SP - 623
EP - 631
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
IS - 3
ER -
