Association of maternal IL-1 receptor antagonist intron 2 gene polymorphism and preterm birth Amy P. Murtha, MD, a Angel Nieves, MD, a Elizabeth R. Hauser, PhD, b Geeta K. Swamy, MD, a Bryan A. Yonish, BS, a Tammy R. Sinclair, BSN, a R. Phillips Heine, MD a Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, a Center for Human Genetics, b Duke University Medical Center, Durham, NC Received for publication March 13, 2006; revised August 31, 2006; accepted September 14, 2006 KEY WORDS Prematurity Genetic Polymorphism Cytokine Inflammation Objective: This study was undertaken to determine whether the interleukin-1 receptor antagonist (IL-1RN) variable number tandem repeat polymorphism is associated with preterm birth. Study design: A case–control study was performed. Cases (n = 95) delivered before 37 weeks after preterm labor (PTL) or preterm premature rupture of membranes (PPROM) and controls (n = 105) delivered after 37 weeks. Maternal DNA was genotyped by polymerase chain reaction for a length polymorphism in intron 2 of the IL-1RN gene. Results: There was no significant difference in maternal age, ethnicity, insurance status, or parity between groups. Allele and genotype frequencies did not differ significantly from that expected under Hardy-Weinberg equilibrium (P = .59) in the total group as well as study groups. Of the 95 cases, 26.8% had at least 1 copy of allele 2 present compared with 12.4% in the control group (P ! .0004). Conclusion: Maternal carriage of at least 1 copy of the IL-1RN allele 2 appears to be associated with increased risk of preterm birth. Ó 2006 Mosby, Inc. All rights reserved. Preterm birth (PTB) is the leading cause of infant mortality and morbidity worldwide. 1 The cause of PTB is largely unknown but is believed to be complex, encompassing multiple genetic, social, and environmen- tal determinants. Evidence exists that genetic polymor- phisms may influence susceptibility to and/or severity of a number of disorders. It is likely that genetic predis- position to inflammation increases the risk of PTB. Understanding the pathogenesis of PTB is paramount to the identification of risk factors and possible preven- tion of PTB. In a healthy state, the proinflammatory immune response is tightly regulated resulting in destruction of the invading stimulus while normal tissue architecture and function is maintained. Resolution of the inflamma- tory process and healing occurs through the activity of anti-inflammatory cytokines. One of these major anti- inflammatory cytokines is interleukin-1 (IL-1) receptor antagonist (RN). IL-1 RN binds to the IL-1 receptor but does not initiate signal transduction; therefore, IL-1RN is a competitive inhibitor of IL-1ß bioactivity. 2 In animal models, IL-1RN has been shown to inhibit IL-1ß- induced preterm labor (PTL). 3 Moreover, in vitro studies demonstrated that IL-1RN inhibits the stimulation of Reprints not available from the authors. 0002-9378/$ - see front matter Ó 2006 Mosby, Inc. All rights reserved. doi:10.1016/j.ajog.2006.09.002 American Journal of Obstetrics and Gynecology (2006) 195, 1249–53 www.ajog.org