530: Next generation sequencing identifies the IL-12 receptor beta gene as a potential mediator in the response to 17-alpha-hydroxyprogesterone caproate for the prevention of recurrent prematurity

receptor beta gene as a potential mediator in the response to 17-alpha-hydroxyprogesterone caproate for the prevention of recurrent prematurity Tracy Manuck, Scott Watkins, Sean Esplin, Marc Jackson, Lynn Jorde, Michael Varner University of Utah, Obstetrics and Gynecology, Salt Lake City, UT, University of Utah, Human Genetics, Salt Lake City, UT, Intermountain Healthcare, Maternal Fetal Medicine, Salt Lake City, UT OBJECTIVE: 17-alpha-hydroxyprogesterone caproate (17P) reduces recurrent preterm birth (PTB) in some, but not all, women. We hypothesized that genetic polymorphisms affect variable response to 17P. STUDY DESIGN: Women with a history of 1 spontaneous singleton PTB 34 wks who received weekly 17P were recruited prospectively from a prematurity prevention clinic from 2008-2010. Women were classified as a 17P responder or non-responder based on the difference in delivery gestational age (GA) between their 17P treated and untreated pregnancy/pregnancies. Whole exome sequencing was performed using Illumina® HiSeq2000 next generation technology. Each individual was sequenced for 180,000 protein-coding exons. Genomes were compared between responders and non-responders using the Variant Annotation, Analysis & Search Tool (VAAST), a probabilistic search tool for identifying disease causing variants in personal genome sequences. Genome-wide significance was set at p 2.4x10. RESULTS: 24 women (19 responders, 5 non-responders), all Caucasian, were included. Responder and non-responder groups did not differ with regards to median number of pregnancies (3 vs. 4, p 0.67), history of cervical insufficiency (26% vs. 20%, p 0.77), or history of PPROM (32% vs. 40%, p 0.72). The GA of each woman’s earliest PTB also did not differ (27.9 vs. 29.7 wks, p 0.35), but responders achieved 9.1 wks longer with 17P, vs. 1.5 wks for nonresponders (p 0.001). All samples met genotype quality filters. The average genome-wide coverage depth was 47.3 (range 20.1-64.6). We assumed recessive inheritance and locus heterogeneity. VAAST identified IL12RB1 (Interleukin-12 receptor beta) as associated with nonresponse to 17P (p 3.03 10 ). CONCLUSION: Response to 17P for the prevention of recurrent PTB may be genetically mediated. These results should be confirmed in a larger cohort and may lead to the development of a ‘17P response panel.’