Association of interferon γ T+874A and interleukin 12 p40 promoter CTCTAA/GC polymorphism with the need for respiratory support and perinatal complications in low birthweight neonates

Background: Data support the role of interferon (IFN)γ and interleukin (IL)12 in perinatal complications. IFNγ T+874A and IL12 p40 promoter CTCTAA/GC polymorphisms may have an effect on cytokine production. Methods: DNA was extracted from dried blood samples of 153 low birthweight (LBW) infants and 172 healthy term infants. IFNγ and IL12 genetic polymorphisms were determined to investigate the association between polymorphisms and ventilation characteristics, bronchopulmonary dysplasia (BPD) and other perinatal disorders. Results: The IFNγ+874A allele was over-represented in LBW infants. Carriers of the IFNγ+874T allele required mechanical ventilation and oxygen supplementation for time periods 41% and 35%, respectively, shorter than those required by those not carrying the IFNγ+874T allele. Stepwise logistic regression analysis showed that carriers of the IFNγ+874T allele were protected against BPD (odds ratio (OR) 0.35 (95% confidence interval (CI) (0.12 to 0.99))) and patent ductus arteriosus (OR 0.43 (95% CI 0.19 to 0.97)), whereas carriers of the IFNγ+874A allele were at higher risk of severe hypotension (OR 3.40 (95% CI 1.01 to 11.52)) and respiratory distress syndrome (OR 4.03 (95% CI 1.30 to 12.50)). Carriers of the IL12 GC allele were protected against pneumonia (OR 0.32 (95% CI 0.14 to 0.75)). Carriers of the IL12 CTCTAA allele were at higher risk of developing necrotising enterocolitis (NEC; OR 2.37 (95% CI 1.01 to 5.53)). Conclusions: Carrier state of the IFNγ+874A allele presents an increased risk for premature birth and lung damage, as well as other perinatal complications. The risks of pneumonia and NEC are higher in heterozygotic carriers of the IL12 CTCTAA/GC polymorphism. Further studies are needed to determine whether these associations are the result of altered cytokine-producing capacity in infants carrying the tested alleles.

[1]  E. Kattner,et al.  Association of two tumour necrosis factor gene polymorphisms with the incidence of severe intraventricular haemorrhage in preterm infants , 2005, Journal of Medical Genetics.

[2]  C. Delacourt,et al.  Control Mechanisms of Lung Alveolar Development and Their Disorders in Bronchopulmonary Dysplasia , 2005, Pediatric Research.

[3]  C. D. Krause,et al.  Interferons, interferon‐like cytokines, and their receptors , 2004, Immunological reviews.

[4]  C. Mullighan,et al.  Interleukins-1, -4, -6, -10, tumor necrosis factor, transforming growth factor-beta, FAS, and mannose-binding protein C gene polymorphisms in Australian women: Risk of preterm birth. , 2004, American journal of obstetrics and gynecology.

[5]  W. McGuire,et al.  Respiratory complications of preterm birth , 2004, BMJ : British Medical Journal.

[6]  Ming-Tseh Lin,et al.  Adverse outcomes after preterm labor are associated with tumor necrosis factor-alpha polymorphism -863, but not -308, in mother-infant pairs. , 2004, American journal of obstetrics and gynecology.

[7]  H. Zola,et al.  Rapid simultaneous measurement of multiple cytokines using 100 µl sample volumes − association with neonatal sepsis , 2004, Clinical and experimental immunology.

[8]  S. Kazzi,et al.  Polymorphism of tumor necrosis factor-alpha and risk and severity of bronchopulmonary dysplasia among very low birth weight infants. , 2004, Pediatrics.

[9]  R. Testa,et al.  Cytokine Gene Polymorphisms in Recurrent Pregnancy Loss of Unknown Cause , 2004, American journal of reproductive immunology.

[10]  R. Mattar,et al.  Cytokines in recurrent pregnancy loss. , 2004, Journal of reproductive immunology.

[11]  J. Goldblatt,et al.  Associations of the IL12B promoter polymorphism in longitudinal data from asthmatic patients 7 to 42 years of age. , 2004, The Journal of allergy and clinical immunology.

