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Pharmacogenomics of 17-Alpha Hydroxyprogesterone Caproate for Recurrent Preterm Birth Prevention Tracy A

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Research www.AJOG.org OBSTETRICS Pharmacogenomics of 17-alpha hydroxyprogesterone caproate for recurrent preterm birth prevention Tracy A. Manuck, MD; W. Scott Watkins, MS; Barry Moore, MS; M. Sean Esplin, MD; Michael W. Varner, MD; G. Marc Jackson, MD; Mark Yandell, PhD; Lynn Jorde, PhD OBJECTIVE: We hypothesized that genetic variation affects respon- classifications were compared with an online reference population to siveness to 17-alpha hydroxyprogesterone caproate (17P) for recur- identify over- and under- represented gene sets. rent preterm birth prevention. RESULTS: Fifty women (9 nonresponders) were included. Responders STUDY DESIGN: Women of European ancestry with 1 spontaneous delivered 9.2 weeks longer with 17P vs 1.3 weeks’ gestation for singleton preterm birth at <34 weeks’ gestation who! received 17P nonresponders (P < .001). A genome-wide search for genetic dif- were recruited prospectively and classified as a 17P responder or ferences implicated the NOS1 gene to be the most likely associated nonresponder by the difference in delivery gestational age between gene from among genes on the KEGG candidate gene list (P < 17P-treated and -untreated pregnancies. Samples underwent whole .00095). PANTHER analysis revealed several over-represented gene exome sequencing. Coding variants were compared between re- ontology categories that included cell adhesion, cell communication, sponders and nonresponders with the use of the Variant Annotation, signal transduction, nitric oxide signal transduction, and receptor Analysis, and Search Tool (VAAST), which is a probabilistic search tool activity (all with significant Bonferroni-corrected probability values). for the identification of disease-causing variants, and were compared CONCLUSION: We identified sets of over-represented genes in key with a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway processes among responders to 17P, which is the first step in the candidate gene list. Genes with the highest VAAST scores were then application of pharmacogenomics to preterm birth prevention. classified by the online Protein ANalysis THrough Evolutionary Re- lationships (PANTHER) system into known gene ontology molecular Key words: pharmacogenomics, progesterone, spontaneous preterm functions and biologic processes. Gene distributions within these birth Cite this article as: Manuck TA, Watkins WS, Moore B, et al. Pharmacogenomics of 17-alpha hydroxyprogesterone caproate for recurrent preterm birth prevention. Am J Obstet Gynecol 2014;210:321.e1-21. ore than 12% of babies are born birth (SPTB) accounts for 50-80% of alpha-hydroxyprogesterone caproate M preterm, which accounts for all preterm infants. Despite the mag- (17P) is one notable exception. When >70% of neonatal morbidity and deaths nitude of this clinical problem, few administered weekly beginning in the among nonanomalous infants in the preventative or acute therapeutic in- mid trimester, intramuscular 17P in- United States.1 Spontaneous preterm terventions have proved effective; 17 jections are effective prophylaxis against recurrent SPTB.2 Unfortunately, pro- phylactic 17P is not always effective, and From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, two-thirds of high-risk women will have Intermountain Healthcare (Drs Manuck, Esplin, Varner, and Jackson), and the Departments of a recurrent preterm birth, despite 17P Obstetrics and Gynecology (Drs Manuck, Esplin, Varner, and Jackson) and Human Genetics therapy. (Drs Yandell and Jorde and Mr Watkins and Mr Moore), University of Utah School of Medicine, There is strong evidence that genes Salt Lake City, UT. contribute to SPTB susceptibility. SPTB Received Nov. 19, 2013; revised Dec. 26, 2013; accepted Jan. 8, 2014. recurs in 35-50% of women and tends to Supported by grants from the University of Utah Program for Personalized Healthcare, Salt Lake City, recur at similar gestational ages.3 Like- UT; the Intermountain Research and Medical Foundation, project #556, Salt Lake City, UT; National Institutes of Health grant number 1K23HD067224; and grant number 8UL1TR000105 from the wise, the probability of SPTB increases National Center for Advancing Translational Sciences/National Institutes of Health. with the number of previous SPTB that a The authors report no conflict of interest. woman has experienced, with the most 4 Presented, in part, in oral format at the 34th annual meeting of the Society for Maternal-Fetal recent birth being the most predictive. Medicine, New Orleans, LA, Feb. 3-8, 2014. Women who themselves were born pre- Reprints not available from the authors. maturely at <30 weeks’ gestation are fl fi fi more likely to deliver premature infants The