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 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 finding regarding the difficulty in identifying genetic determinants of drug concentrations or pharmacokinetics of allopurinol and its metabolites, and 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.

Pharmacogenomics (PGx) is the study of how variations of the patient genetic makeup could influence the selection and dosing of medications, including urate-lowering therapies (ULTs). Patients with gout present with several comorbidities, warranting the use of several long-term medications that increase their pill burden and the risk of adverse drug events. PGx testing can identify individuals who are more or less likely to benefit from a given treatment and ultimately improve adherence and reduce polypharmacy. Gout management involves using various ULTs associated with specific genetic variations that could modulate medication safety and efficacy. Individuals carrying the HLA-B*58:01 variant are at a higher risk of serious and life-threatening skin reactions from taking allopurinol. Besides, racial disparities in HLA-B distribution warrant testing for its status in high-risk populations, specifically some Asian subgroups and African Americans. G6PD-deficient individuals are prone to develop hemolytic anemia and methemoglobinemia with pegloticase and probenecid use. Patients with the less active form of the drug-metabolizing CYP2C9 are at higher risk for NSAID-related upper gastrointestinal (GI) bleeding. The drug-gene pair interactions among various gout therapies were also reviewed. Allopurinol-related genes included AOX, ABCG2, and SLC22A12. Febuxostat-related genes included UGT1A1. Benzbromarone- and probenecid- related genes included SLC22A12 and ABCB1. Colchicine-related genes included CYP2D6, ABCB1, rs6916345 G>A, and SEPHS1. Finally, the corticosteroid-related gene included HCG22; and the anakinra-related gene included IL1RA. This review synthesizes the most contemporary level of evidence for using PGx in gout pharmacotherapy, as referenced in the CPIC guidelines, FDA, PharmGKB, and current literature.