Table 1.
Top pharmacogenomic signals associated with blood pressure response and/or cardiovascular outcomes
| Association | Drug class | Locus (SNP) | Associated allele | Magnitude of effect |
|---|---|---|---|---|
| BP response and CV outcomes | Thiazide diuretic | NEDD4L (rs4149601) | G allele | BP lowering: G allele associated with greater BP response (−19.5 versus −15.0 mmHg SBP and −15.4 versus −14.0 mmHg DBP)38 |
| Adverse CV outcomes: G allele associated with reduced risk of CV outcomes in NORDIL β-blocker/diuretic arm (OR 0.52, P <0.0001)38 | ||||
| G allele (one or two copies) associated with increased risk of CV outcomes when a thiazide diuretic was not included in treatment (OR 8.94–10.7, P = 0.051–0.022)39 | ||||
| β-blocker | ADRB1 (rs1801253 [Arg389Gly]) | C allele | C allele (arginine) homozygotes had greater BP response to metoprolol: −6.5 mmHg in 24 h DBP more than G (glycine) allele carriers (P = 0.0018)45 | |
| ADRB1 (rs1801252 [Ser49Gly]) | A allele | A allele (serine) homozygotes had similar trend for greater DBP response to metoprolol (P = 0.08)45 | ||
| ADRB1 Ser49/Arg389 haplotype | Haplotype | Ser49Arg389/Ser49Arg389 haplotype associated with greater BP response to metoprolol (−14.7 mmHg versus −0.5 mmHg in patients with the Gly49Arg389/Ser49Gly389 haplotype; P = 0.006)45 | ||
| Mortality risk was significantly increased among patients with one or two copies of the Ser49/Arg389 haplotype who were randomly assigned to verapamil SR (HR 8.58, 95% CI 2.06–35.8, P = 0.003) but not in patients assigned to atenolol (HR 2.31, 95% CI 0.82–6.55, P = 0.11)51 | ||||
| BP response | Thiazide diuretic | Chromosome 12, LYZ, YEATS4, FRS2 (rs7297610, rs317689, rs315135) | Primarily driven by C allele of rs7297610 | African Americans who were homozygous for CC alleles had a greater mean SBP response (−13 versus −9.6 mmHg) and DBP response (−8 versus −5.2 mmHg) than homozygous carriers of TT alleles57 |
| PRKCA (rs16960228) | A allele | A allele carriers had a 4/4 mmHg greater BP response than GG homozygotes58 | ||
| GNAS–EDN3 rs2273359 | G allele | G allele carriers had a 7/5 mmHg greater BP response than CC homozygotes58 | ||
| β-blocker | GRK4 (rs2960306 [Arg65Leu], rs1024323 [Ala142Val], rs1081058 [Ala486Val]) | T allele for all three SNPs | Increasing copies of the 65Leu–142Val haplotype were associated with significantly reduced atenolol-induced DBP lowering (−9.1 ± 6.8 versus −6.8 ± 7.1 versus −5.3 ± 6.4 mmHg in participants with zero, one, and two copies of 65Leu–142Val, respectively; P = 0.0088)74 | |
| CV outcomes | CCB | SIGLEC12, A1BG, F5 (rs16982743, rs893184, rs4525) | Risk score with one point given for each genotype that conferred a higher risk in the CCB arm than the β-blocker arm | In patients with a genetic risk score of 0 or 1, CCB treatment was associated with lower risk of treatment-related adverse CV outcomes (heart attack, stroke or death; OR 0.60, 95% CI 0.42–0.86); in patients with a genetic risk score of 2–3, CCB treatment was associated with higher risk (OR 1.31, 95% CI 1.08–1.59; meta-analysis interaction P = 2.39 × 10−5)84 |
ARB, angiotensin-receptor blocker; BP, blood pressure; CCB, calcium channel blocker; CV, cardiovascular; DBP, diastolic blood pressure; SBP, systolic blood pressure; SNP, single nucleotide polymorphism, SR, slow release.