Date: Monday, October 22, 2018
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Association of ABCG2 Q141K (p.141Lys) with poor urate-lowering response to allopurinol has been reported although the mechanism is unclear. ABCG2 has been reported to be an efflux pump for allopurinol and oxypurinol  and for oxypurinol alone . Based on data from the HEK293 cell-line it has been suggested that dysfunctional variants of ABCG2 such as p.141Lys could lead to decreased renal excretion of oxypurinol, higher oxypurinol levels and greater serum urate lowering . To further investigate the apparent inconsistency between ref  and association of p.141Lys with poor allopurinol response, we examined the relationship between ABCG2 p.141Lys and plasma oxypurinol.
Methods: We examined, using linear regression, plasma oxypurinol concentrations using participants from the Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients and Genetics of Gout in Aotearoa studies based on the presence of the ABCG2 p.141Lys.
Of the 688 individuals, 294 (42.7%) were positive for ≥one p.141Lys allele. In a univariate model plasma oxypurinol concentration was significantly lower in these individuals compared to Gln/Gln homozygotes (mean (SEM) 84.8 (3.6) µmol/l vs. 96.6 (3.1); p=0.013) despite higher allopurinol dose (mean (SD) 326 (101.3) vs. 297 (80.5)mg/d; p<0.001) and higher eGFR (72.7 (24.8) vs 67.5 (22.6) ml/min/1.73m2; p=0.004). Of those in the p.141Lys-positive group, fewer were receiving diuretics compared to the Gln/Gln group (22.4% vs. 31.0%; p=0.08). In a multivariate model that included allopurinol dose, eGFR and the use of diuretics, there was no statistically significant difference between plasma oxypurinol concentrations in the p.141Lys-positive and -negative groups, although levels were numerically lower in the p.141Lys-positive group (97.7 (3.5) µmol/l vs. 104.3 (2.8) µmol/l p=0.12).
Our results suggest that there are unidentified factors that influence plasma oxypurinol and, despite the evidence presented from the HEK293 cell-line model , plasma oxypurinol levels are not significantly different in individuals with the ABCG2 p.141Lys variant. We recommend an individualised dose titration to target serum urate strategy for patients establishing on allopurinol.
- Wen, C., et al., Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response. Clin Pharm Ther, 2015. 97(5): p. 518-25.
- Nakamura, M., et al., Investigation of the transport of xanthine oxidase dehydrogenase inhibitors by the urate transporter ABCG2. Drug Metabol Pharmacokinet, 2017. https://doi.org/10.1016/j.dmpk.2017.11.002.
To cite this abstract in AMA style:Stamp LK, Wallace M, Roberts R, Frampton C, Miner J, Merriman TR, Dalbeth N. ABCG2 rs2231142 Q141K and Oxypurinol Concentration in People with Gout Receiving Allopurinol [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/abcg2-rs2231142-q141k-and-oxypurinol-concentration-in-people-with-gout-receiving-allopurinol/. Accessed October 30, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/abcg2-rs2231142-q141k-and-oxypurinol-concentration-in-people-with-gout-receiving-allopurinol/