Pharmacogenomic architecture of antihypertensive switching implicates neurotensin-NTSR1 signaling in ACE inhibitor-induced cough

Early failure of antihypertensive medication treatment affects one in four patients, but the underlying mechanisms are poorly understood. We aimed to identify genetic determinants of antihypertensive treatment failure within the first year. Using longitudinal medication data from >400,000 genotyped antihypertensive medication users across 3 cohorts (FinnGen, the UK Biobank, and the Estonian Biobank), we classified short-term antihypertensive use trajectories as Continue, Switch, or Discontinue. We performed genome-wide association studies of switching across five major medication classes, followed by replication and downstream analyses linking genetic loci to medication-specific adverse events and clinical outcomes. We identified 14 genome-wide significant loci for switching from angiotensin-converting enzyme inhibitors (ACEI) and dihydropyridine calcium channel blockers (dCCB) to other antihypertensive medications. For ACEI switching, multiple independent signals converged on the neurotensin-NTSR1 pathway, including a 320-fold Finnish-enriched protective missense variant in the neurotensin receptor gene NTSR1 (rs148569146 [G301R], allele frequency [AF] 1.4%, odds ratio [OR] 0.49, P=3.3x10-43) and a variant near RASSF9 (rs181941187, AF=9.0%, OR=0.74, P=1.2x10-49) tagging the neurotensin gene NTS. In drug-gene interaction analyses, NTSR1 G301R was associated with reduced ACEI-induced cough risk (OR=0.39, P=8.1x10-4). The dCCB switching locus at CYP3A43 was in near-complete linkage (r2=0.99) with the functional CYP3A4*22 allele (rs35599367, AF=3.4%, OR=1.23, P=6.1x10-10). Our findings extend the bradykinin hypothesis of ACEI-induced cough by implicating neurotensin-NTSR1 signaling. We additionally characterize CYP3A4*22 as a mechanistically supported predictor of dCCB intolerance. Longitudinal medication trajectories offer a rich framework for pharmacogenetic discovery with potential for future genotype-informed antihypertensive medication selection. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/26344813v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@15decc0org.highwire.dtl.DTLVardef@1627086org.highwire.dtl.DTLVardef@1c9982eorg.highwire.dtl.DTLVardef@262730_HPS_FORMAT_FIGEXP M_FIG C_FIG