Jussi P Posti1,2,3, Perttu Salo4, Saku Ruohonen1, Laura Valve1, Mordechai Muszkat5, Gbenga G Sofowora5, Daniel Kurnik5, C Michael Stein5, Markus Perola4, Mika Scheinin1,3, Amir Snapir1,6. 1. Dept. of Pharmacology, Drug Development and Therapeutics, University of Turku, Finland. 2. Dept. of Surgery, Division of Neurosurgery, Turku University Hospital, Turku, Finland. 3. TYKSLAB, Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland. 4. Finnish Institute for Molecular Medicine, Helsinki, Finland. 5. Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA. 6. Orion Corporation, Turku, Finland.
Abstract
OBJECTIVES: α2-Adrenoceptors (α2-AR) mediate both constriction and dilatation of blood vessels. There is considerable interindividual 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 the genetic factors contributing toward the interindividual variability in α2-AR-mediated vascular constriction induced by the selective α2-AR agonist dexmedetomidine. METHODS: DHV constriction responses to a local infusion of dexmedetomidine were assessed by measuring changes in vein diameter with a linear variable differential transformer. The outcome variable for constriction was log-transformed dexmedetomidine ED50. A genome-wide association study (GWAS) of 433 378 single-nucleotide polymorphisms (SNPs) was carried out for determining the sensitivity of DHV responses in 64 healthy Finnish individuals. Twenty SNPs were selected on the basis of 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 DHV constriction (unadjusted P=0.00016 for the combined population). CONCLUSION: Genetic variation in protein kinase C type β may contribute toward the interindividual variation in DHV constriction responses to α2-AR activation by the agonist dexmedetomidine.
OBJECTIVES: α2-Adrenoceptors (α2-AR) mediate both constriction and dilatation of blood vessels. There is considerable interindividual 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 the genetic factors contributing toward the interindividual variability in α2-AR-mediated vascular constriction induced by the selective α2-AR agonist dexmedetomidine. METHODS:DHV constriction responses to a local infusion of dexmedetomidine were assessed by measuring changes in vein diameter with a linear variable differential transformer. The outcome variable for constriction was log-transformed dexmedetomidineED50. A genome-wide association study (GWAS) of 433 378 single-nucleotide polymorphisms (SNPs) was carried out for determining the sensitivity of DHV responses in 64 healthy Finnish individuals. Twenty SNPs were selected on the basis of 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 dexmedetomidineED50 for DHV constriction (unadjusted P=0.00016 for the combined population). CONCLUSION: Genetic variation in protein kinase C type β may contribute toward the interindividual variation in DHV constriction responses to α2-AR activation by the agonist dexmedetomidine.
Authors: Jussi P Posti; Laura Valve; Saku Ruohonen; Juha Akkila; Mika Scheinin; Amir Snapir Journal: Eur J Pharmacol Date: 2010-12-11 Impact factor: 4.432
Authors: S Cotecchia; B K Kobilka; K W Daniel; R D Nolan; E Y Lapetina; M G Caron; R J Lefkowitz; J W Regan Journal: J Biol Chem Date: 1990-01-05 Impact factor: 5.157
Authors: X F Figueroa; M I Poblete; M P Boric; V E Mendizábal; E Adler-Graschinsky; J P Huidobro-Toro Journal: Br J Pharmacol Date: 2001-11 Impact factor: 8.739
Authors: Mordechai Muszkat; Daniel Kurnik; Joseph Solus; Gbenga G Sofowora; Hong-Guang Xie; Lan Jiang; Chara McMunn; Patrick Ihrie; James R Harris; Elliott P Dawson; Scott M Williams; Alastair J J Wood; C Michael Stein Journal: Pharmacogenet Genomics Date: 2005-06 Impact factor: 2.089