PMID- 23889750 OWN - NLM STAT- MEDLINE DCOM- 20130827 LR - 20211021 IS - 1471-2350 (Electronic) IS - 1471-2350 (Linking) VI - 14 DP - 2013 Jul 26 TI - Sequence variants in oxytocin pathway genes and preterm birth: a candidate gene association study. PG - 77 LID - 10.1186/1471-2350-14-77 [doi] AB - 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. FAU - Kim, Jinsil AU - Kim J AD - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA. FAU - Stirling, Kara J AU - Stirling KJ FAU - Cooper, Margaret E AU - Cooper ME FAU - Ascoli, Mario AU - Ascoli M FAU - Momany, Allison M AU - Momany AM FAU - McDonald, Erin L AU - McDonald EL FAU - Ryckman, Kelli K AU - Ryckman KK FAU - Rhea, Lindsey AU - Rhea L FAU - Schaa, Kendra L AU - Schaa KL FAU - Cosentino, Viviana AU - Cosentino V FAU - Gadow, Enrique AU - Gadow E FAU - Saleme, Cesar AU - Saleme C FAU - Shi, Min AU - Shi M FAU - Hallman, Mikko AU - Hallman M FAU - Plunkett, Jevon AU - Plunkett J FAU - Teramo, Kari A AU - Teramo KA FAU - Muglia, Louis J AU - Muglia LJ FAU - Feenstra, Bjarke AU - Feenstra B FAU - Geller, Frank AU - Geller F FAU - Boyd, Heather A AU - Boyd HA FAU - Melbye, Mads AU - Melbye M FAU - Marazita, Mary L AU - Marazita ML FAU - Dagle, John M AU - Dagle JM FAU - Murray, Jeffrey C AU - Murray JC LA - eng GR - HL-103010/HL/NHLBI NIH HHS/United States GR - HD57192/HD/NICHD NIH HHS/United States GR - Z01 ES045002/ES/NIEHS NIH HHS/United States GR - R01 HD052953/HD/NICHD NIH HHS/United States GR - HL-102926/HL/NHLBI NIH HHS/United States GR - HL-102925/HL/NHLBI NIH HHS/United States GR - HL-102923/HL/NHLBI NIH HHS/United States GR - P30 ES005605/ES/NIEHS NIH HHS/United States GR - R01 HD057192/HD/NICHD NIH HHS/United States GR - Z01 ES040007/ES/NIEHS NIH HHS/United States GR - HL-102924/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20130726 PL - England TA - BMC Med Genet JT - BMC medical genetics JID - 100968552 RN - 0 (Inositol Phosphates) RN - 0 (OXTR protein, human) RN - 0 (Receptors, Oxytocin) RN - 50-56-6 (Oxytocin) RN - EC 3.4.11.3 (Cystinyl Aminopeptidase) RN - EC 3.4.11.3 (leucyl-cystinyl aminopeptidase) SB - IM MH - Alleles MH - Animals MH - Argentina MH - COS Cells MH - Case-Control Studies MH - Chlorocebus aethiops MH - Cystinyl Aminopeptidase/*genetics/metabolism MH - Denmark MH - Female MH - Finland MH - *Genetic Association Studies MH - Genetic Predisposition to Disease MH - *Genomic Structural Variation MH - Gestational Age MH - Haplotypes MH - Humans MH - Inheritance Patterns MH - Inositol Phosphates/metabolism MH - Mutation, Missense MH - Oxytocin/genetics/metabolism MH - Polymorphism, Single Nucleotide MH - Pregnancy MH - Premature Birth/*genetics MH - Protein Binding MH - Receptors, Oxytocin/*genetics/metabolism MH - Risk Factors PMC - PMC3737028 EDAT- 2013/07/31 06:00 MHDA- 2013/08/28 06:00 PMCR- 2013/07/26 CRDT- 2013/07/30 06:00 PHST- 2012/03/12 00:00 [received] PHST- 2013/07/18 00:00 [accepted] PHST- 2013/07/30 06:00 [entrez] PHST- 2013/07/31 06:00 [pubmed] PHST- 2013/08/28 06:00 [medline] PHST- 2013/07/26 00:00 [pmc-release] AID - 1471-2350-14-77 [pii] AID - 10.1186/1471-2350-14-77 [doi] PST - epublish SO - BMC Med Genet. 2013 Jul 26;14:77. doi: 10.1186/1471-2350-14-77.