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

BMC Medical Genetics

Jeffrey C Murray⁹  John M Dagle⁹  Mary L Marazita³  Mads Melbye⁸  Heather A Boyd⁸  Frank Geller⁸  Bjarke Feenstra⁸  Louis J Muglia^1,11  Kari A Teramo^1,12  Jevon Plunkett⁴  Mikko Hallman⁵  Min Shi¹  Cesar Saleme⁷  Enrique Gadow²  Viviana Cosentino²  Kendra L Schaa⁹  Lindsey Rhea⁹  Kelli K Ryckman⁹  Erin L McDonald⁹  Allison M Momany⁹  Mario Ascoli⁶  Margaret E Cooper³  Kara J Stirling⁹  Jinsil Kim^1,10 

[1] Biostatistics Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA;Centro de Educación Médica e Inverstigaciones Clínicas, Buenos Aires 1431, Argentina;Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA;Human and Statistical Genetics Program, Washington University, St. Louis, MO 63110, USA;Institute of Clinical Medicine, Department of Pediatrics, University of Oulu, Oulu 90014, Finland;Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA;Instituto de Maternidad y Ginecología Nuestra Señora de las Mercedes, San Miguel de Tucumán 4000, Argentina;Department of Epidemiology Research, Statens Serum Institut, Copenhagen, S 2300, Denmark;Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA;Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA;Perinatal Institute, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA;Department of Obstetrics and Gynecology, University of Helsinki, Helsinki 00290, Finland

