Large, observational genetic studies are commonly used to identify genetic factors associated with diseases and disease‐related traits. Such cohorts have not been commonly used to identify genetic predictors of drug dosing or concentrations, perhaps because of the heterogeneity in drug dosing and formulation, and the random timing of blood sampling. We hypothesized that large sample sizes relative to traditional pharmacokinetic studies would compensate for this variability and enable the identification of pharmacogenetic predictors of drug concentrations. We performed a cross‐sectional, proof‐of‐concept association study to replicate the well‐established association between metoprolol concentrations and CYP2D6 genotype‐inferred metabolizer phenotypes in participants from the Montreal Heart Institute Hospital Cohort undergoing metoprolol therapy. Plasma concentrations of metoprolol and α‐hydroxymetoprolol (α‐OH‐metoprolol) were measured in samples collected randomly regarding the previous metoprolol dose. A total of 999 individuals were included. The metoprolol daily dose ranged from 6.25 to 400 mg (mean 84.3 ± 57.1 mg). CYP2D6‐inferred phenotype was significantly associated with both metoprolol and α‐OH‐metoprolol in unadjusted and adjusted models (all p < 10 −14 ). Models for metoprolol daily dose showed consistent results. Our study suggests that randomly drawn blood samples from biobanks can serve as a new approach to discover genetic associations related to drug concentrations and dosing, with potentially broader implications for genomewide association studies on the pharmacogenomics of drug metabolism.

Background and Purpose Patients with nonvalvular atrial fibrillation (NVAF) who survive an intracranial hemorrhage (ICH) have an increased risk of ischemic stroke and systemic embolism (IS/ SE). We investigated whether starting oral anticoagulants (OACs) among older NVAF patients after an ICH was associated with a lower risk of IS/SE and mortality but offset by an increase in major bleeding. Methods We assembled a patient cohort from the Quebec Régie de l’Assurance Maladie du Québec (RAMQ) and Med-Echo administrative databases. We identified older adults with NVAF from 1995 to 2015. All patients with incident ICH and discharged in community were included. Patients were categorized according to OAC exposure. Outcomes included IS/SE, all-cause mortality, recurrent ICH and major bleeding after a quarantine period of 6 weeks. Crude event rates were calculated at 1-year of follow-up, and Cox proportional hazard models with a time-dependent binary exposure were used to assess adjusted hazard ratios (AHRs). Results The cohort of 683 NVAF patients with ICH aged 83 years on average. The rates (per 100 person-years) for IS/SE, death, ICH and major bleeding were 3.3, 40.6, 11.4, and 2.7 for the no OAC group; and 2.6, 16.3, 5.2, and 5.2 for OAC group, respectively. The AHR for IS/SE and death was 0.10 (95% confidence interval [CI], 0.05 to 0.21), 0.43 (95% CI, 0.19 to 0.97) for recurrent ICH and 1.73 (95% CI, 0.71 to 4.20) for major extracranial bleeding comparing OAC exposure to non-exposed. Conclusions Initiating OAC after ICH in older individuals with NVAF is associated with a reduction of IS/SE and mortality and a trend in recurrent ICH supporting its use after ICH.

ABCG2 is a gene that codes for the human breast cancer resistance protein (BCRP). It is established that rs2231142 G>T, a single nucleotide polymorphism of the ABCG2 gene, is associated with gout and poor response to allopurinol, a uric acid‐lowering agent used to treat this condition. It has also been suggested that oxypurinol, the primary active metabolite of allopurinol, is a substrate of the BCRP. We thus hypothesized that carrying the rs2231142 variant would be associated with decreased oxypurinol concentrations, which would explain the lower reduction in uric acid. We performed a cross‐sectional study to investigate the association between the ABCG2 rs2231142 variant and oxypurinol, allopurinol, and allopurinol riboside concentrations in 459 participants from the Montreal Heart Institute Hospital Cohort. Age, sex, weight, use of diuretics, and estimated glomerular filtration rate were all significantly associated with oxypurinol plasma concentration. No association was found between rs2231142 and oxypurinol, allopurinol and allopurinol riboside plasma concentrations. Rs2231142 was not significantly associated with daily allopurinol dose in the overall population, but an association was observed in men, with T carriers receiving higher doses. Our results do not support a major role of ABCG2 in the pharmacokinetics of allopurinol or its metabolites. The underlying mechanism of the association between rs2231142 and allopurinol efficacy requires further investigation.