title: Genetic polymorphisms and risk of recurrent wheezing in pediatric age.
abstract: BACKGROUND
  Wheezing during early life is a very common disorder, but the reasons underlying the different wheezing phenotypes are still unclear. The aims of this study were to analyse the potential correlations between the risk of developing recurrent wheezing and the presence of specific polymorphisms of some genes regulating immune system function, and to study the relative importance of the associations of different viruses and genetic polymorphisms in causing recurrent episodes.
  
  
  METHODS
  The study involved 119 otherwise healthy infants admitted to hospital for a first episode of wheezing (74 of whom subsequently experienced recurrent episodes) and 119 age- and sex-matched subjects without any history of respiratory problem randomly selected from those attending our outpatient clinic during the study period. All of the study subjects were followed up for two years, and 47 single nucleotide polymorphisms (SNPs) in 33 candidate genes were genotyped on whole blood using an ABI PRISM 7900 HT Fast Real-time instrument.
  
  
  RESULTS
  IL8-rs4073AT, VEGFA-rs833058CT, MBL2-rs1800450CT and IKBKB-rs3747811AT were associated with a significantly increased risk of developing wheezing (p = 0.02, p = 0.03, p = 0.05 and p = 0.0018), whereas CTLA4-rs3087243AG and NFKBIB-rs3136641TT were associated with a significantly reduced risk (p = 0.05 and p = 0.04). IL8-rs4073AT, VEGFA-rs2146323AA and NFKBIA-rs2233419AG were associated with a significantly increased risk of developing recurrent wheezing (p = 0.04, p = 0.04 and p = 0.03), whereas TLR3-rs3775291TC was associated with a significantly reduced risk (p = 0.03). Interestingly, the study of gene-environment interactions showed that rhinovirus was significantly associated with recurrent wheezing in the presence of IL4Ra-rs1801275GG and G (odds ratio [OR] 6.03, 95% confidence interval [CI]: 1.21-30.10, p = 0.03) and MAP3K1-rs702689AA (OR 4.09, 95% CI: 1.14-14.61, p = 0.03).
  
  
  CONCLUSIONS
  This study shows a clear relationship between the risk of wheezing and polymorphisms of some genes involved in the immune response. Although further studies are needed to confirm the results, these findings may be useful for the early identification of children at the highest risk of developing recurrent episodes and possibly subsequent asthma.
authors.affiliation: Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Commenda 9, 20122 Milan, Italy. susanna.esposito@unimi.it.
authors.forename: Susanna
authors.initials: S
authors.lastname: Esposito
authors.forename: Valentina
authors.initials: V
authors.lastname: Ierardi
authors.forename: Cristina
authors.initials: C
authors.lastname: Daleno
authors.forename: Alessia
authors.initials: A
authors.lastname: Scala
authors.forename: Leonardo
authors.initials: L
authors.lastname: Terranova
authors.forename: Claudia
authors.initials: C
authors.lastname: Tagliabue
authors.forename: Walter Peves
authors.initials: WP
authors.lastname: Rios
authors.forename: Claudio
authors.initials: C
authors.lastname: Pelucchi
authors.forename: Nicola
authors.initials: N
authors.lastname: Principi
mesh_terms: D060908:CTLA-4 Antigen / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D059647:Gene-Environment Interaction; D005838:Genotype; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics; D020672:I-kappa B Proteins / Q000235:genetics; D007223:Infant; D007231:Infant, Newborn; D053662:Interleukin-4 Receptor alpha Subunit / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics; D008297:Male; D037601:Mannose-Binding Lectin / Q000235:genetics; D000072000:NF-KappaB Inhibitor alpha; D010850:Picornaviridae Infections / Q000150:complications*; D020641:Polymorphism, Single Nucleotide; D012008:Recurrence; D012135:Respiratory Sounds / Q000209:etiology / Q000235:genetics*; D012229:Rhinovirus; D012307:Risk Factors; D051196:Toll-Like Receptor 3 / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D053662:Interleukin-4 Receptor alpha Subunit; D016209:Interleukin-8; C445619:MBL2 protein, human; D037601:Mannose-Binding Lectin; C000606204:NFKBIA protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D042461:Vascular Endothelial Growth Factor A; D000072000:NF-KappaB Inhibitor alpha; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human