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

Others  :  1127652
DOI  :  10.1186/1471-2350-14-77

 received in 2012-03-12, accepted in 2013-07-18,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Kim et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Dizon-Townson DS: Preterm labour and delivery: a genetic predisposition. Paediatr Perinat Epidemiol 2001, 15:57-62.
• [2]Beck S, Wojdyla D, Say L, Pilar Betran A, Merialdi M, Harris Requejo J, Rubens C, Menon R, Van Look P: The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity. Bull World Health Organ 2010, 88:31-38.
• [3]Martin JA, Hamilton BE, Ventura SJ, Osterman MJ, Mathews TJ: Births: final Data for 2011. Natl Vital Stat Rep 2013, 62(1):1-90.
• [4]Gotsch F, Romero R, Erez O, Vaisbuch E, Kusanovic JP, Mazaki-Tovi S, Kim SK, Hassan S, Yeo L: The preterm parturition syndrome and its implications for understanding the biology, risk assessment, diagnosis, treatment and prevention of preterm birth. J Matern Fetal Neonatal Med 2009, 22(Suppl 2):5-23.
• [5]Crider KS, Whitehead N, Buus RM: Genetic variation associated with preterm birth: a huge review. Genet Med 2005, 7(9):593-604.
• [6]Adams KM, Eschenbach DA: The genetic contribution towards preterm delivery. Semin Fetal Neonatal Med 2004, 9(6):445-452.
• [7]Muglia LJ, Katz M: The enigma of spontaneous preterm birth. N Eng J Med 2010, 362(6):529-535.
• [8]Gimpl G, Fahrenholz F: The oxytocin receptor system: structure, function, and regulation. Physiol Rev 2001, 81(2):629-683.
• [9]Blanks AM, Shmygol A, Thornton S: Regulation of oxytocin receptors and oxytocin receptor signaling. Semin Reprod Med 2007, 25(1):52-59.
• [10]Trzidou V: Biochemical and endocrinological preparation for parturition. Best Pract Res Clin Obstet Gynaecol 2007, 21:729-756.
• [11]Vrachnis N, Malamas FM, Sifakis S, Deligeoroglou E, Iliodromiti Z: The oxytocin-oxytocin receptor system and its antagonists as tocolytic agents. International journal of endocrinology 2011, 2011:350546.
• [12]Lampelo S, Vanhaperttula T: Fractionation and characterization of cystine aminopeptidase (oxytocinase) and arylamidase of human serum during pregnancy. J Reprod Fertil 1980, 58(1):225-235.
• [13]Nomura S, Ito T, Yamamoto E, Sumigama S, Iwase A, Okada M, Shibata K, Ando H, Ino K, Kikkawa F, et al.: Gene regulation and physiological function of placental leucine arninopeptidase/oxytocinase during pregnancy. Biochimica Et Biophysica Acta-Proteins and Proteomics 2005, 1751(1):19-25.
• [14]Tsatsaris V, Carbonne B, Cabrol D: Atosiban for preterm labour. Drugs 2004, 64(4):375-382.
• [15]Dolan SM, Hollegaard MV, Merialdi M, Betran AP, Allen T, Abelow C, Nace J, Lin BK, Khoury MJ, Ioannidis JP, et al.: Synopsis of preterm birth genetic association studies: the preterm birth genetics knowledge base (PTBGene). Public Health Genomics 2010, 13(7–8):514-523.
• [16]Olsen J, Melbye M, Olsen SF, Sorensen TI, Aaby P, Andersen AM, Taxbol D, Hansen KD, Juhl M, Schow TB, et al.: The Danish national birth cohort–its background, structure and aim. Scand J Public Health 2001, 29(4):300-307.
• [17]Ehn NL, Cooper ME, Orr K, Shi M, Johnson MK, Caprau D, Dagle J, Steffen K, Johnson K, Marazita ML, et al.: Evaluation of fetal and maternal genetic variation in the progesterone receptor gene for contributions to preterm birth. Pediatr Res 2007, 62(5):630-635.
• [18]Ascoli M, Pignataro OP, Segaloff DL: The inositol phosphate/diacylglycerol pathway in MA-10 leydig tumor cells. Activation by arginine vasopressin and lack of effect of epidermal growth factor and human choriogonadotropin. J Biol Chem 1989, 264(12):6674-6681.
• [19]Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira M, Bender D, Maller J, Sklar P, de Bakker P, Daly M, et al.: PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007, 81(3):559-575.
• [20]Barrett JC, Fry B, Maller J, Daly MJ: Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005, 21(2):263-265.
• [21]Rabinowitz D, Laird N: A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Hum Hered 2000, 50(4):211-223.
• [22]Laird NM, Horvath S, Xu X: Implementing a unified approach to family-based tests of association. Genet Epidemiol 2000, 19:S36-S42.
• [23]Spielman RS, McGinnis RE, Ewens WJ: Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993, 52(3):506-516.
• [24]Weinberg CR, Wilcox AJ: Distinguishing the effects of maternal and offspring genes through studies of 'case-parent triads' " and "a new method for estimating the risk ratio in studies using case-parental control design. Am J Epidemiol 1999, 150(4):428-429.
• [25]Schaid DJ, Sommer SS: Genotype relative risks: methods for design and analysis of candidate-gene association studies. Am J Hum Genet 1993, 53(5):1114-1126.
• [26]Weinberg CR: Allowing for missing parents in genetic studies of case-parent triads. Am J Hum Genet 1999, 64(4):1186-1193.
• [27]Shi M, Umbach DM, Vermeulen SH, Weinberg CR: Making the most of case-mother/control-mother studies. Am J Epidemiol 2008, 168(5):541-547.
• [28]The 1000 Genomes Project Consortium: A map of human genome variation from population-scale sequencing. Nature 2010, 467(7319):1061-1073.
• [29]The 1000 genomes project http://www.1000genomes.org/ webcite
• [30]Exome variant server, NHLBI exome sequencing project (ESP). Seattle, WA; (URL: http://evs.gs.washington.edu/EVS/ webcite) [date (February, 2013) accessed]
• [31]The SeattleSeq annotation server [http://gvs.gs.washington.edu/SeattleSeqAnnotation/ webcite]
• [32]Dolan SM: Genetic and environmental contributions to racial disparities in preterm birth. Mt Sinai J Med 2010, 77(2):160-165.
• [33]Ramensky V, Bork P, Sunyaev S: Human non-synonymous SNPs: server and survey. Nucleic Acids Research 2002, 30(17):3894-3900.
• [34]Ng PC, Henikoff S: Accounting for human polymorphisms predicted to affect protein function. Genome Research 2002, 12(3):436-446.
• [35]Boyd HA, Poulsen G, Wohlfahrt J, Murray JC, Feenstra B, Melbye M: Maternal contributions to preterm delivery. American Journal of Epidemiology 2009, 170(11):1358-1364.
• [36]Svensson AC, Sandin S, Cnattingius S, Reilly M, Pawitan Y, Hultman CM, Lichtenstein P: Maternal effects for preterm birth: a genetic epidemiologic study of 630,000 families. American Journal of Epidemiology 2009, 170(11):1365-1372.
• [37]Ishii M, Naruse K, Hattori A, Tsujimoto M, Ishiura S, Numaguchi Y, Murohara T, Kobayashi H, Mizutani S: Oxytocin hypersensitivity in pregnant P-LAP deficient mice. Life Sciences 2009, 84(19–20):668-672.
• [38]Postina R, Kojro E, Fahrenholz F: Separate agonist and peptide antagonist binding sites of the oxytocin receptor defined by their transfer into the V-2 vasopressin receptor. Journal of Biological Chemistry 1996, 271(49):31593-31601.
• [39]Grazzini E, Guillon G, Mouillac B, Zingg HH: Inhibition of oxytocin receptor function by direct binding of progesterone. Nature 1998, 392(6675):509-512.
• [40]Gellersen B, Fernandes MS, Brosens JJ: Non-genomic progesterone actions in female reproduction. Hum Reprod Update 2009, 15(1):119-138.
• [41]Dunlap KA, Stormshak F: Nongenomic inhibition of oxytocin binding by progesterone in the ovine uterus. Biol Reprod 2004, 70(1):65-69.
• [42]Chini B, Mouillac B, Balestre MN, TrumppKallmeyer S, Hoflack J, Hibert M, Andriolo M, Pupier S, Jard S, Barberis C: Two aromatic residues regulate the response of the human oxytocin receptor to the partial agonist arginine vasopressin. Febs Letters 1996, 397(2–3):201-206.
• [43]Chan WY, Wo NC, Manning M: The role of oxytocin receptors and vasopressin V-1a receptors in uterine contractions in rats: implications for tocolytic therapy with oxytocin antagonists. American Journal of Obstetrics and Gynecology 1996, 175(5):1331-1335.
• [44]Tahara A, Tsukada J, Tomura Y, Wada K, Kusayama T, Ishii N, Yatsu T, Uchida W, Tanaka A: Pharmacologic characterization of the oxytocin receptor in human uterine smooth muscle cells. British Journal of Pharmacology 2000, 129(1):131-139.