Interleukin-10 High Producer Allele and Ultrasound-Defined Periventricular White Matter Abnormalities in Preterm Infants: A Preliminary Study

Abstract

Objectives: Inflammation plays a role in prematurity, in neonatal disorders of the brain, lung, eye, bowel, and in developmental disability among preterm infants. We initiated a pilot study in preterm children to determine the prevalence of single nucleotide polymorphisms (SNPs) in the infection/inflammation-associated genes for interleukin (IL)-10 (- 1082 G/A), IL-1β (+ 3953 C/T), tumor necrosis factor (TNF)-α (- 308 G/A) and toll-like receptor 4 (TLR-4) (Asp299Gly) and whether these SNPs affect the risk for neonatal disorders. Study Design: We genotyped 73 children ≥ 2 years of age whose gestational age at birth was < 32 weeks, and explored the associations between genotypes and neonatal disorders and developmental status at age 2 + years. Results: Infants homozygous for the high IL-10 producer - 1082 G‐allele (n = 15) were significantly less likely to develop ultrasound-defined periventricular echodensities. A non-significant, but prominent, risk reduction for bronchopulmonary dysplasia, high-grade retinopathy, cerebral palsy, and developmental delay at age 2 + years was present. Polymorphisms in the IL-1β, TNF-α, and TLR-4 genes were too infrequent in our pilot sample to allow for reasonable analysis. Conclusion: Infants homozygous for the IL-10 high producer - 1082 G allele might be at reduced risk for prematurity-associated disorders.

