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

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.

Oxypurinol pharmacokinetics and pharmacodynamics in healthy volunteers: Influence of BCRP Q141K polymorphism and patient characteristics

“…[3][4][5] Recently, breast cancer resistant protein (BCRP) p.Q141K (rs2231142) has been shown to associate with poor response to allopurinol (i.e., greater than the rheumatologist recommended SUA levels of <6 mg/dl). [6][7][8] Both allopurinol and oxypurinol, the active metabolite of allopurinol, are substrates of BCRP, which acts as an efflux pump on the apical membrane of the renal proximal tubule and intestinal epithelia and on the canalicular membrane of hepatocytes. 7 Allopurinol is rapidly and extensively metabolized to oxypurinol, as reflected by its short half-life (1-2 h).…”

Relationships Between Allopurinol Dose, Oxypurinol Concentration and Urate‐Lowering Response—In Search of a Minimum Effective Oxypurinol Concentration

“…These data are consistent with ABCG2 141K being associated with poor response to allopurinol. It is important to note that other genes may be involved in allopurinol response, including GREM2 and GLUT 9, and further research will be required to determine how they might helpful clinically …”

“…It is important to note that other genes may be involved in allopurinol response, including GREM2 and GLUT 9, and further research will be required to determine how they might helpful clinically. 17 Measurement of plasma oxypurinol concentrations is not currently part of routine clinical care, although measurement may assist in assessing patient adherence with allopurinol therapy. 18 A plasma oxypurinol concentration of 100 μmol/L has been suggested to be the upper end of the therapeutic range, with most people with gout achieving "normal" SU, defined as < 7.6 mg/dL (0.45 mmol/L), at concentrations < 100 μmol/L.…”

Medically Important Alterations in Transport Function and Trafficking of ABCG2

“…A subsequent study demonstrated that ABCG2 transports oxypurinol, but not allopurinol itself [ 154 ]. Further pharmacogenomic analyses established the link between presence of the Q141K allele and increased risk of poor response to allopurinol [ 155 , 156 , 157 ], but the underlying mechanism, how Q141K influences allopurinol disposition and the clinical response, is yet to be clarified.…”