Abstract
Objective:
To evaluate the association between maternal interleukin (IL)-6 G(−174)C polymorphism and cystic periventricular leukomalacia (cPVL) of the preterm newborn.
Study Design:
After searching a local database, we recruited 132 preterm infants with diagnosis of cPVL, 44 Caucasian mothers were also recruited to participate in this candidate gene-association study at a single teritary care center. Data related to maternal IL-6 G(−174)C polymorphisms were compared with 41 controls, and furthermore compared with data from umbilical cord blood samples from a consecutive birth cohort of 395 healthy newborns, and published data from Caucasian populations including 1104 adults, respectively. In addition, subgroup analysis was performed in cases with either history of preterm premature rupture of the membranes (PPROM) or clinical chorioamnionitis (CCA). IL-6 genotyping was performed using an allele-specific polymerase chain reaction technique.
Result:
Frequencies of the IL-6 G(−174)C polymorphisms did not differ between cases (GG, 29.5%; GC, 54.5% and CC, 15.9%) and controls (GG, 34.2; GC, 51.2 and CC, 14.6%). Subgroup analysis of 31 cases with history of PPROM (GG, 25.8; GC, 54.8 and CC 19.4%) and controls did not reveal significant differences, but a significantly higher frequency of the CC genotype was found in 23 cases with a history of CCA (34.8%) compared with controls by either univariate (P=0.032; odds ratio 3.11, 95% confidence interval (CI) 1.11 to 8.68) or multivariate analysis (P=0.049, odds ratio 2.54, 95% CI 1.01 to 6.45). These data were confirmed by a comparing the CC genotype frequency to 395 term controls (CC 14.7%, P=0.005) and to the mean CC genotype frequency of 1104 Caucasian adults (CC 15.6%, P<0.0001).
Conclusion:
Frequencies of the IL-6 G(−174)C polymorphisms did not differ between groups. Subgroup analysis revealed an association of the CC genotype with CCA and cPVL in the preterm newborn.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hillier SL, Martius J, Kiviat N, Holmes KK, Eschenbach DA . A case–control study of chorioamniotic infection and histologic chorioamnionitis in prematurity. N Engl J Med 1988; 319: 972–978.
Leviton A, Paneth N, Reuss ML, Susser M, Allred EN, Damman O et al. Maternal infection, fetal inflammatory response, and brain damage in very low birth weight infants. Pediatr Res 1999; 46: 566–575.
Døllner H, Vatten L, Halgunset J, Rahimipoor S, Austgulen R . Histologic chorioamnionitis and umbilical serum levels of pro-inflammatory cytokines and cytokine inhibitors. Br J Obstet Gynaecol 2002; 109: 534–539.
Debillon T, Gras-Leguen C, Leroy S, Caillon J, Roze JC, Gressens P . Patterns of cerebral inflammatory response in a rabbit model of intrauterine infection-mediated brain lesion. Dev Brain Res 2003; 145: 39–48.
Duncan JR, Cock ML, Scheerlinck JP, Westcott KT, McLean C, Harding R et al. White matter injury after repeated endotoxin exposure in the preterm ovine fetus. Pediatr Res 2002; 52: 941–949.
Verma U, Tejani N, Klein S, Reale MR, Beneck D, Figueroa R et al. Obstetric antecedents of intraventricular haemorrhage and periventricular leukomalacia in the low-birth-weight neonate. Am J Obstet Gynecol 1997; 176: 275–281.
Alexander JM, Gilstrap LC, Cox SM, McIntire D, Leveno KJ . Clinical chorioamnionitis and the prognosis for very low birth weight infants. Obstet Gynecol 1998; 91: 725–729.
Yoon BH, Romero R, Yang SH, Jun JK, Kim IO, Choi JH et al. Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia. Am J Obstet Gynecol 1996; 174: 1433–1440.
Resch B, Vollaard E, Maurer U, Haas J, Rosegger H, Müller W . Risk factors and determinants of neurodevelopmental outcome in cystic periventricular leukomalacia. Eur J Pediatr 2000; 159: 663–670.
Loddick SA, Turnbull AV, Rothwell NJ . Cerebral interleukin-6 is neuroprotective during permanent focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 1998; 18: 176–179.
Parish CL, Finkelstein DI, Tripanichkul W, Satoskar AR, Drago J, Horne MK . The role of interleukin-1, interleukin-6, and glia in inducing growth of neuronal terminal arbors in mice. J Neurosci 2002; 22: 8034–8041.
Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 1998; 102: 1369–1376.
Kilpinen S, Hulkkonen J, Wang XY, Hurme M . The promotor polymorphism of the interleukin-6 gene regulates interleukin-6 production in neonates but not in adults. Eur Cytokine Netw 2001; 12: 62–68.
