European Journal of Clinical Pharmacology

, Volume 75, Issue 10, pp 1379–1386 | Cite as

Effects of PDE4 gene polymorphisms on efficacy and adverse drug events of ritodrine therapy in preterm labor patients: a prospective observational study

  • Jeong Yee
  • Han Sung Hwang
  • Jee Eun Chung
  • Jin Young Park
  • Kyung Eun Lee
  • Young Ju KimEmail author
  • Hye Sun GwakEmail author



Phosphodiesterase (PDE) terminates the signaling pathway of myometrial relaxation by degradating cAMP to the inactive 5′-AMP. The PDE4 family is one of the most predominant PDE families that display high affinity to cAMP. The objective of this study was to evaluate the effects of PDE4 gene polymorphisms on tocolytic effects and adverse drug events (ADEs) of ritodrine therapy in patients with preterm labor.


A total of 170 preterm labor patients were included in this study. To elucidate the effects of genetic polymorphisms on the inter-individual variability of ritodrine efficacy and ADEs, 8 single nucleotide polymorphisms (SNPs) were genotyped: PDE4D (rs1544791, rs983280, rs1504982, rs10940648, rs829259) and PDE4B2 (rs598961, rs2180335, and rs17128809). Additionally, rs1042719 of the ADRB2 gene was included for multivariate analysis. The primary endpoint of this prospective study was the time to delivery (hr). The secondary endpoint was ritodrine-induced ADEs.


The mutant-type homozygote carriers of PDE4B2 rs598961 polymorphism showed shorter median time to delivery than those with other genotypes (adjusted hazard ratio 1.6, 95% confidence interval 1.0 to 2.4, P = 0.035). On the other hand, patients with wild-type homozygotes of PDE4B2 rs17128809 showed 2.6~2.9 times higher ADEs compared to those with other genotypes. Among demographic characteristics, gestational age at start of drug therapy and modified Bishop score were significant factors for time to delivery, whereas height, weight, and BSA were significant factors for ritodrine-induced ADEs after adjusting other factors.


This pharmacogenomic study suggested that PDE4 genetic polymorphisms impact individual susceptibility to β2-adrenergic receptor targeted therapy in patients with preterm labor.


Ritodrine Preterm labor Phosphodiesterase 4D gene Phosphodiesterase 4B2 gene Single nucleotide polymorphism Time to delivery Adverse drug events 


Sources of funding

This work was supported by the National Research Foundation of Korea (NRF) grant (No. NRF-2010-0022544) funded by the Korea Government (MEST), the Korea Health Industry Development Institute (KHIDI) (No. HI14C0306) funded by the Ministry of Health and Welfare, and the Ewha Womans University scholarship of 2018.

Authors’ contributions

All authors have contributed significantly to the work and have read and approved the manuscript for publication. H. H, Y. K., and H. G. were responsible for the study concept and design. J. Y. and J. P participated in data collection. J.Y., J. C., and K. L. analyzed the data. J. Y., Y. K., and H. S. contributed to the manuscript writing and discussion.

Compliance with ethical standards

This study was approved by Ethics Committee of the Ewha Womans University Mokdong Hospital Institutional Review Board (IRB No.: 217-1-26)

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

228_2019_2719_MOESM1_ESM.docx (197 kb)
ESM 1 (DOCX 196 kb)