Key words

Infant - premature - brain - cytokine - polymorphism

References

• 1 An H, Nishimaki S, Ohyama M, Haruki A, Naruto T, Kobayashi N. et al . Interleukin-6, interleukin-8, and soluble tumor necrosis factor receptor-I in the cord blood as predictors of chronic lung disease in premature infants.  Am J Obstet Gynecol. 2004;  191 1649-1654
• 2 Arbour N C, Lorenz E, Schutte B C, Zabner J, Kline J N, Jones M. et al . TLR4 mutations are associated with endotoxin hyporesponsiveness in humans.  Nat Genet. 2000;  25 187-191
• 3 Bancalari E, Claure N, Sosenko I RS. Bronchopulmonary dysplasia: changes in pathogenesis, epidemiology and definition.  Semin Neonatol. 2003;  8 63-71
• 4 Bos A F, Martijn A, Okken A, Prechtl H F. Quality of general movements in preterm infants with transient periventricular echodensities.  Acta Paediatrica. 1998;  87 328-335
• 5 Chen C C, Huang C B, Chung M Y, Huang L T, Yang C Y. Periventricular echogenicity is related to delayed neurodevelopment of preterm infants.  Am J Perinatol. 2004;  2 483-489
• 6 Dammann O, Leviton A. Duration of transient hyperechoic images of white matter in very-low-birth weight infants: a proposed classification.  Dev Med Child Neurol. 1997;  39 2-5
• 7 Dammann O, Leviton A. Inflammatory brain damage in preterm newborns - dry numbers, wet lab, and causal inference.  Early Hum Dev. 2004;  79 1-15
• 8 De Vries L S, Van Haastert I L, Rademaker K J, Koopman C, Groenendaal F. Ultrasound abnormalities preceding cerebral palsy in high-risk preterm infants.  J Pediatr. 2004;  144 815-820
• 9 Dommergues M A, Patkai J, Renauld J C, Evrard P, Gressens P. Proinflammatory cytokines and interleukin-9 exacerbate excitotoxic lesions of the newborn murine neopallium.  Ann Neurol. 2000;  47 54-63
• 10 Erickson S J, Grauaug A, Gurrin L, Swaminathan M. Hypocarbia in the ventilated preterm infant and its effect on intraventricular haemorrhage and bronchopulmonary dysplasia.  J Paediatr Child Health. 2002;  38 560-562
• 11 Fazzi E, Orcesi S, Caffi L, Ometto A, Rondini G, Telesca C. et al . Neurodevelopmental outcome at 5 - 7 years in preterm infants with periventricular leukomalacia.  Neuropediatrics. 1994;  25 134-139
• 12 Frankenburg W K, Dodds J, Archer P, Shapiro H, Bresnick B. The Denver II: a major revision and restandardization of the Denver developmental screening test.  Pediatrics. 1992;  89 91-97
• 13 Froen J F, Munkeby B H, Stray-Pedersen B, Saugstad O D. Interleukin-10 reverses acute detrimental effects of endotoxin-induced inflammation on perinatal cerebral hypoxia-ischemia.  Brain Res. 2002;  942 87-94
• 14 Goepfert A R, Andrews W W, Carlo W, Ramsey P S, Cliver S P, Goldenberg R L. et al . Umbilical cord plasma interleukin-6 concentrations in preterm infants and risk of neonatal morbidity.  Am J Obstet Gynecol. 2004;  191 1375-1381
• 15 Goldenberg R L, Hauth J C, Andrews W W. Intrauterine infection and preterm delivery.  N Engl J Med. 2000;  342 1500-1507
• 16 Goldstein B, Giroir B, Randolph A. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics.  Pediatr Crit Care Med. 2005;  6 2-8
• 17 Gopel W, Kattner E, Seidenberg J, Kohlmann T, Segerer H, Moller J. The effect of the Val34Leu polymorphism in the factor XIII gene in infants with a birth weight below 1500 g.  J Pediatr. 2002;  140 688-692
• 18 Hansen B M, Hoff B, Uldall P, Greisen G, Kamper J, Djernes B. et al . Perinatal risk factors of adverse outcome in very preterm children: a role of initial treatment of respiratory insufficiency?.  Acta Paediatr. 2004;  93 185-189
• 19 Harding D, Brull D, Humphries S E, Whitelaw A, Montgomery H, Marlow N. Variation in the interleukin-6 gene is associated with impaired cognitive development in children born prematurely: a preliminary study.  Pediatr Res. 2005;  58 117-120
• 20 ICROP . An international classification of retinopathy of prematurity.  Pediatrics. 1984;  74 127-133
• 21 Inder T E, Anderson N J, Spencer C, Wells S, Volpe J J. White matter injury in the premature infant: a comparison between serial cranial sonographic and MR findings at term.  AJNR Am J Neuroradiol. 2003;  24 805-809
• 22 Jobe A H. Antenatal factors and the development of bronchopulmonary dysplasia.  Semin Neonatol. 2003;  8 9-17
• 23 Jones C A, Cayabyab R G, Kwong K Y, Stotts C, Wong B, Hamdan H. et al . Undetectable interleukin (IL)-10 and persistent IL‐8 expression early in hyaline membrane disease: a possible developmental basis for the predisposition to chronic lung inflammation in preterm newborns.  Pediatr Res. 1996;  39 966-975
• 24 Kerk J, Dordelmann M, Bartels D B, Brinkhaus M J, Dammann C EL, Dork T. et al . Multiplex measurement of cytokine/receptor gene polymorphisms and interaction between interleukin 10 (- 1082) genotype and chorioamnionitis in extreme preterm delivery.  J Soc Gynecol Investig. 2006;  13 350
