title: Pharmacogenomics of 17-alpha hydroxyprogesterone caproate for recurrent preterm birth: a case-control study.
abstract: 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).
  
  
  
  Case-control.
  
  
  
  Three tertiary-care centres across the USA.
  
  
  
  Women (n = 99) with ≥ 1 prior singleton spontaneous PTB, receiving 17-P.
  
  
  
  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).
  
  
  
  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).
  
  
  
  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).
  
  
  
  A novel analytic approach revealed several genetic differences among women delivering early vs later with 17-P.
  
  
  
  Several key genetic differences are present in women with recurrent preterm birth despite 17-P treatment.
authors.affiliation: Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.|Intermountain Healthcare Department of Maternal Fetal Medicine, Salt Lake City, UT, USA.|Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Manuck
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
authors.forename: W S
authors.initials: WS
authors.lastname: Watkins
authors.affiliation: Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.|Intermountain Healthcare Department of Maternal Fetal Medicine, Salt Lake City, UT, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Esplin
authors.affiliation: Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine and Center for Women's Reproductive Health, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Biggio
authors.affiliation: Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Bukowski
authors.affiliation: Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Parry
authors.affiliation: Collaborative Center for Statistics in Science, Yale University School of Public Health, New Haven, CT, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhan
authors.affiliation: Collaborative Center for Statistics in Science, Yale University School of Public Health, New Haven, CT, USA.
authors.forename: H
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine and Center for Women's Reproductive Health, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: W
authors.initials: W
authors.lastname: Andrews
authors.affiliation: Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Saade
authors.affiliation: Magee-Womens Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Sadovsky
authors.affiliation: Pregnancy and Perinatology Branch, Center for Developmental Biology and Perinatal Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
authors.forename: U M
authors.initials: UM
authors.lastname: Reddy
authors.affiliation: Pregnancy and Perinatology Branch, Center for Developmental Biology and Perinatal Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ilekis
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
authors.forename: M
authors.initials: M
authors.lastname: Yandell
authors.affiliation: Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.|Intermountain Healthcare Department of Maternal Fetal Medicine, Salt Lake City, UT, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Varner
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
authors.forename: L B
authors.initials: LB
authors.lastname: Jorde
mesh_terms: D000077713:17 alpha-Hydroxyprogesterone Caproate / Q000627:therapeutic use*; D000328:Adult; D000704:Analysis of Variance; D016022:Case-Control Studies; D005260:Female; D005865:Gestational Age; D006801:Humans; D010597:Pharmacogenetics; D011247:Pregnancy; D011256:Pregnancy Outcome / Q000453:epidemiology; D047928:Premature Birth / Q000453:epidemiology / Q000235:genetics / Q000517:prevention & control; D011372:Progestins / Q000627:therapeutic use; D012008:Recurrence; D014481:United States / Q000453:epidemiology; D000073359:Exome Sequencing / Q000379:methods / Q000706:statistics & numerical data
chemical_list: D011372:Progestins; D000077713:17 alpha-Hydroxyprogesterone Caproate
keywords: 17-Alpha hydroxyprogesterone caproate; current preterm birth; pharmacogenomics; spontaneous prematurity