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 Kim; Hye Sun Gwak

doi:10.1007/s00228-019-02719-9

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 Kim, Hye Sun Gwak

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

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

Original language	English
Pages (from-to)	1379-1386
Number of pages	8
Journal	European Journal of Clinical Pharmacology
Volume	75
Issue number	10
DOIs	https://doi.org/10.1007/s00228-019-02719-9
State	Published - 1 Oct 2019

Bibliographical note

Funding Information:
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.

Funding Information:
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.

Publisher Copyright:
© 2019, Springer-Verlag GmbH Germany, part of Springer Nature.

Keywords

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

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10.1007/s00228-019-02719-9

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@article{5a02e428c6ad4289b57e0a31eb719341,

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

abstract = "Purpose: 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. Methods: 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. Results: 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. Conclusions: This pharmacogenomic study suggested that PDE4 genetic polymorphisms impact individual susceptibility to β2-adrenergic receptor targeted therapy in patients with preterm labor.",

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

author = "Jeong Yee and Hwang, {Han Sung} and Chung, {Jee Eun} and Park, {Jin Young} and Lee, {Kyung Eun} and Kim, {Young Ju} and Gwak, {Hye Sun}",

note = "Funding Information: 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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2019, Springer-Verlag GmbH Germany, part of Springer Nature.",

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doi = "10.1007/s00228-019-02719-9",

language = "English",

volume = "75",

pages = "1379--1386",

journal = "European Journal of Clinical Pharmacology",

issn = "0031-6970",

publisher = "Springer Verlag",

number = "10",

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TY - JOUR

T1 - Effects of PDE4 gene polymorphisms on efficacy and adverse drug events of ritodrine therapy in preterm labor patients

T2 - a prospective observational study

AU - Yee, Jeong

AU - Hwang, Han Sung

AU - Chung, Jee Eun

AU - Park, Jin Young

AU - Lee, Kyung Eun

AU - Kim, Young Ju

AU - Gwak, Hye Sun

N1 - Funding Information: 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. Funding Information: 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. Publisher Copyright: © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Purpose: 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. Methods: 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. Results: 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. Conclusions: This pharmacogenomic study suggested that PDE4 genetic polymorphisms impact individual susceptibility to β2-adrenergic receptor targeted therapy in patients with preterm labor.

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

KW - Adverse drug events

KW - Phosphodiesterase 4B2 gene

KW - Phosphodiesterase 4D gene

KW - Preterm labor

KW - Ritodrine

KW - Single nucleotide polymorphism

KW - Time to delivery

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DO - 10.1007/s00228-019-02719-9

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JF - European Journal of Clinical Pharmacology

IS - 10

ER -

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

Abstract

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Keywords

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