title: Pathway analysis of genetic factors associated with spontaneous preterm birth and pre-labor preterm rupture of membranes.
abstract: BACKGROUND
  Pre-term birth (PTB) remains the leading cause of infant mortality and morbidity. Its etiology is multifactorial, with a strong genetic component. Genetic predisposition for the two subtypes, spontaneous PTB with intact membranes (sPTB) and preterm prelabor rapture of membranes (PPROM), and differences between them, have not yet been systematically summarised.
  
  
  RESULTS
  Our literature search identified 15 association studies conducted in 3,600 women on 2175 SNPs in 274 genes. We used Ingenuity software to impute gene pathways and networks related to sPTB and PPROM. Detailed insight in the defined functional ontologies clearly separated integrated datasets for sPTB and PPROM. Our analysis of upstream regulators of genes suggests that glucocorticoid receptor (NR3C1), peroxisome proliferator activated receptor γ (PPARG) and interferon regulating factor 3 (IRF3) may be sPTB specific. PPROM-specific genes may be regulated by estrogen receptor2 (ESR2) and signal transducer and activator of transcription (STAT1). The inflammatory transcription factor NFκB is linked to both sPTB and PPROM, however, their inflammatory response is distinctly different.
  
  
  CONCLUSIONS
  Based on our analyses, we propose an autoimmune/hormonal regulation axis for sPTB, whilst pathways implicated in the etiology of PPROM include hematologic/coagulation function disorder, collagen metabolism, matrix degradation and local inflammation. Our hypothesis generating study has identified new candidate genes in the pathogenesis of PPROM and sPTB, which should be validated in large cohorts.
authors.affiliation: Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Antonio
authors.initials: A
authors.lastname: Capece
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Olga
authors.initials: O
authors.lastname: Vasieva
authors.affiliation: Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Shireen
authors.initials: S
authors.lastname: Meher
authors.affiliation: Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Zarko
authors.initials: Z
authors.lastname: Alfirevic
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Ana
authors.initials: A
authors.lastname: Alfirevic
mesh_terms: D015551:Autoimmunity / Q000235:genetics; D005260:Female; D005322:Premature Rupture of Fetal Membranes / Q000453:epidemiology* / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007226:Infant Mortality; D007231:Infant, Newborn; D050838:Interferon Regulatory Factor-3 / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics; D011110:Polymorphism, Genetic; D011247:Pregnancy; D011248:Pregnancy Complications / Q000453:epidemiology / Q000235:genetics; D047928:Premature Birth / Q000453:epidemiology* / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000235:genetics
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; C497713:NR3C1 protein, human; D047495:PPAR gamma; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human