Background/Purpose: Allopurinol is the most widely used urate-lowering drug. However, some patients treated with allopurinol do not achieve serum urate (SU) treatment target of <6mg/dl, despite daily doses >300mg.  ABCG2 rs2231142 has been reported to be associated with poor response to allopurinol, while there are conflicting data on the association between ABCG2 rs10011796 and allopurinol response.  The aim of this study was to replicate the association of ABCG2 rs2231142 and rs10011796 with allopurinol response and perform a meta-analysis.

Methods: Participants in the Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients (LASSO) with available allopurinol dose, plasma allopurinol, oxypurinol, serum urate and genotyping data from a single visit were studied (n=395). In patients with evidence of adherence to allopurinol therapy (oxypurinol >20μmol/l), good response was defined as serum urate (SU) <6mg/dl on allopurinol ≤300mg/d and poor response as SU≥6mg/dl despite allopurinol >300mg/d. Association of rs2231142 and rs10011796 with poor response was tested in logistic regression models that included age, sex, body mass index (BMI), ethnicity and estimated glomerular filtration rate (eGFR).  Results from the LASSO study and a subset of participants in Genetics of Gout in Aotearoa study on allopurinol with available data as outlined above (n=296, including 264 from the previously published report) were combined by meta-analysis.

Results: 24.3% (96/395) of the LASSO cohort and 13.5% (40/296) of the NZ cohort either did not fit the pre-defined response criteria and/or had plasma oxypurinol suggestive of non-adherence (<20μmol/l) and were therefore excluded. 46.5% (139/299) of patients in the LASSO cohort and 50.8% (130/256) of patients in the NZ cohort were defined as poor responders. There was evidence for association of rs22322142 with allopurinol response (OR=2.35_{A allele}, P=7.3×10^-4) but not for rs10011796 (OR=1.21 _{G allele}, P=0.33) in the LASSO cohort using a fully adjusted logistic regression model. Meta-analysis with the Genetics of Gout in Aotearoa study participants provided strong and consistent evidence of an association for rs2231142 with allopurinol response (OR=2.43, P=6.2×10^-7), but not for rs10011796 (OR=1.06, P=0.69) (Figure).

Conclusion: This study replicates the association of ABCG2 rs2231142 with poor response to allopurinol.  Testing ABCG2 rs2231142 may assist in prediction of SU response in people treated with allopurinol.