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The association among cytochrome P450 3A, progesterone receptor polymorphisms, plasma 17-alpha hydroxyprogesterone caproate concentrations, and spontaneous preterm birth.
Am J Obstet Gynecol. 2017 09; 217(3):369.e1-369.e9.AJ

Abstract

BACKGROUND

Infants born <37 weeks' gestation are of public health concern since complications associated with preterm birth are the leading cause of mortality in children <5 years of age and a major cause of morbidity and lifelong disability. The administration of 17-alpha hydroxyprogesterone caproate reduces preterm birth by 33% in women with history of spontaneous preterm birth. We demonstrated previously that plasma concentrations of 17-alpha hydroxyprogesterone caproate vary widely among pregnant women and that women with 17-alpha hydroxyprogesterone caproate plasma concentrations in the lowest quartile had spontaneous preterm birth rates of 40% vs rates of 25% in those women with higher concentrations. Thus, plasma concentrations are an important factor in determining drug efficacy but the reason 17-alpha hydroxyprogesterone caproate plasma concentrations vary so much is unclear. Predominantly, 17-alpha hydroxyprogesterone caproate is metabolized by CYP3A4 and CYP3A5 enzymes.

OBJECTIVE

We sought to: (1) determine the relation between 17-alpha hydroxyprogesterone caproate plasma concentrations and single nucleotide polymorphisms in CYP3A4 and CYP3A5; (2) test the association between progesterone receptor single nucleotide polymorphisms and spontaneous preterm birth; and (3) test whether the association between plasma concentrations of 17-alpha hydroxyprogesterone caproate and spontaneous preterm birth varied by progesterone receptor single nucleotide polymorphisms.

STUDY DESIGN

In this secondary analysis, we evaluated genetic polymorphism in 268 pregnant women treated with 17-alpha hydroxyprogesterone caproate, who participated in a placebo-controlled trial to evaluate the benefit of omega-3 supplementation in women with history of spontaneous preterm birth. Trough plasma concentrations of 17-alpha hydroxyprogesterone caproate were measured between 25-28 weeks of gestation after a minimum of 5 injections of 17-alpha hydroxyprogesterone caproate. We extracted DNA from maternal blood samples and genotyped the samples using TaqMan (Applied Biosystems, Foster City, CA) single nucleotide polymorphism genotyping assays for the following single nucleotide polymorphisms: CYP3A4*1B, CYP3A4*1G, CYP3A4*22, and CYP3A5*3; and rs578029, rs471767, rs666553, rs503362, and rs500760 for progesteronereceptor. We adjusted for prepregnancy body mass index, race, and treatment group in a multivariable analysis. Differences in the plasma concentrations of 17-alpha hydroxyprogesterone caproate by genotype were evaluated for each CYP single nucleotide polymorphism using general linear models. The association between progesterone receptor single nucleotide polymorphisms and frequency of spontaneous preterm birth was tested using logistic regression. A logistic model also tested interaction between 17-alpha hydroxyprogesterone caproate concentrations with each progesterone receptor single nucleotide polymorphism for the outcome of spontaneous preterm birth.

RESULTS

The association between CYP single nucleotide polymorphisms *22, *1G, *1B, and *3 and trough plasma concentrations of 17-alpha hydroxyprogesterone caproate was not statistically significant (P = .68, .44, .08, and .44, respectively). In an adjusted logistic regression model, progesterone receptor single nucleotide polymorphisms rs578029, rs471767, rs666553, rs503362, and rs500760 were not associated with the frequency of spontaneous preterm birth (P = .29, .10, .76, .09, and .43, respectively). Low trough plasma concentrations of 17-alpha hydroxyprogesterone caproate were statistically associated with a higher frequency of spontaneous preterm birth (odds ratio, 0.78; 95% confidence ratio, 0.61-0.99; P = .04 for trend across quartiles), however no significant interaction with the progesterone receptor single nucleotide polymorphisms rs578029, rs471767, rs666553, rs503362, and rs500760 was observed (P = .13, .08, .10, .08, and .13, respectively).

CONCLUSION

The frequency of recurrent spontaneous preterm birth appears to be associated with trough 17-alpha hydroxyprogesterone caproate plasma concentrations. However, the wide variation in trough 17-alpha hydroxyprogesterone caproate plasma concentrations is not attributable to polymorphisms in CYP3A4 and CYP3A5 genes. Progesterone receptor polymorphisms do not predict efficacy of 17-alpha hydroxyprogesterone caproate. The limitations of this secondary analysis include that we had a relative small sample size (n = 268) and race was self-reported by the patients.