racing ag logo above indicates that this article was rushed to press for the bene t of the scienti c fi community. (odds ratio, 2.38; 95% con dence inter- 5 0002-9378/$36.00 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ajog.2014.01.013 val, 1.37e4.16). Population studies have demonstrated a higher rate of SPTB APRIL 2014 American Journal of Obstetrics & Gynecology 321.e1 Research Obstetrics www.AJOG.org among African American women, even women provided written informed con- agarose gel before genomic library con- when adjustment is made for epidemi- sent, and this study was approved by the struction. Genomic libraries were then ologic risk factors, which again suggests institutional review boards at Inter- constructed, and samples underwent genetics as a contributing factor.6,7 The mountain Healthcare and the University additional quality control measures that heritable nature of this complication is of Utah. included quantitative polymerase chain further supported by the findings that Women with a history of either idio- reaction quantitation of library concen- the risk of SPTB is elevated in women pathic spontaneous onset of contractions tration with primers (Illumina Inc, San whose sisters have experienced an SPTB and cervical dilation or preterm prema- Diego, CA) and evaluation of the library (odds ratio, 1.94; 95% confidence inter- ture rupture of membranes (PPROM) in on an Agilent Bioanalyzer DNA 1000 val, 1.26e2.99).8 a previous pregnancy were considered to chip (Agilent Technologies Inc, Santa Multiple candidate gene studies have have a previous SPTB and were included. Clara, CA). A PhiX control library (Illu- demonstrated associations between sev- We excluded women with a known mina Inc) was spiked into each lane at a eral genes and SPTB, with genes involved or suspected cause of SPTB, which concentration that represented approxi- in inflammation and coagulation path- included women who experienced SPTB mately 0.5% of the reads. This platform ways most commonly implicated.9-15 after polyhydramnios, within 2 weeks of targeted approximately 180,000 protein- Despite this knowledge, few studies amniocentesis, because of hypertensive coding exons, in approximately 20,000 have examined the role of genetic vari- disorders that included preeclampsia or genes, for capture. Whole exome ation in the response to medications that were related to abdominal trauma. sequencing was then performed at The are given for the prophylaxis or treat- Women with known uterine anomalies University of Utah Huntsman Cancer ment of SPTB. An understanding of or a history of treatment for cervical Institute’s Microarray Core Facility with the reason that some women respond to dysplasia with cryotherapy, loop electro- Illumina HiSeq2000 (Illumina Inc) 17P and others do not is crucial to surgical excision procedure, or cervical technology. We indexed 4 samples per understanding the cause of SPTB and conization were also excluded. lane, with a goal of approximately 40- optimizing prediction and therapeutic Women were classified as a 17P 50 average depth of coverage per sample. strategies. responder or nonresponder based on Sequences were then called simulta- We hypothesize that genetic variation response to 17P. Specifically, the differ- neously on all samples with the Univer- influences this variability in response to ence between the earliest delivery gesta- sity of Utah Department of Human 17P, particularly among women with tional age because of SPTB without 17P Genetics variant-calling software pipe- more severe SPTB phenotypes (early and the delivery gestational age with line. Paired-end 101 base pair fastq reads <34 weeks’ gestation and/or recurrent 17P was calculated and was termed the were aligned to the reference genome SPTB). Specifically, we sought to inter- “17P effect.” If a woman had multiple (b37) with the Burrows-Wheeler aligner rogate the coding regions of the genome pregnancies that had been treated with software.17 Additional processing that and compare genotypes between women 17P after her initial SPTB, the 17P effects included sorting, mate-fixing, and with recurrent SPTB despite 17P pro- from each individual pregnancy were duplicate read removal was performed phylaxis with those who have a favorable averaged to generate an overall 17P ef- with Samtools and Picard Tools.18 Inser- response to 17P. Additionally, we aimed fect. Women with an overall 17P effect tion and deletion realignment and base to determine whether there are gene sets of 3 weeks (ie, the individual’s preg- recalibration was performed with the that are represented differentially when nancy! or pregnancies that had been Genome Analysis Tool Kit (Broad Insti- comparing those genes with the greatest treated with 17P delivered at least 3 tute, Cambridge, MA).19,20 Processed variation between these 2 groups of weeks later
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