title: Risk of spontaneous preterm birth is associated with common proinflammatory cytokine polymorphisms.
abstract: BACKGROUND
  Preliminary data suggest that common genetic variation in immune response genes can contribute to the risk for spontaneous preterm birth and possibly small-for-gestational age (SGA).
  
  
  METHODS
  We investigated the relationship of polymorphisms in 6 cytokine genes associated with inflammation-interleukin (IL)1alpha, IL1beta, IL2, IL6, tumor necrosis factor (TNF), and lymphotoxin alpha (LTA)-with spontaneous preterm and SGA birth in a nested case-control study drawn from a prospective pregnancy cohort. Women were recruited between 24 and 29 weeks' gestation at the Wake County and University of North Carolina, Chapel Hill obstetric clinics between February 1996 and June 2000. We inferred haplotypes using the EM algorithm and the Bayesian method, PHASE. We then compared haplotype frequency distributions and implemented semi-Bayesian hierarchical logistic regression analyses to obtain odds ratio (OR) estimates and 95% confidence intervals (CIs) for each polymorphism.
  
  
  RESULTS
  Two haplotypes spanning the TNF/LTA genes were associated with increased risk for spontaneous preterm birth in white subjects (for the AGG haplotype, OR = 1.5 [95% CI=0.8-2.6]; for the GAC haplotype, 1.6 [0.9-2.9]). Additionally, carriers of the GAG haplotype were found to have decreased risk of spontaneous preterm birth (0.6; 0.3-1.0). The TNF(-488)A and LTA(IVS1-82)C variants, constituents of the AGG and GAC haplotypes respectively, were also strongly associated with increased risk of spontaneous preterm birth.
  
  
  CONCLUSIONS
  Our results suggest that common genetic variants in proinflammatory cytokine genes could influence the risk for spontaneous preterm birth. Selected TNF/LTA haplotypes were associated with spontaneous preterm birth in both African-American and white subjects. Our data do not support an inflammatory etiology for SGA.
authors.affiliation: Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, North Carolina, USA. Stephanie.Engel@mssm.edu
authors.forename: Stephanie A Mulherin
authors.initials: SA
authors.lastname: Engel
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Erichsen
authors.forename: David A
authors.initials: DA
authors.lastname: Savitz
authors.forename: John
authors.initials: J
authors.lastname: Thorp
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Olshan
mesh_terms: D001741:Black or African American / Q000235:genetics*; D001499:Bayes Theorem; D016207:Cytokines / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005865:Gestational Age; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D016015:Logistic Models; D009657:North Carolina / Q000453:epidemiology; D011110:Polymorphism, Genetic / Q000276:immunology; D011247:Pregnancy; D047928:Premature Birth / Q000208:ethnology / Q000235:genetics* / Q000276:immunology*; D011446:Prospective Studies; D012307:Risk Factors; D014626:Vaginal Smears; D016585:Vaginosis, Bacterial / Q000175:diagnosis / Q000208:ethnology; D044465:White People / Q000235:genetics*
chemical_list: D016207:Cytokines