Abstract
In this study, we determined the genotype frequencies of polymorphisms of cytokine genes and investigated their association with the risk of respiratory distress syndrome (RDS) in preterm infants. Genetic polymorphisms in the cytokines interleukin (IL)-10, IL-8, and tumor necrosis factor (TNF) α, were studied in 342 white Italian newborns (112 without RDS, 66 prematurely born with RDS, and 164 infants born at term who were included as healthy controls). The polymorphisms were analyzed by polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP). The IL-10 mRNA levels were analyzed according to genotype by quantitative real-time PCR (QRT-PCR) in Epstein-Barr virus–transformed lymphoblastoid cell lines (EBV-LCLs) of 42 full-term healthy infants. Logistic regression analysis demonstrated the risk of RDS to be significantly lower in preterm infants with an IL-10 –1082 GG/GA genotype than in those with an AA genotype [odds ratio (OR) = 0.48, 95% confidence interval (CI): 0.24–0.95, p = 0.03]. QRT-PCR analyses showed that the IL-10 mRNA levels were significantly higher in 27 IL-10 –1082 GG/GA carriers compared with 15 IL-10 –1082 AA carriers (p = 0.03). We conclude that the IL-10 –1082 GG/GA polymorphism may have a role in RDS development in premature infants.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- EBV-LCLs:
-
Epstein-Barr virus–transformed lymphoblastoid cell lines
- NF-κB:
-
nuclear factor κB
- QRT-PCR:
-
quantitative real-time PCR
- SNPs:
-
single nucleotide polymorphisms
- SP:
-
surfactant protein
References
Pryhuber GS 1998 Regulation and function of pulmonary surfactant protein B. Mol Genet Metab 64: 217–228
Haataja R, Ramet M, Martilla R, Hallman M 2000 Surfactant proteins A and B as interactive genetic determinants of neonatal respiratory distress syndrome. Hum Mol Genet 9: 2751–2760
Haataja R, Martilla R, Uimar P, Lofgren J, Ramet M, Hallman M 2001 Respiratory distress syndrome: evaluation of genetic susceptibility and protection by transmission disequilibrium test. Hum Genet 109: 351–355
Rämet M, Haataja R, Marttila R, Floros J, Hallman M 2000 Association between the surfactant protein A (SP-A) gene locus and respiratory-distress syndrome in the Finnish population. Am J Hum Genet 66: 1569–1579
Copland IB, Post M 2002 Understanding the mechanisms of infant respiratory distress and chronic lung disease. Am J Respir Cell Mol Biol 26: 261–265
Speer CP, Ruess D, Harms K, Herting E, Gefeller O 1993 Neutrophil elastase and acute pulmonary damage in neonates with severe respiratory distress syndrome. Pediatrics 91: 794–799
Wispe JR, Clark JC, Warner BB, Fajardo D, Hull WE, Holtzman RB, Whitsett JA 1990 Tumor necrosis factor-alpha inhibits expression of pulmonary surfactant protein. J Clin Invest 86: 1954–1960
Wright JR 1997 Immunomodulatory functions of surfactant. Physiol Rev 77: 931–962
Murch SH, Costeloe K, Klein NJ, MacDonald TT 1996 Early production of macrophage inflammatory protein-1 alpha occurs in respiratory distress syndrome and is associated with poor outcome. Pediatr Res 40: 490–497
Brus F, Vanoeveren W, Okken A, Oetom SB 1996 Activation of circulating polymorphonuclear leukocytes in preterm infants with severe idiopathic respiratory distress syndrome. Pediatr Res 39: 456–463
Ferreira PJ, Bunch TJ, Albertine KH, Carlton DP 2000 Circulating neutrophil concentration and respiratory distress in premature infants. J Pediatr 136: 466–472
Nupponen I, Pesonen E, Andersson S, Makela A, Turnen R, Kautiainen H 2002 Neutrophil activation in preterm infants who have respiratory distress syndrome. Pediatrics 110: 36–41
Jones CA, Cayabyab RG, Kwong KY, Stotts C, Wong B, Hamdan H 1996 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 39: 966–975
Kwong KY, Jones CA, Cayabyab R 1998 Differential regulation of IL-8 by IL-1beta and TNFalpha in hyaline membrane disease. J Clin Immunol 18: 71–80
Bidwell J, Keen L, Gallagher G, Kimberly R, Huizinga T, McDermott MF, Oksenberg J, McNicholl J, Pociot F, Hardt C, D'Alfonso S 2001 Cytokine gene polymorphism in human disease: on-line databases. Genes Immun 2: 61–70
Chomczynski P, Sacchi N 1987 Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156–159
Livak KJ, Schmitteng TD 2001 Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)). Methods 25: 402–408
Asadullah K, Sterry W, Volk HD 2003 Interleukin-10 therapy—review of a new approach. Pharmacol Rev 55: 241–269
Hajeer AH, Lazarus M, Turner D, Mageed RA, Vencovsky J, Sinnott P, Hajeer AH, Lazarus M, Turner D, Mageed RA, Vencovsky J, Sinnott P, Hutchinson IV, Ollier WE 1998 IL10 gene promoter polymorphisms in rheumatoid arthritis. Scand J Rheumatol 27: 142–145
Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV 1997 An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 24: 1–8
Eskdale J, Gallagher G, Verweij CL, Keijsers V, Westendorp RG, Huizinga TW 1998 Interleukin 10 secretion in relation to human IL-10 locus haplotypes. Proc Natl Acad Sci U S A 95: 9465–9470
