Pharmacogenetics may explain part of the interindividual
variability of dobutamine pharmacodynamics in neonates
Maarja Hallik1, Hiie Soeorg2, Tiina
Kahre3,4, Ülle Murumets3, Mari-Liis
Ilmoja5, Karin Kipper6,7,8, Tuuli
Metsvaht9
The authors confirm that the PI for this paper is Maarja Hallik and that
she had direct clinical responsibility for patients.
1 Department of Anaesthesiology and Intensive Care,
Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
2 Department of Microbiology, Institute of Biomedicine
and Translational Medicine, University of Tartu, Tartu, Estonia
3 Department of Clinical Genetics, United
Laboratories, Tartu University Hospital, Tartu, Estonia
4 Department of Clinical Genetics, Institute of
Clinical Medicine, University of Tartu, Tartu, Estonia
5Department of Anaesthesiology and Intensive Care,
Tallinn Children’s Hospital, Tallinn, Estonia
6 Institute of Chemistry, University of Tartu, Tartu,
Estonia
7 Chalfont Centre for Epilepsy, Buckinghamshire,
United Kingdom
8 Department of Clinical and Experimental Epilepsy,
Faculty of Brain Sciences, University College London, United Kingdom
9Department of Paediatrics, Institute of Clinical
Medicine, University of Tartu, Tartu, Estonia
Running head: Dobutamine pharmacogenetics in neonates
Keywords: neonatology, intensive care, cardiovascular pharmacology,
pharmacogenetics.
Corresponding author: Maarja Hallik, Department of Anaesthesiology and
Intensive Care, Institute of Clinical Medicine, University of Tartu, L.
Puusepa 8 - G1. 209, 50406, Tartu, Estonia; e-mail:
maarja.hallik@ut.ee ;
phone: 003725055369;
Word count: 3804, table count: 2, figure count: 3
What is already known about this subject?
Some genetic variation in human cardiac β-adrenoceptor pathway that
might result in different response to inotropic therapy have been
described.
In vivo data about the effects of genetic variation to
cardiovascular response come from adult studies with small number of
healthy volunteers or heart failure patients.
What this study adds?
- The study describes the genetic variability in dobutamine
pharmacodynamics in critically ill neonates.
- The large interindividual variability of the cardiovascular effects of
dobutamine in early postnatal life may partly be explained by
adrenoceptor and Gs protein α-subunit gene sequence variants.
- Results from adult studies cannot be readily extrapolated to neonates.
ABSTRACT
Aim: To determine whether the known single nucleotide polymorphisms in
adrenoreceptor associated genes affect the hemodynamic response to
dobutamine in critically ill neonates.
Methods: Alleles in the known genetic single nucleotide polymorphisms in
β1 and β2 adrenoceptor (AR) genes and Gs protein α-subunit gene (GNAS)
possibly affecting inotropic effect were identified in patients of
neonatal dobutamine pharmacokinetic-pharmacodynamic study. Linear
mixed-effect models were used to describe the effect of genetic
polymorphisms to heart rate (HR), left ventricular output (LVO) and
right ventricular output (RVO) during dobutamine treatment.
Results: 26 neonates (5 term, 21 preterm) were studied. Dobutamine
plasma concentration and exposure time respective HR (adjusted to
gestational age) is dependent on β1-AR Arg389Gly polymorphism so that in
G/G (Gly) homozygotes and G/C heterozygotes dobutamine increases HR more
than in C/C (Arg) homozygotes, with parameter estimate (95% CI) of 38.3
(15.8 – 60.7) bpm per AUC of 100 mg·h, p=0.0005. LVO (adjusted to
antenatal glucocorticoid administration and illness severity) and RVO
(adjusted to gestational age and illness severity) is dependent on GNAS
c.393C>T polymorphism so that in T/T homozygotes and C/T
heterozygotes but not in C/C homozygotes LVO and RVO increase with
dobutamine treatment, 24.5 (6.2 – 42.9) mL kg-1min-1 per AUC of 100 mg·h, p=0.0116 and 33.2 (12.1 –
54.3) mL kg-1 min-1 per AUC of 100
mg·h, p=0.0025, respectively.
Conclusion: In critically ill neonates, β1-AR Arg389Gly and GNAS
c.393C>T polymorphisms may play a role in the haemodynamic
response to dobutamine during the first hours and days of life.