Influence of phenotype and pharmacokinetics on β-blocker drug target pharmacogenetics

Abstract

Two common polymorphisms in the b 1 -adrenergic receptor gene, Ser49Gly and Arg389Gly, are associated with variable antihypertensive response to metoprolol. We sought to determine whether similar pharmacogenetic associations were present with the negative chronotropic response phenotype to metoprolol. Metoprolol was titrated in 54 untreated hypertensive patients to achieve blood pressure control. We found no association between either resting or exercise heart rate at baseline (untreated) or in response to metoprolol by codon 389 genotype. In contrast, when compared by codon 49 genotype, Ser49 homozygotes had significantly higher resting heart rates at baseline (untreated) than Gly49 carriers (82710 versus 74711 bpm, respectively, P ¼ 0.016). When corrected for plasma concentration, we found no difference in reduction in exercise heart rate in response to metoprolol between Ser49 homozygotes and Gly49 carriers (0.7570.11 versus 0.5770.17%/ng/ml, respectively, P ¼ 0.37). However, if one fails to account for plasma concentration, trends toward a significant difference in heart rate reduction are seen between Ser49 homozygotes and Gly49 carriers (31% reduction versus 25% reduction, P ¼ 0.05). Our data suggest that neither the b 1 -adrenergic receptor Arg389Gly, nor the Ser49Gly polymorphisms are associated with variable negative chronotropic response to metoprolol. In addition, our data highlight the importance of measuring metoprolol concentration in order to account for variable pharmacokinetics and avoid misinterpretation of the data.

Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine

“…Likewise, a patient study reported that long-term treatment with metoprolol yielded greater blood pressure reductions in Arg389 carriers (Johnson et al, 2003). However, four other studies did not confirm greater hemodynamic effects of ␤-AR antagonists in patients with an Arg389 compared with those with a Gly389 genotype (summarized in Table 6) (O'Shaughnessy et al, 2000;Filigheddu et al, 2004;Karlsson et al, 2004;Beitelshees et al, 2006).…”

Dissecting complex traits: recent advances in hypertension genomics

“…The fall in BP after dosing with metoprolol is consistently predicted by the ADRB1 genotype, with carriers of an arginine at position 389 behaving as good responders [30,31]. However, there is no consensus on the impact of these SNPs on the response of the resting or exercise-induced heart rate to beta-blocker therapy [32,33]. Exercise-induced heart rates are a robust index of β 1 -receptor activation in vivo , so these differences are probably attributable to patient selection and small sample sizes.…”

Genetic Dependency of Blood Pressure and Heart Rate in Patients with Arterial Hypertension and Obesity

“…В последнее время в публикациях зарубежных ис-следователей анализируются и результаты исследования связи между полиморфизмом Arg389Gly гена β 1 -адре-норецепторов (ADRβ 1 ), полиморфизмом T393C гена α-субъединицы G-белка (GNAS1) и течением АГ [14][15][16][17][18][19][20][21][22]. Анализ этих связей позволил установить, что взаимосвязь полиморфизма Arg389Gly гена ADRβ 1 с уровнем систоли-ческого и диастолического артериального давления (САД и ДАД) и ЧСС имеет более распространенный характер.…”

“…Так, по результатам исследований, которые проводились в 2011 г., можно утверждать, что респонденты Global BPgen Consortium (n =34 433) и Women's Genome Health Study (n =23 019), являющиеся носителями аллеля Gly389, имели более низкие показатели САД, ДАД, чем носители аллеля Arg389 [14]. Однако не все ученые подтверждают эту взаимосвязь, а отличия в полученных данных связы-вают с этнической принадлежностью пациентов [15]. В то же время связь полиморфизма T393C гена GNAS1 с САД, ДАД и ЧСС исследована недостаточно и также имеет противоречивый характер [16,17].…”

“…Савельева и Л.А. Ми-нушкина (Россия) также не подтвердили существования зависимости между данным полиморфизмом и изучаемы-ми показателями [15,21,22].…”