Tracy A Manuck1, W Scott Watkins2, Barry Moore2, M Sean Esplin1, Michael W Varner1, G Marc Jackson1, Mark Yandell2, Lynn Jorde2. 1. 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. 2. Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT.
Abstract
OBJECTIVE: We hypothesized that genetic variation affects responsiveness to 17-alpha hydroxyprogesterone caproate (17P) for recurrent preterm birth prevention. STUDY DESIGN: 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). CONCLUSION: 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. Published by Mosby, Inc.
OBJECTIVE: We hypothesized that genetic variation affects responsiveness to 17-alpha hydroxyprogesterone caproate (17P) for recurrent preterm birth prevention. STUDY DESIGN: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). CONCLUSION: 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. Published by Mosby, Inc.
Authors: Alkes L Price; Nick J Patterson; Robert M Plenge; Michael E Weinblatt; Nancy A Shadick; David Reich Journal: Nat Genet Date: 2006-07-23 Impact factor: 38.330
Authors: Hongyan Wang; Samuel Parry; George Macones; Mary D Sammel; Helena Kuivaniemi; Gerard Tromp; George Argyropoulos; Indrani Halder; Mark D Shriver; Roberto Romero; Jerome F Strauss Journal: Proc Natl Acad Sci U S A Date: 2006-08-28 Impact factor: 11.205
Authors: A Bisits; G Madsen; M Knox; A Gill; R Smith; G Yeo; K Kwek; M Daniel; T N Leung; K Cheung; T Chung; I Jones; J Toohill; D Tudehope; W Giles Journal: Am J Obstet Gynecol Date: 2004-09 Impact factor: 8.661
Authors: Tracy A Manuck; Gregory J Stoddard; Rebecca C Fry; M Sean Esplin; Michael W Varner Journal: Am J Obstet Gynecol Date: 2016-07-11 Impact factor: 8.661
Authors: Tracy A Manuck; M Sean Esplin; Joseph Biggio; Radek Bukowski; Samuel Parry; Heping Zhang; Hao Huang; Michael W Varner; William Andrews; George Saade; Yoel Sadovsky; Uma M Reddy; John Ilekis Journal: Am J Obstet Gynecol Date: 2015-12-12 Impact factor: 8.661
Authors: David B Nelson; Donald D McIntire; Jeffrey McDonald; John Gard; Paula Turrichi; Kenneth J Leveno Journal: Am J Obstet Gynecol Date: 2017-02-20 Impact factor: 8.661
Authors: Tracy A Manuck; Lisa Smeester; Elizabeth M Martin; Martha S Tomlinson; Christina Smith; Michael W Varner; Rebecca C Fry Journal: Am J Perinatol Date: 2017-12-14 Impact factor: 1.862
Authors: Terrence K Allen; Liping Feng; Matthew Nazzal; Chad A Grotegut; Irina A Buhimschi; Amy P Murtha Journal: Anesth Analg Date: 2015-05 Impact factor: 6.627
Authors: Tracy A Manuck; Lauren A Eaves; Julia E Rager; Karen Sheffield-Abdullah; Rebecca C Fry Journal: Epigenetics Date: 2021-07-24 Impact factor: 4.861