A Genome-Wide Association Study of Oxypurinol Concentrations in Patients Treated with Allopurinol

TL;DR

This study looked for genetic factors affecting allopurinol and its metabolite concentrations but found no significant associations.

Contribution

The study is a genome-wide investigation into allopurinol metabolism and dosing in a clinical cohort.

Findings

No genetic associations met the genome-wide significance threshold for any endpoints.

Results align with previous challenges in identifying genetic determinants of allopurinol pharmacokinetics.

Larger and more diverse cohorts may be needed to uncover relevant pharmacogenomic factors.

Abstract

Cohort studies have identified several genetic determinants that could predict the clinical response to allopurinol. However, they have not been commonly used for genome-wide investigations to identify genetic determinants on allopurinol metabolism and concentrations. We conducted a genome-wide association study of a prior cross-sectional investigation of patients from the Montreal Heart Institute Biobank undergoing allopurinol therapy. Four endpoints were investigated, namely plasma concentrations of oxypurinol, the active metabolite of allopurinol, allopurinol, and allopurinol-riboside, as well as allopurinol daily dosing. A total of 439 participants (mean age 69.4 years; 86.4% male) taking allopurinol (mean daily dose 194.5 mg) and who had quantifiable oxypurinol concentrations were included in the genome-wide analyses. Participants presented with multiple comorbidities and received concomitant cardiovascular medications. No association achieved the predefined genome-wide threshold values for any of the endpoints (all p > 5 × 10−8). Our results are consistent with prior findings regarding the difficulty in identifying genetic determinants of drug concentrations or pharmacokinetics of allopurinol and its metabolites, as well as allopurinol daily dosing. Given the size of this genome-wide study, collaborative investigations involving larger and diverse cohorts may be required to further identify pharmacogenomic determinants of allopurinol and measure their clinical relevance to personalize allopurinol therapy.

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