title: Sequence variants in oxytocin pathway genes and preterm birth: a candidate gene association study.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Jinsil
authors.initials: J
authors.lastname: Kim
authors.forename: Kara J
authors.initials: KJ
authors.lastname: Stirling
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Mario
authors.initials: M
authors.lastname: Ascoli
authors.forename: Allison M
authors.initials: AM
authors.lastname: Momany
authors.forename: Erin L
authors.initials: EL
authors.lastname: McDonald
authors.forename: Kelli K
authors.initials: KK
authors.lastname: Ryckman
authors.forename: Lindsey
authors.initials: L
authors.lastname: Rhea
authors.forename: Kendra L
authors.initials: KL
authors.lastname: Schaa
authors.forename: Viviana
authors.initials: V
authors.lastname: Cosentino
authors.forename: Enrique
authors.initials: E
authors.lastname: Gadow
authors.forename: Cesar
authors.initials: C
authors.lastname: Saleme
authors.forename: Min
authors.initials: M
authors.lastname: Shi
authors.forename: Mikko
authors.initials: M
authors.lastname: Hallman
authors.forename: Jevon
authors.initials: J
authors.lastname: Plunkett
authors.forename: Kari A
authors.initials: KA
authors.lastname: Teramo
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Muglia
authors.forename: Bjarke
authors.initials: B
authors.lastname: Feenstra
authors.forename: Frank
authors.initials: F
authors.lastname: Geller
authors.forename: Heather A
authors.initials: HA
authors.lastname: Boyd
authors.forename: Mads
authors.initials: M
authors.lastname: Melbye
authors.forename: Mary L
authors.initials: ML
authors.lastname: Marazita
authors.forename: John M
authors.initials: JM
authors.lastname: Dagle
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
mesh_terms: D000483:Alleles; D000818:Animals; D001118:Argentina; D019556:COS Cells; D016022:Case-Control Studies; D002522:Chlorocebus aethiops; D010122:Cystinyl Aminopeptidase / Q000235:genetics* / Q000378:metabolism; D003718:Denmark; D005260:Female; D005387:Finland; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D056914:Genomic Structural Variation; D005865:Gestational Age; D006239:Haplotypes; D006801:Humans; D040582:Inheritance Patterns; D007295:Inositol Phosphates / Q000378:metabolism; D020125:Mutation, Missense; D010121:Oxytocin / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D047928:Premature Birth / Q000235:genetics*; D011485:Protein Binding; D018045:Receptors, Oxytocin / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors
chemical_list: D007295:Inositol Phosphates; C569600:OXTR protein, human; D018045:Receptors, Oxytocin; D010121:Oxytocin; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase
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