Pharmacogenomics of 17-alpha hydroxyprogesterone caproate for recurrent preterm birth: A case-control study

T. A. Manuck, W. S. Watkins, M. S. Esplin, J. Biggio, R. Bukowski, S. Parry, H. Zhan, H. Huang, W. Andrews, George Saade, Y. Sadovsky, U. M. Reddy, J. Ilekis, M. Yandell, M. W. Varner, L. B. Jorde

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Abstract

Objective: To compare maternal genotypes between women with and without significant prolongation of pregnancy in the setting of 17-alpha hydroxyprogesterone caproate (17-P) administration for the prevention of recurrent preterm birth (PTB). Design: Case-control. Setting: Three tertiary-care centres across the USA. Population: Women (n = 99) with ≥ 1 prior singleton spontaneous PTB, receiving 17-P. Methods: Women were classified as having successful prolongation of pregnancy during the 17-P treated pregnancy, in two ways: (1) Definition A: success/non-success based on difference in gestational age at delivery between 17-P-treated and untreated pregnancies (success: delivered ≥ 3 weeks later with 17-P) and (2) Definition B: success/non-success based on reaching term (success: delivered at term with 17-P). Main outcome measures: To assess genetic variation, all women underwent whole exome sequencing. Between-group sequence variation was analysed with the Variant Annotation, Analysis, and Search Tool (VAAST). Genes scored by VAAST with P < 0.05 were then analysed with two online tools: (1) Protein ANalysis THrough Evolutionary Relationships (PANTHER) and (2) Database for Annotation, Visualization, and Integrated Discovery (DAVID). Results: Using Definition A, there were 70 women with successful prolongation and 29 without; 1375 genes scored by VAAST had P < 0.05. Using Definition B, 47 women had successful prolongation and 52 did not; 1039 genes scored by VAAST had P < 0.05. PANTHER revealed key differences in gene ontology pathways. Many genes from definition A were classified as prematurity genes (P = 0.026), and those from definition B as pharmacogenetic genes (P = 0.0018); (P, non-significant after Bonferroni correction). Conclusion: A novel analytic approach revealed several genetic differences among women delivering early vs later with 17-P. Tweetable abstract: Several key genetic differences are present in women with recurrent preterm birth despite 17-P treatment.

Original languageEnglish (US)
JournalBJOG: An International Journal of Obstetrics and Gynaecology
DOIs
StateAccepted/In press - 2017

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Keywords

  • 17-Alpha hydroxyprogesterone caproate
  • Current preterm birth
  • Pharmacogenomics
  • Spontaneous prematurity

ASJC Scopus subject areas

  • Obstetrics and Gynecology

Cite this

Manuck, T. A., Watkins, W. S., Esplin, M. S., Biggio, J., Bukowski, R., Parry, S., Zhan, H., Huang, H., Andrews, W., Saade, G., Sadovsky, Y., Reddy, U. M., Ilekis, J., Yandell, M., Varner, M. W., & Jorde, L. B. (Accepted/In press). Pharmacogenomics of 17-alpha hydroxyprogesterone caproate for recurrent preterm birth: A case-control study. BJOG: An International Journal of Obstetrics and Gynaecology. https://doi.org/10.1111/1471-0528.14485