title: Pharmacogenomics of 17-alpha hydroxyprogesterone caproate for recurrent preterm birth prevention.
abstract: OBJECTIVE
  We hypothesized that genetic variation affects responsiveness to 17-alpha hydroxyprogesterone caproate (17P) for recurrent preterm birth prevention.
  
  
  METHODS
  Women of European ancestry with ≥1 spontaneous singleton preterm birth at <34 weeks' gestation who received 17P were recruited prospectively and classified as a 17P responder or nonresponder by the difference in delivery gestational age between 17P-treated and -untreated pregnancies. Samples underwent whole exome sequencing. Coding variants were compared between responders and nonresponders with the use of the Variant Annotation, Analysis, and Search Tool (VAAST), which is a probabilistic search tool for the identification of disease-causing variants, and were compared with a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway candidate gene list. Genes with the highest VAAST scores were then classified by the online Protein ANalysis THrough Evolutionary Relationships (PANTHER) system into known gene ontology molecular functions and biologic processes. Gene distributions within these classifications were compared with an online reference population to identify over- and under- represented gene sets.
  
  
  RESULTS
  Fifty women (9 nonresponders) were included. Responders delivered 9.2 weeks longer with 17P vs 1.3 weeks' gestation for nonresponders (P < .001). A genome-wide search for genetic differences implicated the NOS1 gene to be the most likely associated gene from among genes on the KEGG candidate gene list (P < .00095). PANTHER analysis revealed several over-represented gene ontology categories that included cell adhesion, cell communication, signal transduction, nitric oxide signal transduction, and receptor activity (all with significant Bonferroni-corrected probability values).
  
  
  CONCLUSIONS
  We identified sets of over-represented genes in key processes among responders to 17P, which is the first step in the application of pharmacogenomics to preterm birth prevention.
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Intermountain Healthcare, Salt Lake City, UT; Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Manuck
authors.affiliation: Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: W Scott
authors.initials: WS
authors.lastname: Watkins
authors.affiliation: Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: Barry
authors.initials: B
authors.lastname: Moore
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Intermountain Healthcare, Salt Lake City, UT; Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: M Sean
authors.initials: MS
authors.lastname: Esplin
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Intermountain Healthcare, Salt Lake City, UT; Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Varner
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Intermountain Healthcare, Salt Lake City, UT; Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: G Marc
authors.initials: GM
authors.lastname: Jackson
authors.affiliation: Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: Mark
authors.initials: M
authors.lastname: Yandell
authors.affiliation: Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: Lynn
authors.initials: L
authors.lastname: Jorde
mesh_terms: D000077713:17 alpha-Hydroxyprogesterone Caproate; D016022:Case-Control Studies; D004965:Estrogen Antagonists / Q000008:administration & dosage*; D059472:Exome; D005260:Female; D014644:Genetic Variation; D006801:Humans; D006908:Hydroxyprogesterones / Q000008:administration & dosage*; D019001:Nitric Oxide Synthase / Q000235:genetics; D052248:Nitric Oxide Synthase Type I / Q000235:genetics; D010597:Pharmacogenetics; D011247:Pregnancy; D047928:Premature Birth / Q000517:prevention & control*; D011446:Prospective Studies; D055502:Secondary Prevention; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: D004965:Estrogen Antagonists; D006908:Hydroxyprogesterones; D000077713:17 alpha-Hydroxyprogesterone Caproate; C496320:NOS1 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I
keywords: pharmacogenomics; progesterone; spontaneous preterm birth