  1. 1.
    Report of a WHO Expert Committee (1970) The prevention of perinatal mortality and morbidity. World Health Organ Tech Rep Ser 457:1–60Google Scholar
  2. 2.
    Scheid CR, Honeyman TW, Fay FS (1979) Mechanism of beta-adrenergic relaxation of smooth muscle. Nature 277:32–36CrossRefGoogle Scholar
  3. 3.
    Park JY, Lee NR, Lee KE, Park S, Kim YJ, Gwak HS (2014) Effects of beta2-adrenergic receptor gene polymorphisms on ritodrine therapy in pregnant women with preterm labor: prospective follow-up study. Int J Mol Sci 15:12885–12894CrossRefGoogle Scholar
  4. 4.
    Yuan W, Bernal AL (2007) Cyclic AMP signalling pathways in the regulation of uterine relaxation. BMC Pregnancy Childbirth 7:S10CrossRefGoogle Scholar
  5. 5.
    Mehats C, Tanguy G, Dallot E, Robert B, Rebourcet R, Ferre F et al (1999) Selective up-regulation of phosphodiesterase-4 cyclic adenosine 3′,5′-monophosphate (cAMP)-specific phosphodiesterase variants by elevated cAMP content in human myometrial cells in culture. Endocrinology 140:3228–3237CrossRefGoogle Scholar
  6. 6.
    Leroy MJ, Méhats C, Duc-Goiran P, Tanguy G, Robert B, Dallot E, Mignot TM, Grangé G, Ferré F (1999) Effect of pregnancy on PDE4 cAMP-specific phosphodiesterase messenger ribonucleic acid expression in human myometrium. Cell Signal 11:31–37CrossRefGoogle Scholar
  7. 7.
    Bruss MD, Richter W, Horner K, Jin SL, Conti M (2008) Critical role of PDE4D in beta2-adrenoceptor-dependent cAMP signaling in mouse embryonic fibroblasts. J Biol Chem 283:22430–22442CrossRefGoogle Scholar
  8. 8.
    Trian T, Burgess JK, Niimi K, Moir LM, Ge Q, Berger P, Liggett SB, Black JL, Oliver BG (2011) Beta2-agonist induced cAMP is decreased in asthmatic airway smooth muscle due to increased PDE4D. PLoS One 6:e20000CrossRefGoogle Scholar
  9. 9.
    Fatemi SH, King DP, Reutimaqn TJ, Folsom TD, Laurence JA, Fan Y et al (2008) PDE4B polymorphisms and decreased PDE4B expression are associated with schizophrenia. Schizophr Res 101:36–49CrossRefGoogle Scholar
  10. 10.
    Leroy MJ, Cedrin I, Breuiller M, Giovagrandi Y, Ferre F (1989) Correlation between selective inhibition of the cyclic nucleotide phosphodiesterases and the contractile activity in human pregnant myometrium near term. Biochem Pharmacol 38:9–15CrossRefGoogle Scholar
  11. 11.
    Schmitz T, Souil E, Herve R, Nicco C, Batteux F, Germain G et al (2007) PDE4 inhibition prevents preterm delivery induced by an intrauterine inflammation. J Immunol 178:1115–1121CrossRefGoogle Scholar
  12. 12.
    Omori K, Kotera J (2007) Overview of PDEs and their regulation. Circ Res 100:309–327CrossRefGoogle Scholar
  13. 13.
    Willoughby D, Baillie GS, Lynch MJ, Ciruela A, Houslay MD, Cooper DM (2007) Dynamic regulation, desensitization, and cross-talk in discrete subcellular microdomains during beta2-adrenoceptor and prostanoid receptor cAMP signaling. J Biol Chem 282:34235–34249CrossRefGoogle Scholar
  14. 14.
    Labuda M, Laberge S, Brière J, Bérubé D, Beaulieu P, Pastinen T et al (2011) Phosphodiesterase type 4D gene polymorphism: association with the response to short-acting bronchodilators in paediatric asthma patients. Mediat Inflamm 2011:301695CrossRefGoogle Scholar
  15. 15.
    Numata S, Ueno S, Iga J, Song H, Nakataki M, Tayoshi S et al (2008) Positive association of the PDE4B (phosphodiesterase 4B) gene with schizophrenia in the Japanese population. J Psychiatr Res 43:7–12CrossRefGoogle Scholar
  16. 16.
    Feng Y, Cheng D, Zhang C, Li Y, Zhang Z, Wang J, Shi Y (2016) Association of PDE4B polymorphisms with susceptibility to schizophrenia: a meta-analysis of case-control studies. PLoS One 11:e0147092CrossRefGoogle Scholar
  17. 17.
    Ward LD, Kellis M (2012) HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 40:D930–D934CrossRefGoogle Scholar
  18. 18.
    Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229CrossRefGoogle Scholar
  19. 19.
    Rozenberg P, Rudant J, Chevret S, Boulogne AI, Ville Y (2004) Repeat measurement of cervical length after successful tocolysis. Obstet Gynecol 104:995–999CrossRefGoogle Scholar
  20. 20.
    Abdel-Latif AA (2001) Cross talk between cyclic nucleotides and polyphosphoinositide hydrolysis, protein kinases, and contraction in smooth muscle. Exp Biol Med 226:153–163CrossRefGoogle Scholar
  21. 21.
    Verli J, Klukovits A, Kormányos Z, Hajagos-Tóth J, Ducza E, Seres AB, Falkay G, Gáspár R (2013) Uterus-relaxing effect of beta2-agonists in combination with phosphodiesterase inhibitors: studies on pregnant rat in vivo and on pregnant human myometrium in vitro. J Obstet Gynaecol Res 39:31–39CrossRefGoogle Scholar
  22. 22.
    Méhats C, Schmitz T, Oger S, Hervé R, Cabrol D, Leroy M (2007) PDE4 as a target in preterm labour. BMC Pregnancy Childbirth 7:S10CrossRefGoogle Scholar
  23. 23.
    Himes BE, Hunninghake GM, Baurley JW, Rafaels NM, Sleiman P, Strachan DP, Wilk JB, Willis-Owen SAG, Klanderman B, Lasky-Su J, Lazarus R, Murphy AJ, Soto-Quiros ME, Avila L, Beaty T, Mathias RA, Ruczinski I, Barnes KC, Celedón JC, Cookson WOC, Gauderman WJ, Gilliland FD, Hakonarson H, Lange C, Moffatt MF, O'Connor GT, Raby BA, Silverman EK, Weiss ST (2009) Genome-wide association analysis identifies PDE4D as an asthma-susceptibility gene. Am J Hum Genet 84:581–593CrossRefGoogle Scholar
  24. 24.
    Raponi M, Baralle D (2010) Alternative splicing: good and bad effects of translationally silent substitutions. FEBS J 277:836–840CrossRefGoogle Scholar
  25. 25.
    Pagani F, Baralle FE (2004) Genomic variants in exons and introns: identifying the splicing spoilers. Nat Rev Genet 5:389–396CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.College of Pharmacy and Division of Life & Pharmaceutical SciencesEwha Womans UniversitySeoulRepublic of Korea
  2. 2.Department of Obstetrics and Gynecology, Konkuk University Medical CenterKonkuk University School of MedicineSeoulSouth Korea
  3. 3.College of Pharmacy and Institute of Pharmaceutical Science and TechnologyHanyang UniversityAnsanSouth Korea
  4. 4.College of PharmacyChungbuk National UniversityCheongjuSouth Korea
  5. 5.Department of Obstetrics and GynecologyEwha Womans University School of MedicineSeoulRepublic of Korea

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