Suarez A, Castro P, Alonso R, Mozo L, Gutierrez C 2003 Interindividual variations in constitutive interleukin-10 messenger RNA and protein levels and their association with genetic polymorphisms. Transplantation 75: 711–717
Reuss E, Fimmers R, Kruger A, Becker C, Rittner C, Hohler T 2002 Differential regulation of interleukin-10 production by genetic and environmental factors - a twin study. Genes Immun 3: 407–413
Huang HC, Yang MY, Huang CB, Yang KD 2000 Profiles of inflammatory cytokines in bronchoalveolar lavage fluid from premature infants with respiratory distress disease. J Microbiol Immunol Infect 33: 19–24
Jonsson B, Li YH, Noack G, Brauner A, Tullus K 2000 Downregulatory cytokines in tracheobronchial aspirate fluid from infants with chronic lung disease of prematurity. Acta Paediatr 89: 1375–1380
Yanamandra K, Boggs P, Loggins J, Baier RJ 2005 Interleukin-10 –1082 G/A polymorphism and risk of death or bronchopulmonary dysplasia in ventilated very low birth weight infants. Pediatr Pulmonol 39: 426–432
Groneck P, Speer CP 1995 Inflammatory mediators and bronchopulmonary dysplasia. Arch Dis Child Fetal Neonatal Ed 73: F1–F3
Jobe AH, Bancalari E 2001 Bronchopulmonary dysplasia. Am J Respir Crit Care Med 163: 1723–1729
Kwong KY, Jones CA, Cayabyab R 1998 The effects of IL-10 on proinflammatory cytokine expression (IL-1beta and IL-8) in hyaline membrane disease (HMD). Clin Immunol Immunopathol 88: 105–113
Gong MN, Thompson BT, Williams PL, Zhou W, Wang MZ, Pothier L, Christiani DC 2006 Interleukin-10 polymorphism in position -1082 and acute respiratory distress syndrome. Eur Respir J 27: 674–681
Henao MI, Montes C, Paris SC, Garcia LF 2006 Cytokine gene polymorphisms in Colombian patients with different clinical presentations of tuberculosis. Tuberculosis (Edinb) 86: 11–19
Chong WP, Ip WK, Wong WH 2004 Association of interleukin-10 promoter polymorphisms with systemic lupus erythematosus. Genes Immun 5: 484–492
Moraes MO, Pacheco AG, Schonkeren JJ 2004 Interleukin-10 promoter single-nucleotide polymorphisms as markers for disease susceptibility and disease severity in leprosy. Genes Immun 5: 592–595
Bry K, Lappalainen U, Hallman M 1997 Intraamniotic interleukin-1 accelerates surfactant protein synthesis in fetal rabbits and improves lung stability after premature birth. J Clin Invest 99: 2992–2999
Emerson GA, Bry K, Hallman M, Jobe AH, Wada N, Ervin MG, Ikegami M 1997 Intra-amniotic interleukin-1 alpha treatment alters postnatal adaptation in premature lambs. Biol Neonate 72: 370–379
Glumoff V, Vayrynen O, Kangas T, Hallman M 2000 Degree of lung maturity determines the direction of the interleukin-1-induced effect on the expression of surfactant proteins. Am J Respir Cell Mol Biol 22: 280–288
Watterberg KL, Demers LM, Scott SM, Murphy S 1996 Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 97: 210–215
Hallak M, Bottoms SF 1993 Accelerated pulmonary maturation from preterm premature rupture of membranes: a myth. Am J Obstet Gynecol 169: 1045–1049
Schottelius AJ, Mayo MW, Sartor RB, Baldwin AS Jr 1999 Interleukin-10 signaling blocks inhibitor of kappaB kinase activity and nuclear factor kappaB DNA binding. J Biol Chem 274: 31868–31874
Wang P, Wu P, Siegel MI, Egan RW, Billah MM 1995 Interleukin (IL)-10 inhibits nuclear factor kappa B (NF kappa B) activation in human monocytes. IL-10 and IL-4 suppress cytokine synthesis by different mechanisms. J Biol Chem 270: 9558–9563
Cao L, Liu C, Cai B, Jia X, Kang L, Speer CP, Sun B 2004 Nuclear factor-kappa B expression in alveolar macrophages of mechanically ventilated neonates with respiratory distress syndrome. Biol Neonate 86: 116–123
Acknowledgements
The authors thank the parents of the newborn infants who agreed to participate in this project.
Author information
Authors and Affiliations
Corresponding author
Additional information
This work was partially supported by AIRC, MURST- PRIN, Ministero Sanità, and Telethon.
Rights and permissions
About this article
Cite this article
Capasso, M., Avvisati, R., Piscopo, C. et al. Cytokine Gene Polymorphisms in Italian Preterm Infants: Association Between Interleukin-10 –1082 G/A Polymorphism and Respiratory Distress Syndrome. Pediatr Res 61, 313–317 (2007). https://doi.org/10.1203/pdr.0b013e318030d108
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/pdr.0b013e318030d108
This article is cited by
-
The association of LPCAT1-rs9728 polymorphism with cord blood IL-10, MIF, and VEGF levels in neonatal respiratory distress syndrome: a case–control study
The Egyptian Journal of Bronchology (2024)
-
Interesting effects of interleukins and immune cells on acute respiratory distress syndrome
Clinical and Experimental Medicine (2023)
-
IL-10 c.-592C>A (rs1800872) polymorphism is associated with cervical cancer
Journal of Cancer Research and Clinical Oncology (2020)
-
HIF-1 transcription activity: HIF1A driven response in normoxia and in hypoxia
BMC Medical Genetics (2019)
-
Association of IL-10 Gene Polymorphism (−819C > T, −592C > A and −1082G > A) with Preterm Birth
The Indian Journal of Pediatrics (2018)