[12]  R. Carini,et al.  Age-Related Changes in Intracellular Th1/Th2 Cytokine Production, Immunoproliferative T Lymphocyte Response and Natural Killer Cell Activity in Newborns, Children and Adults , 2003, Neonatology.

[13]  J. O’Shea,et al.  The biology of IL-12: coordinating innate and adaptive immune responses. , 2003, Cytokine & growth factor reviews.

[14]  B. Vásárhelyi,et al.  Genetic Variants of TNF-α, IL-1β, IL-4 Receptor α-Chain, IL-6 and IL-10 Genes Are Not Risk Factors for Sepsis in Low-Birth-Weight Infants , 2003, Neonatology.

[15]  Geng Li,et al.  Proinflammatory and anti-inflammatory cytokine responses in preterm infants with systemic infections , 2003, Archives of disease in childhood. Fetal and neonatal edition.

[16]  J. Penninger,et al.  IL-1 Receptor-Associated Kinase 4 Is Essential for IL-18-Mediated NK and Th1 Cell Responses1 , 2003, The Journal of Immunology.

[17]  P. Bartmann,et al.  Modulation of pro- and anti-inflammatory cytokine production in very preterm infants. , 2003, Cytokine.

[18]  C. Speer.  Inflammation and bronchopulmonary dysplasia. , 2003, Seminars in neonatology : SN.

[19]  W. Hop,et al.  Are cytokine gene polymorphisms related to in vitro cytokine production profiles? , 2003, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[20]  A. Pain,et al.  A promoter polymorphism in the gene encoding interleukin-12 p40 (IL12B) is associated with mortality from cerebral malaria and with reduced nitric oxide production , 2002, Genes and Immunity.

[21]  G. Morahan,et al.  Association of IL12B promoter polymorphism with severity of atopic and non-atopic asthma in children , 2002, The Lancet.

[22]  L. Maródi.  Down‐regulation of Th1 responses in human neonates , 2002, Clinical and experimental immunology.

[23]  H. Van Bever,et al.  The role of inflammation in the development of chronic lung disease in neonates , 2001, European Journal of Pediatrics.

[24]  L. Bont,et al.  Local interferon-gamma levels during respiratory syncytial virus lower respiratory tract infection are associated with disease severity. , 2001, The Journal of infectious diseases.

[25]  G. Morahan,et al.  Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele , 2001, Nature Genetics.

[26]  G. Morahan,et al.  Complete primary structure, chromosomal localisation, and definition of polymorphisms of the gene encoding the human interleukin-12 p40 subunit , 2000, Genes and Immunity.

[27]  A. Stevens,et al.  A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production. , 2000, Human immunology.

[28]  A. Jobe,et al.  Mechanisms initiating lung injury in the preterm. , 1998, Early human development.

[29]  R. Ballard,et al.  Avery's Diseases of the Newborn , 1998 .

[30]  F. Belardelli,et al.  IFN-γ Expression in Macrophages and Its Possible Biological Significance , 1998 .

[31]  P. Tarczy-Hornoch,et al.  Amniotic fluid tumor necrosis factor-alpha and the risk of respiratory distress syndrome among preterm infants. , 1997, American journal of obstetrics and gynecology.

[32]  B. Vásárhelyi,et al.  The association of the carrier state of the tumor necrosis factor-α (TNFα) -308 A allele with the duration of oxygen supplementation in preterm neonates , 2005 .

[33]  B. Vásárhelyi,et al.  The association of the carrier state of the tumor necrosis factor-alpha (TNFalpha) -308A allele with the duration of oxygen supplementation in preterm neonates. , 2005, European cytokine network.

[34]  L. Monte,et al.  [Bronchopulmonary dysplasia]. , 2005, Jornal de pediatria.

[35]  L. Maródi.  IL-12 and IFN-gamma deficiencies in human neonates. , 2001, Pediatric research.

[36]  F. Belardelli,et al.  IFN-gamma expression in macrophages and its possible biological significance. , 1998, Cytokine & growth factor reviews.