Authors+Show Affiliations

Department of Obstetrics and Gynecology at University of Pittsburgh, Pittsburgh, PA.Department of Obstetrics and Gynecology at University of Pittsburgh, Pittsburgh, PA. Electronic address: carisn@mail.magee.edu.George Washington University Biostatistics Center, Washington, DC.Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD.Wayne State University, Detroit, MI.University of North Carolina at Chapel Hill, Chapel Hill, NC.University of Utah Health Sciences Center, Salt Lake City, UT.Columbia University, New York, NY.Ohio State University, Columbus, OH.Women and Infants Hospital, Brown University, Providence, RI.Northwestern University, Chicago, IL.Case Western Reserve University-MetroHealth Medical Center, Cleveland, OH.Drexel University College of Medicine, Philadelphia, PA.University of Alabama at Birmingham, Birmingham, AL.University of Texas Health Science Center at Houston, Houston, TX.No affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28522317

Citation

Bustos, Martha L., et al. "The Association Among Cytochrome P450 3A, Progesterone Receptor Polymorphisms, Plasma 17-alpha Hydroxyprogesterone Caproate Concentrations, and Spontaneous Preterm Birth." American Journal of Obstetrics and Gynecology, vol. 217, no. 3, 2017, pp. 369.e1-369.e9.
Bustos ML, Caritis SN, Jablonski KA, et al. The association among cytochrome P450 3A, progesterone receptor polymorphisms, plasma 17-alpha hydroxyprogesterone caproate concentrations, and spontaneous preterm birth. Am J Obstet Gynecol. 2017;217(3):369.e1-369.e9.
Bustos, M. L., Caritis, S. N., Jablonski, K. A., Reddy, U. M., Sorokin, Y., Manuck, T., Varner, M. W., Wapner, R. J., Iams, J. D., Carpenter, M. W., Peaceman, A. M., Mercer, B. M., Sciscione, A., Rouse, D. J., & Ramin, S. M. (2017). The association among cytochrome P450 3A, progesterone receptor polymorphisms, plasma 17-alpha hydroxyprogesterone caproate concentrations, and spontaneous preterm birth. American Journal of Obstetrics and Gynecology, 217(3), e1-e9. https://doi.org/10.1016/j.ajog.2017.05.019
Bustos ML, et al. The Association Among Cytochrome P450 3A, Progesterone Receptor Polymorphisms, Plasma 17-alpha Hydroxyprogesterone Caproate Concentrations, and Spontaneous Preterm Birth. Am J Obstet Gynecol. 2017;217(3):369.e1-369.e9. PubMed PMID: 28522317.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The association among cytochrome P450 3A, progesterone receptor polymorphisms, plasma 17-alpha hydroxyprogesterone caproate concentrations, and spontaneous preterm birth. AU - Bustos,Martha L, AU - Caritis,Steve N, AU - Jablonski,Kathleen A, AU - Reddy,Uma M, AU - Sorokin,Yoram, AU - Manuck,Tracy, AU - Varner,Michael W, AU - Wapner,Ronald J, AU - Iams,Jay D, AU - Carpenter,Marshall W, AU - Peaceman,Alan M, AU - Mercer,Brian M, AU - Sciscione,Anthony, AU - Rouse,Dwight J, AU - Ramin,Susan M, AU - ,, Y1 - 2017/05/15/ PY - 2017/03/03/received PY - 2017/05/07/accepted PY - 2017/5/20/pubmed PY - 2017/9/19/medline PY - 2017/5/20/entrez KW - 17-alpha hydroxyprogesterone caproate KW - CYP3A4 KW - CYP3A5 and progesterone receptor KW - prematurity KW - single nucleotide polymorphisms KW - spontaneous preterm birth SP - 369.e1 EP - 369.e9 JF - American journal of obstetrics and gynecology JO - Am J Obstet Gynecol VL - 217 IS - 3 N2 - BACKGROUND: Infants born <37 weeks' gestation are of public health concern since complications associated with preterm birth are the leading cause of mortality in children <5 years of age and a major cause of morbidity and lifelong disability. The administration of 17-alpha hydroxyprogesterone caproate reduces preterm birth by 33% in women with history of spontaneous preterm birth. We demonstrated previously that plasma concentrations of 17-alpha hydroxyprogesterone caproate vary widely among pregnant women and that women with 17-alpha hydroxyprogesterone caproate plasma concentrations in the lowest quartile had spontaneous preterm birth rates of 40% vs rates of 25% in those women with higher concentrations. Thus, plasma concentrations are an important factor in determining