12: Genetic variation may influence response to 17-alpha hydroxyprogesterone caproate (17P) for recurrent preterm birth (PTB) prevention


      We hypothesized that maternal genotype affects variable response to 17P for recurrent PTB prevention.

      Study Design

      Secondary analysis of the GPN prospective multicenter cohort study of PTB. Women (n=106) with ≥1 prior singleton SPTB who received 17P during pregnancy were classified as 17P responders (RES) or non-responders (NRES) in 2 ways: (A) a difference in delivery gestational age (GA) between 17P treated and untreated pregnancies (RES=delivered ≥3 weeks later w/17P vs. without 17P), and (B) Term vs. PTB in the studied pregnancies (RES=delivered ≥37 weeks w/17P). To assess genetic variation, all women were exome sequenced. Between-group sequence variation was analyzed with the Variant Annotation, Analysis & Search Tool (VAAST) using a recessive inheritance model with locus heterogeneity. Genes scored by VAAST with p<0.05 were then analyzed with 2 online tools: 1) Protein Analysis Through Evolutionary Relationships (PANTHER), and 2) Database for Annotation, Visualization, and Integrated Discovery (DAVID). These tools group genes into gene sets, pathways, and gene ontology (GO) groups. They assess over-/under- representation (PANTHER and DAVID) and gene groupings including known disease associations (DAVID).


      RES and NRES, regardless of definition A or B, had similar ancestry (50% European) and PTB histories. Using definition A, there were 70 RES and 36 NRES; 797 genes scored by VAAST had p<0.05. Using definition B, there were 47 RES and 59 NRES; 957 genes scored by VAAST had p<0.05. PANTHER revealed that more genes are categorized into GO Transporter Activity and Receptor Activity groups than expected by chance (Table 1). ∼20% of genes had previous disease associations and were classified by DAVID into disease groups (Table 2). DAVID results were non-significant after Bonferroni correction, but the power to detect association was limited by the small sample size.


      A novel analytic approach revealed several genetic differences among 17P RES, and highlighted genes in pathways suspected in PTB pathogenesis. Results vary by the definition of 17P RES, emphasizing the importance of refining the definition of a 17P responder. These results provide additional evidence for the role of pharmacogenomics in the variable response to 17P for recurrent PTB prevention.
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