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Aim:Few genome-wide association studies (GWASs) have been conducted to identify predictors of drug concentrations. The authors therefore sought to discover the pharmacogenomic markers involved in metoprolol pharmacokinetics. Patients & methods:The authors performed a GWAS of a cross-sectional study of 993 patients from the Montreal Heart Institute Biobank taking metoprolol. Results:A total of 391 and 444 SNPs reached the significance threshold of 5 × 10-8for metoprolol and α-OH-metoprolol concentrations, respectively. All were located on chromosome 22 at or near the CYP2D6gene, encoding CYP450 2D6, metoprolol's main metabolizing enzyme. Conclusion:The results reinforce previous findings of the importance of the CYP2D6locus for metoprolol concentrations and confirm that large biobanks can be used to identify genetic determinants of drug pharmacokinetics at a GWAS significance level.

Aim:To evaluate the impact of AGTR1A1166C (rs5186) on the response to candesartan in patients with heart failure. Materials & methods:Prospective, multicentre, open-label study. We studied 299 symptomatic patients with heart failure presenting a left ventricular ejection fraction ≤40. Results:Reductions in the primary end points of natriuretic peptides were not significantly associated with AGTR1A1166C. Nevertheless, carrying the 1166C allele was associated with a greater compensatory increase in renin activity (p  0.037) after 16 weeks of treatment with candesartan and a more modest effect on aldosterone concentrations (p  0.022). Conclusion:AGTR11166C carriers may experience a greater long-term compensatory renin–angiotensin–aldosterone system activation following treatment with candesartan. Whether these associations ultimately influence clinical outcomes requires investigation.Clinicaltrials.gov: NCT00400582