drug efficacy but the reason 17-alpha hydroxyprogesterone caproate plasma concentrations vary so much is unclear. Predominantly, 17-alpha hydroxyprogesterone caproate is metabolized by CYP3A4 and CYP3A5 enzymes. OBJECTIVE: We sought to: (1) determine the relation between 17-alpha hydroxyprogesterone caproate plasma concentrations and single nucleotide polymorphisms in CYP3A4 and CYP3A5; (2) test the association between progesterone receptor single nucleotide polymorphisms and spontaneous preterm birth; and (3) test whether the association between plasma concentrations of 17-alpha hydroxyprogesterone caproate and spontaneous preterm birth varied by progesterone receptor single nucleotide polymorphisms. STUDY DESIGN: In this secondary analysis, we evaluated genetic polymorphism in 268 pregnant women treated with 17-alpha hydroxyprogesterone caproate, who participated in a placebo-controlled trial to evaluate the benefit of omega-3 supplementation in women with history of spontaneous preterm birth. Trough plasma concentrations of 17-alpha hydroxyprogesterone caproate were measured between 25-28 weeks of gestation after a minimum of 5 injections of 17-alpha hydroxyprogesterone caproate. We extracted DNA from maternal blood samples and genotyped the samples using TaqMan (Applied Biosystems, Foster City, CA) single nucleotide polymorphism genotyping assays for the following single nucleotide polymorphisms: CYP3A4*1B, CYP3A4*1G, CYP3A4*22, and CYP3A5*3; and rs578029, rs471767, rs666553, rs503362, and rs500760 for progesteronereceptor. We adjusted for prepregnancy body mass index, race, and treatment group in a multivariable analysis. Differences in the plasma concentrations of 17-alpha hydroxyprogesterone caproate by genotype were evaluated for each CYP single nucleotide polymorphism using general linear models. The association between progesterone receptor single nucleotide polymorphisms and frequency of spontaneous preterm birth was tested using logistic regression. A logistic model also tested interaction between 17-alpha hydroxyprogesterone caproate concentrations with each progesterone receptor single nucleotide polymorphism for the outcome of spontaneous preterm birth. RESULTS: The association between CYP single nucleotide polymorphisms *22, *1G, *1B, and *3 and trough plasma concentrations of 17-alpha hydroxyprogesterone caproate was not statistically significant (P = .68, .44, .08, and .44, respectively). In an adjusted logistic regression model, progesterone receptor single nucleotide polymorphisms rs578029, rs471767, rs666553, rs503362, and rs500760 were not associated with the frequency of spontaneous preterm birth (P = .29, .10, .76, .09, and .43, respectively). Low trough plasma concentrations of 17-alpha hydroxyprogesterone caproate were statistically associated with a higher frequency of spontaneous preterm birth (odds ratio, 0.78; 95% confidence ratio, 0.61-0.99; P = .04 for trend across quartiles), however no significant interaction with the progesterone receptor single nucleotide polymorphisms rs578029, rs471767, rs666553, rs503362, and rs500760 was observed (P = .13, .08, .10, .08, and .13, respectively). CONCLUSION: The frequency of recurrent spontaneous preterm birth appears to be associated with trough 17-alpha hydroxyprogesterone caproate plasma concentrations. However, the wide variation in trough 17-alpha hydroxyprogesterone caproate plasma concentrations is not attributable to polymorphisms in CYP3A4 and CYP3A5 genes. Progesterone receptor polymorphisms do not predict efficacy of 17-alpha hydroxyprogesterone caproate. The limitations of this secondary analysis include that we had a relative small sample size (n = 268) and race was self-reported by the patients. SN - 1097-6868 UR - https://www.unboundmedicine.com/medline/citation/28522317/The_association_among_cytochrome_P450_3A_progesterone_receptor_polymorphisms_plasma_17_alpha_hydroxyprogesterone_caproate_concentrations_and_spontaneous_preterm_birth_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-9378(17)30628-2 DB - PRIME DP - Unbound Medicine ER -