TY - JOUR
T1 - Pharmacogenomics of 17-alpha hydroxyprogesterone caproate for recurrent preterm birth
T2 - a case–control study
AU - the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Genomics and Proteomics Network for Preterm Birth Research (GPN-PBR)
AU - Manuck, T. A.
AU - Watkins, W. S.
AU - Esplin, M. S.
AU - Biggio, J.
AU - Bukowski, R.
AU - Parry, S.
AU - Zhan, H.
AU - Huang, H.
AU - Andrews, W.
AU - Saade, G.
AU - Sadovsky, Y.
AU - Reddy, U. M.
AU - Ilekis, J.
AU - Yandell, M.
AU - Varner, M. W.
AU - Jorde, L. B.
N1 - Publisher Copyright:
© 2017 Royal College of Obstetricians and Gynaecologist/1.
PY - 2018/2
Y1 - 2018/2
N2 - Objective: To compare maternal genotypes between women with and without significant prolongation of pregnancy in the setting of 17-alpha hydroxyprogesterone caproate (17-P) administration for the prevention of recurrent preterm birth (PTB). Design: Case–control. Setting: Three tertiary-care centres across the USA. Population: Women (n = 99) with ≥ 1 prior singleton spontaneous PTB, receiving 17-P. Methods: Women were classified as having successful prolongation of pregnancy during the 17-P treated pregnancy, in two ways: (1) Definition A: success/non-success based on difference in gestational age at delivery between 17-P-treated and untreated pregnancies (success: delivered ≥ 3 weeks later with 17-P) and (2) Definition B: success/non-success based on reaching term (success: delivered at term with 17-P). Main outcome measures: To assess genetic variation, all women underwent whole exome sequencing. Between-group sequence variation was analysed with the Variant Annotation, Analysis, and Search Tool (VAAST). Genes scored by VAAST with P < 0.05 were then analysed with two online tools: (1) Protein ANalysis THrough Evolutionary Relationships (PANTHER) and (2) Database for Annotation, Visualization, and Integrated Discovery (DAVID). Results: Using Definition A, there were 70 women with successful prolongation and 29 without; 1375 genes scored by VAAST had P < 0.05. Using Definition B, 47 women had successful prolongation and 52 did not; 1039 genes scored by VAAST had P < 0.05. PANTHER revealed key differences in gene ontology pathways. Many genes from definition A were classified as prematurity genes (P = 0.026), and those from definition B as pharmacogenetic genes (P = 0.0018); (P, non-significant after Bonferroni correction). Conclusion: A novel analytic approach revealed several genetic differences among women delivering early vs later with 17-P. Tweetable abstract: Several key genetic differences are present in women with recurrent preterm birth despite 17-P treatment.
AB - Objective: To compare maternal genotypes between women with and without significant prolongation of pregnancy in the setting of 17-alpha hydroxyprogesterone caproate (17-P) administration for the prevention of recurrent preterm birth (PTB). Design: Case–control. Setting: Three tertiary-care centres across the USA. Population: Women (n = 99) with ≥ 1 prior singleton spontaneous PTB, receiving 17-P. Methods: Women were classified as having successful prolongation of pregnancy during the 17-P treated pregnancy, in two ways: (1) Definition A: success/non-success based on difference in gestational age at delivery between 17-P-treated and untreated pregnancies (success: delivered ≥ 3 weeks later with 17-P) and (2) Definition B: success/non-success based on reaching term (success: delivered at term with 17-P). Main outcome measures: To assess genetic variation, all women underwent whole exome sequencing. Between-group sequence variation was analysed with the Variant Annotation, Analysis, and Search Tool (VAAST). Genes scored by VAAST with P < 0.05 were then analysed with two online tools: (1) Protein ANalysis THrough Evolutionary Relationships (PANTHER) and (2) Database for Annotation, Visualization, and Integrated Discovery (DAVID). Results: Using Definition A, there were 70 women with successful prolongation and 29 without; 1375 genes scored by VAAST had P < 0.05. Using Definition B, 47 women had successful prolongation and 52 did not; 1039 genes scored by VAAST had P < 0.05. PANTHER revealed key differences in gene ontology pathways. Many genes from definition A were classified as prematurity genes (P = 0.026), and those from definition B as pharmacogenetic genes (P = 0.0018); (P, non-significant after Bonferroni correction). Conclusion: A novel analytic approach revealed several genetic differences among women delivering early vs later with 17-P. Tweetable abstract: Several key genetic differences are present in women with recurrent preterm birth despite 17-P treatment.
KW - 17-Alpha hydroxyprogesterone caproate
KW - current preterm birth
KW - pharmacogenomics
KW - spontaneous prematurity
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U2 - 10.1111/1471-0528.14485
DO - 10.1111/1471-0528.14485
M3 - Article
C2 - 28139890
AN - SCOPUS:85011281178
SN - 1470-0328
VL - 125
SP - 343
EP - 350
JO - BJOG: An International Journal of Obstetrics and Gynaecology
JF - BJOG: An International Journal of Obstetrics and Gynaecology
IS - 3
ER -