Side effects in hypertension treatment: a pharmacogenomic analysis

Genome-wide analysis of medication use trajectories implicates the neurotensin-NTSR1 pathway in ACE inhibitor-induced cough and the functional CYP3A4 22 allele in dihydropyridine calcium channel blocker switching.

Up to half of patients switch or discontinue antihypertensive medication within the first year, with mechanisms that remain unclear. The authors classified short-term medication use trajectories (Continue, Switch, Discontinue) in more than 400,000 genotyped users across three cohorts (FinnGen, UK Biobank, Estonian Biobank) and ran genome-wide association studies for five medication classes. Fourteen genome-wide significant loci were identified for switching from ACE inhibitors (ACEI) and dihydropyridine calcium channel blockers (dCCB), including a 320-fold Finnish-enriched protective missense variant in NTSR1 (rs148569146, G301R; OR 0.49, P = 3.3 × 10⁻⁴³) and a variant near RASSF9 tagging the neurotensin gene NTS (rs181941187, OR 0.74, P = 1.2 × 10⁻⁴⁹). In drug-gene interaction analyses NTSR1 G301R was associated with reduced ACEI-induced cough risk (OR 0.39, P = 8.1 × 10⁻⁴), and the dCCB switching locus at CYP3A43 was in near-complete linkage (r2 = 0.99) with the functional CYP3A4 22 allele (rs35599367, OR 1.23, P = 6.1 × 10⁻¹⁰). A polygenic risk score for ACEI switching predicted two-fold ACEI cough risk in the top 10 % compared with the middle 20 % in an independent Estonian Biobank sample.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The directly transferable contribution is not the NTSR1 signal, spectacular but almost restricted to Finland: it is CYP3A4 22, an already known allele already present on most pharmacogenetic panels, which here predicts tolerance failure for a drug class prescribed to millions. The weakness is the endpoint — switching or stopping a drug is not a documented adverse reaction, and the analysis cannot say whether the patient was intolerant, poorly informed or simply lost to follow-up. Before genotyping ahead of a dCCB prescription, a trial must show that a CYP3A4 22-guided choice genuinely improves treatment persistence.

Analysis by Dr Thibaut Benquey