Reiman M, Kujari H, Ekholm E, Lapinleimu H, Lehtonen L, Haataja L . Interleukin-6 polymorphism is associated with chorioamnionitis and neonatal infections in preterm infants. J Pediatr 2008; 153: 19–24.
Resch B, Radinger A, Mannhalter C, Binder A, Haas J, Müller WD . Interleukin-6 G(−174)C polymorphism is associated with mental retardation in cystic periventricular leucomalacia of preterm infants. Arch Dis Child Fetal Neonatal Ed 2009; 94 (4): F304–F306. online first 15 January 2009.
Resch B, Gallistl S, Kutschera J, Mannhalter C, Muntean W, Müller W . Thrombophilic polymorphisms—factor V Leiden, prothrombin G20210A, and methylene-tetrahydrofolate reductase C677G mutations—and preterm birth. Wien Klin Wschr 2004; 116: 622–626.
Kurzawski M, Pawlik M, Czerny B, Domanski L, Rozanski J, Drozdzik M . Frequencies of the common promotor polymorphisms in cytokine genes in a Polish population. Int J Immunogenet 2005; 32: 285–291.
Donn RP, Barrett JH, Farhan A, Stopford A, Pepper L, Shelley E et al. Cytokine gene polymorphism and susceptibility to juvenile idiopathic arthritis. British Rheumatology Study Group. Arthritis Rheum 2001; 44: 802–810.
Nieters A, Brems S, Becker N . Cross-sectional study of cytokine polymorphisms, cytokine production after T-cell stimulation and clinical parameters in a random sample of German population. Hum Genet 2001; 108: 241–248.
Poli F, Nocco A, Berra S, Scalamogna M, Taioli E, Longhi E et al. Allele frequencies of polymorphisms of TNFA, IL-6, IL-10 and IFNG in an Italian Caucasian population. Eur J Immunogenet 2002; 29: 237–240.
Hoffmann SC, Stanley EM, Cox ED, DiMercurio BS, Koziol DE, Harlan DM et al. Ethnicity greatly influences cytokine gene polymorphism distribution. Am J Transplant 2002; 2: 560–567.
Haring D, Endler G, Hsieh K, Mannhalter C . Comparison of methods for determination of interleukin 6 G(−174)C promoter polymorphism. Biotechniques 2002; 33: 1114–1117.
Harding DR, Dhamrait S, Whitelaw A, Humphries S, Marlow N, Montgomery HE . Does interleukin6 genotype influence cerebral injury or developmental progress after preterm birth? Pediatrics 2004; 114: 941–947.
Speer EM, Gentile DA, Zeevi A, Pillage G, Huo D, Skoner DP . Role of single nucleotide polymorphisms of cytokine genes in spontaneous preterm delivery. Hum Immunol 2006; 67: 915–923.
Shah DK, Doyle LW, Anderson PJ, Bear M, Daley AJ, Hunt RW et al. Adverse neurodevelopment in preterm infants with postnatal sepsis or necrotizing enterocolitis is mediated by white matter abnormalities on magnetic resonance imaging at term. J Pediatr 2008; 153: 170–175.
Silveira RC, Procianoy RS, Dill JC, da Costa CS . Periventricular leukomalacia in very low birth weight preterm neonates with high risk for neonatal sepsis. J Pediatr (Rio J) 2008; 84: 211–216.
Acknowledgements
The study was supported by scholarships from the Medical University of Graz and the Erich-Lackner-Stiftung.
Contribution to authorship: BR und AR planned and performed the study and are mainly responsible for the paper; IL-6 genotyping was performed and procedures have been described for the Methods section by CM and BH; AB, WZ, WW and BP contributed data of the term newborns control group; WW and BP added significantly to the writing and discussion of the paper; JH did the statistical analyses and WM was the supervisor of the study (senior author). The study was approved by the local ethics committee (number 16-049 ex 04/05).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
The study was presented, in part, at the Meeting of the European Society of Paediatric Research in Prague in October 2007 (oral presentation).
Rights and permissions
About this article
Cite this article
Resch, B., Radinger, A., Mannhalter, C. et al. Maternal interleukin-6 (−174) C/C polymorphism is associated with chorioamnionitis and cystic periventricular leucomalacia of the preterm infant. J Perinatol 30, 712–716 (2010). https://doi.org/10.1038/jp.2010.30
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/jp.2010.30
Keywords
This article is cited by
-
The association between sex-related interleukin-6 gene polymorphisms and the risk for cerebral palsy
Journal of Neuroinflammation (2014)