• 25 Kreuzer C, Urlesberger B, Maurer U, Muller W. (Transient periventricular echodensities [TPE] in preterm infants under 1500 gramms: an analysis of the outcome of the last 10 years).  Klin Padiatr. 2003;  215 252-256
• 26 Kuban K C, Leviton A. Cerebral palsy.  N Engl J Med. 1994;  330 188-195
• 27 Kwong K Y, Jones C A, Cayabyab R, Lecart C, Khuu N, Rhandhawa I. et al . The effects of IL‐10 on proinflammatory cytokine expression (IL-1beta and IL‐8) in hyaline membrane disease (HMD).  Clin Immunol Immunopathol. 1998;  88 105-113
• 28 Lai F F, Tsou K Y. Transient periventricular echodensities and developmental outcome in preterm infants.  Pediatr Neurol. 1999;  21 797-801
• 29 Leviton A, Paneth N, Reuss M L, Susser M, Allred E N, Dammann O. et al . Maternal infection, fetal inflammatory response, and brain damage in very low birth weight infants.  Pediatric Research. 1999;  46 566-575
• 30 Lyng K, Munkeby B H, Saugstad O D, Stray-Pedersen B, Froen J F. Effect of interleukin-10 on newborn piglet brain following hypoxia-ischemia and endotoxin-induced inflammation.  Biol Neonate. 2005;  87 207-216
• 31 Maalouf E F, Duggan P J, Counsell S J, Rutherford M A, Cowan F, Azzopardi D. et al . Comparison of findings on cranial ultrasound and magnetic resonance imaging in preterm infants.  Pediatrics. 2001;  107 719-727
• 32 Mesples B, Plaisant F, Gressens P. Effects of interleukin-10 on neonatal excitotoxic brain lesions in mice.  Brain Res Dev Brain Res. 2003;  141 25-32
• 33 Moore K W, de Waal Malefyt R, Coffman R L, O'Garra A. Interleukin-10 and the interleukin-10 receptor.  Ann Rev Immunol. 2001;  19 683-765
• 34 Mormann M, Rieth H, Hua T D, Assohou C, Roupelieva M, Hu S L. et al . Mosaics of gene variations in the Interleukin-10 gene promoter affect interleukin-10 production depending on the stimulation used.  Genes Immun. 2004;  5 246-255
• 35 Nelson K B, Dambrosia J M, Iovannisci D M, Cheng S, Grether J K, Lammer E. Genetic polymorphisms and cerebral palsy in very preterm infants.  Pediatr Res. 2005;  57 494-499
• 36 Ogunyemi D, Murillo M, Jackson U, Hunter N, Alperson B. The relationship between placental histopathology findings and perinatal outcome in preterm infants.  J Matern Fetal Neonatal Med. 2003;  13 102-109
• 37 O'Shea T M, Kothadia J M, Roberts D D, Dillard R G. Perinatal events and the risk of intraparenchymal echodensity in very-low-birth weight neonates.  Paediatr Perinat Epidemiol. 1998;  12 408-421
• 38 Pinsky M R, Vincent J L, Deviere J, Alegre M, Kahn R J, Dupont E. Serum cytokine levels in human septic shock. Relation to multiple-system organ failure and mortality.  Chest. 1993;  103 565-575
• 39 Pociot F, Molvig J, Wogensen L, Worsaae H, Nerup J. A TaqI polymorphism in the human interleukin-1 beta (IL‐1 beta) gene correlates with IL‐1 beta secretion in vitro.  Eur J Clin Invest. 1992;  22 396-402
• 40 Resch B, Vollaard E, Maurer U, Haas J, Rosegger H, Muller W. Risk factors and determinants of neurodevelopmental outcome in cystic periventricular leucomalacia.  Eur J Pediatr. 2000;  159 663-670
• 41 Rodts-Palenik S, Wyatt-Ashmead J, Pang Y, Thigpen B, Cai Z, Rhodes P. et al . Maternal infection-induced white matter injury is reduced by treatment with interleukin-10.  Am J Obstet Gynecol. 2004;  191 1387-1392
• 42 Sonnander K. Early identification of children with developmental disabilities.  Acta Paediatr Suppl. 2000;  89 17-23
• 43 Speer C P. Pre- and postnatal inflammatory mechanisms in chronic lung disease of preterm infants.  Paediatr Respir Rev. 2004;  5 (Suppl A) S241-S244
• 44 Stoelhorst G M, Rijken M, Martens S E, van Zwieten P H, Feenstra J, Zwinderman A H. et al . Developmental outcome at 18 and 24 months of age in very preterm children: a cohort study from 1996 to 1997.  Early Hum Dev. 2003;  72 83-95
• 45 Turner D M, Williams D M, Sankaran D, Lazarus M, Sinnott P J, Hutchinson I V. An investigation of polymorphism in the interleukin-10 gene promoter.  Eur J Immunogenet. 1997;  24 1-8
• 46 Vohr B R, Wright L L, Dusick A M, Perritt R, Poole W K, Tyson J E. et al . Center differences and outcomes of extremely low birth weight infants.  Pediatrics. 2004;  113 781-789
• 47 Voigt M, Schneider K T, Jahrig K. [Analysis of a 1992 birth sample in Germany. 1: New percentile values of the body weight of newborn infants].  Geburtsh Frauenheilkd. 1996;  56 550-558
• 48 Wilson A G, Symons J A, McDowell T L, McDevitt H O, Duff G W. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation.  Proc Natl Acad Sci USA. 1997;  94 3195-3199
• 49 Wu Y W. Systematic review of chorioamnionitis and cerebral palsy.  Mental Retardation and Developmental Disabilities Research Reviews. 2002;  8 25-29
• 50 Yanamandra K, Boggs P, Loggins J, Baier R J. Interleukin-10 - 1082 G/A polymorphism and risk of death or bronchopulmonary dysplasia in ventilated very low birth weight infants.  Pediatr Pulmonol. 2005;  39 426-432

1 These two authors contributed equally