Arg16 homozygosity of the beta2-adrenergic receptor improves the outcome after beta2-agonist tocolysis for preterm labor.
BACKGROUND
Beta(2)-adrenergic receptor (beta(2)AR) agonists are not consistently successful when administered as tocolytic therapy. The beta(2)AR displays genetic variability; an arginine-to-glycine substitution at codon 16 (Arg16Gly) has been shown to increase receptor desensitization in response to agonist exposure, whereas a substitution of glutamate for glutamine at codon 27 (Gln27Glu) decreases down-regulation. We have demonstrated that homozygosity for Arg16 protects against preterm delivery. Our goal was to determine whether beta(2)-agonists are more effective in women with the Arg16 genotype and preterm labor.


METHODS
Sixty white women with preterm labor between 24 and 34 weeks' gestation were treated for 48 hours with intravenous hexoprenaline. The effect of tocolysis and outcome of pregnancy were recorded. The beta(2)AR genotypes at codons 16 and 27 of ADRB2 were determined. A control group of 116 women delivered at term was also genotyped.


RESULTS
Preterm labor was not associated with beta(2)AR genotype at codon 16 (17% of patients with preterm labor were Arg16 homozygotes versus 19% of control subjects) or codon 27. Gestation was significantly prolonged in Arg16 homozygotes (median, 69 days; interquartile range, 63-79 days) compared with the other 2 genotypes (median, 58 days; interquartile range, 2-72 days) (P = .04). Tocolysis was 100% successful in delaying delivery for 48 hours in Arg16 homozygotes (n = 10), just failing to achieve statistical significance (P = .069). In contrast, only 37 of 50 women carrying 1 or 2 glycine alleles (74%) had delivery delayed by more than 48 hours with tocolysis. Neonatal outcomes were significantly better in babies born to mothers homozygous for arginine than in women with 1 or 2 Gly16 alleles.


CONCLUSIONS
This is the first study examining the pharmacogenetics of beta(2)AR agonist therapy for preterm labor. It appears that Arg16 homozygosity improves pregnancy outcome after beta(2)-agonist tocolysis. The relatively low frequency of Arg16 homozygotes in our population limited the power of this investigation. Future assessments of tocolytic therapy may need to assess beta(2)AR genotype.
Landau
Ruth
R
Division of Anesthesiology and Department of Obstetrics and Gynecology, University Hospital of Geneva, University of Geneva Medical School, Geneva, Switzerland. ruth.landau@hcuge.ch
Morales
Michel A
MA
Antonarakis
Stylianos E
SE
Blouin
Jean-Louis
JL
Smiley
Richard M
RM
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000627:therapeutic use; D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution / Q000235:genetics; D001120:Arginine / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005998:Glycine / Q000235:genetics; D006239:Haplotypes; D006594:Hexoprenaline / Q000008:administration & dosage / Q000627:therapeutic use*; D006720:Homozygote; D006801:Humans; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D007752:Obstetric Labor, Premature / Q000235:genetics / Q000517:prevention & control*; D011247:Pregnancy; D011256:Pregnancy Outcome; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D012127:Respiratory Distress Syndrome, Newborn / Q000235:genetics; D013610:Tachycardia / Q000235:genetics; D015145:Tocolysis / Q000379:methods; D015149:Tocolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D018343:Receptors, Adrenergic, beta-2; D015149:Tocolytic Agents; D001120:Arginine; D006594:Hexoprenaline; D005998:Glycine