A polymorphism in the protein kinase C gene PRKCB is associated with α2-adrenoceptor-mediated vasoconstriction

Abstract

Objectives α2-Adrenoceptors (α2-AR) mediate both constriction and dilatation of blood vessels. There is substantial inter-individual variability in dorsal hand vein (DHV) constriction responses to α2-AR agonist activation. Genetic factors appear to contribute significantly to this variation. The present study was designed to identify genetic factors contributing to the inter-individual variability in α2-AR-mediated vascular constriction induced by the selective α2-AR agonist dexmedetomidine. Methods DHV constriction responses to local infusion of dexmedetomidine were assessed by measuring changes in vein diameter with a linear variable differential transformer. The outcome variable was log-transformed dexmedetomidine ED50 for constriction. A genome-wide association study (GWAS) of 433,378 single nucleotide polymorphisms (SNPs) was performed for the sensitivity of DHV responses in 64 healthy Finnish subjects. 20 SNPs were selected based on the GWAS results and their associations with the ED50 of dexmedetomidine were tested in an independent North American study population of 68 healthy individuals. Results In both study populations (GWAS and replication samples), the SNP rs9922316 in the gene for protein kinase C type β was consistently associated with dexmedetomidine ED50 for dorsal hand vein constriction (unadjusted p = 0.00016 for the combined population). Conclusions Genetic variation in protein kinase C type β may contribute to the inter-individual variation in dorsal hand vein constriction responses to α2-AR activation by the agonist dexmedetomidine.

Evolving mechanisms of vascular smooth muscle contraction highlight key targets in vascular disease

“…PKC plays a role in hypertension, and mutations of PKC may influence the individual susceptibility to vascular hyper-reactivity and hypertension. A consistent association has been found between the single nucleotide polymorphism (SNP) rs9922316 in PKCβ gene ( PRKCB ) and inter-individual variation in the constriction responses of dorsal hand vein to the α2-adrenergic receptor agonist dexmedetomidine [445]. PKCα plays a role in Ca 2+ -dependent contraction of VSM [446], and overexpression of PKCα has been implicated in the pathogenesis of hypertension [447].…”

Protein Kinase C as Regulator of Vascular Smooth Muscle Function and Potential Target in Vascular Disorders

“…For instance, a consistent association is found between the single nuclear polymorphism (SNP) rs9922316 in PKCβ gene ( PRKCB ) and inter-individual variation in the constriction responses of dorsal hand vein to the selective α2 adrenergic receptor agonist dexmedetomidine (Posti et al, 2013). Also, PKCδ mRNA expression and protein levels are increased in VSM from SHR rats.…”

Lack of Association Between Adrenoreceptor Genotype and the Vasoconstriction Response to Dexmedetomidine

“…A genome-wide association study seeking an association between SNPs and responses to dexmedetomidine was undertaken, and PRKCB rs9922316 was found to be consistently associated with the ED 50 of dexmedetomidine to cause dorsal hand vein constriction in healthy adults. 9 Although this was a study of venoconstriction, the authors argued that its results were applicable to arterial vasoconstriction, as protein kinase C is involved in calcium ion sensitization of vascular smooth muscle in α-2 adrenoreceptor–mediated arterial vasoconstriction in response to dexmedetomidine. 16 The frequency of the SNP PRKCB rs9922316 in the adult male population ranges from 11% to 32%.…”

“…7 Two variants, however, have been associated with the response to dexmedetomidine: a deletion in the α-2B adrenoreceptor gene ( ADRA2B deletion) 5,8 and the single nucleotide polymorphism (SNP) rs9922316 in the gene for protein kinase C type β ( PRKCB ). 9 Homozygotes for these polymorphisms have been associated with exaggerated vasoconstriction responses to dexmedetomidine, while heterozygotes displayed responses similar to the wild-type homozygotes. We hypothesized that children with a marked SVR increase following an intravenous dexmedetomidine bolus would carry genotypes that were homozygous for the variant polymorphisms.…”