Genetic Variation Within Adrenergic Pathways Determines In Vivo Effects of Presynaptic Stimulation in Humans

Abstract

Background— Catecholamines govern stress blood pressure responses. Catecholaminergic responses may be partially genetic and contribute to the complex heritability of hypertension. Methods and Results— To evaluate catecholaminergic responses without systemic counterregulation, we infused graded concentrations of tyramine, an indirect presynaptic norepinephrine releaser, into dorsal hand veins of 49 normotensive men and women of 5 ethnicities. Vascular responses were coupled to common (minor allele frequency >10%) single-nucleotide polymorphisms at adrenergic target loci within presynaptic pathways. Significance was set at P <0.003 after Bonferroni correction. Generalized analysis of molecular variance (GAMOVA) was performed to determine whether genetic admixture contributed to results. Venoconstriction progressed to 47% with increasing concentrations of tyramine (0.129 to 25.8 mmol/L; P <0.001). Family history of hypertension ( P <0.001) and female sex ( P =0.02) predicted blunted tyramine responses. Two genetic loci significantly predicted vascular response: chromogranin B, which encodes a protein that catalyzes catecholamine vesicle formation ( CHGB , exon 4, Glu348Glu; P =0.002), and cytochrome b-561 ( CYB561 , intron 1, C719G; P <0.001), an electron shuttle for catecholamine synthesis. Stepwise regression suggested important effects for the CHGB locus, with polymorphisms for the vacuolar-ATPase β-subunit ( ATP6V1B1 , exon 1, Ile30Thr) and flavin-containing monooxygenase-3 ( FMO3 , exon 3, Lys158Glu, P =0.002). GAMOVA did not show a significant relationship between overall genetic profile and hand-vein constriction ( P =0.29), which indicates that population stratification did not contribute to this phenotype. Conclusions— Locally infused tyramine produced dose-dependent pressor responses, predicted by family history of hypertension, sex, and genetic variants at loci, particularly CHGB , that encode the biosynthesis, storage, and metabolism of catecholamines. Such variants may influence the complex heritability of adrenergic responses and perhaps hypertension.