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Sequence variants in oxytocin pathway genes and preterm birth: a candidate gene association study

Jinsil Kim1, Kara J Stirling2, Margaret E Cooper3, Mario Ascoli4, Allison M Momany2, Erin L McDonald2, Kelli K Ryckman2, Lindsey Rhea2, Kendra L Schaa2, Viviana Cosentino5, Enrique Gadow5, Cesar Saleme6, Min Shi7, Mikko Hallman8, Jevon Plunkett9, Kari A Teramo10, Louis J Muglia11, Bjarke Feenstra12, Frank Geller12, Heather A Boyd12, Mads Melbye12, Mary L Marazita133, John M Dagle2 and Jeffrey C Murray12*

Author affiliations

1 Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA

2 Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA

3 Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA

4 Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA

5 Centro de Educación Médica e Inverstigaciones Clínicas, Buenos Aires 1431, Argentina

6 Instituto de Maternidad y Ginecología Nuestra Señora de las Mercedes, San Miguel de Tucumán 4000, Argentina

7 Biostatistics Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA

8 Institute of Clinical Medicine, Department of Pediatrics, University of Oulu, Oulu 90014, Finland

9 Human and Statistical Genetics Program, Washington University, St. Louis, MO 63110, USA

10 Department of Obstetrics and Gynecology, University of Helsinki, Helsinki 00290, Finland

11 Perinatal Institute, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA

12 Department of Epidemiology Research, Statens Serum Institut, Copenhagen, S 2300, Denmark

13 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15219, USA

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Citation and License

BMC Medical Genetics 2013, 14:77  doi:10.1186/1471-2350-14-77

Published: 26 July 2013



Preterm birth (PTB) is a complex disorder associated with significant neonatal mortality and morbidity and long-term adverse health consequences. Multiple lines of evidence suggest that genetic factors play an important role in its etiology. This study was designed to identify genetic variation associated with PTB in oxytocin pathway genes whose role in parturition is well known.


To identify common genetic variants predisposing to PTB, we genotyped 16 single nucleotide polymorphisms (SNPs) in the oxytocin (OXT), oxytocin receptor (OXTR), and leucyl/cystinyl aminopeptidase (LNPEP) genes in 651 case infants from the U.S. and one or both of their parents. In addition, we examined the role of rare genetic variation in susceptibility to PTB by conducting direct sequence analysis of OXTR in 1394 cases and 1112 controls from the U.S., Argentina, Denmark, and Finland. This study was further extended to maternal triads (maternal grandparents-mother of a case infant, N=309). We also performed in vitro analysis of selected rare OXTR missense variants to evaluate their functional importance.


Maternal genetic effect analysis of the SNP genotype data revealed four SNPs in LNPEP that show significant association with prematurity. In our case–control sequence analysis, we detected fourteen coding variants in exon 3 of OXTR, all but four of which were found in cases only. Of the fourteen variants, three were previously unreported novel rare variants. When the sequence data from the maternal triads were analyzed using the transmission disequilibrium test, two common missense SNPs (rs4686302 and rs237902) in OXTR showed suggestive association for three gestational age subgroups. In vitro functional assays showed a significant difference in ligand binding between wild-type and two mutant receptors.


Our study suggests an association between maternal common polymorphisms in LNPEP and susceptibility to PTB. Maternal OXTR missense SNPs rs4686302 and rs237902 may have gestational age-dependent effects on prematurity. Most of the OXTR rare variants identified do not appear to significantly contribute to the risk of PTB, but those shown to affect receptor function in our in vitro study warrant further investigation. Future studies with larger sample sizes are needed to confirm the findings of this study.

Preterm birth; Genetic association analysis; Oxytocin pathway; Single nucleotide polymorphism; Rare variant