title: IL-33 polymorphisms are associated with increased risk of hay fever and reduced regulatory T cells in a birth cohort.
abstract: IL-33 polymorphisms influence the susceptibility to asthma. IL-33 indirectly induces Th2-immune responses via dendritic cell activation, being important for development of atopic diseases. Furthermore, IL-33 upregulates regulatory T cells (Tregs), which are critical for healthy immune homeostasis. This study investigates associations between IL-33 polymorphisms during the development of childhood atopic diseases and underlying mechanisms including immune regulation of Tregs.
  
  
  
  Genotyping of IL-33-polymorphisms (rs928413, rs1342326) was performed by MALDI-TOF-MS in 880 of 1133 PASTURE/EFRAIM children. In 4.5-year-old German PASTURE/EFRAIM children (n = 99), CD4+CD25highFOXP3+Tregs were assessed by flow cytometry following 24-h incubation of PBMCs with PMA/ionomycin, LPS or without stimuli (U). SOCS3, IL1RL1, TLR4 mRNA expression and sST2 protein levels ex vivo were measured in PASTURE/EFRAIM children by real-time PCR or ELISA, respectively. Health outcomes (hay fever, asthma) were assessed by questionnaires at the age of 6 years.
  
  
  
  rs928413 and rs1342326 were positively associated with hay fever (OR = 1.77, 95%CI = 1.02-3.08; OR = 1.79, 95%CI = 1.04-3.11) and CD4+CD25highFOXP3+Tregs (%) decreased in minor allele homozygotes/heterozygotes compared to major allele homozygotes (p(U) = 0.004; p(LPS) = 0.005; p(U) = 0.001; p(LPS) = 0.012). SOCS3 mRNA expression increased in minor allele homozygotes and heterozygotes compared with major allele homozygotes for both IL-33-polymorphisms (p(rs928413) = 0.032, p(rs1342326) = 0.019) and negatively correlated to Tregs.
  
  
  
  IL-33-polymorphisms rs928413 and rs1342326 may account for an increased risk of hay fever with the age of 6 years. Lower Tregs and increased SOCS3 in combined heterozygotes and minor allele homozygotes may be relevant for hay fever development, pointing towards dysbalanced immune regulation and insufficient control of allergic inflammation.
authors.affiliation: LMU Munich, University Children's Hospital, Munich, Germany.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Schröder
authors.affiliation: LMU Munich, University Children's Hospital, Munich, Germany.
authors.forename: Vera I
authors.initials: VI
authors.lastname: Casaca
authors.affiliation: LMU Munich, University Children's Hospital, Munich, Germany.
authors.forename: Sabina
authors.initials: S
authors.lastname: Illi
authors.affiliation: Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.|Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Schieck
authors.affiliation: Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.|Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Michel
authors.affiliation: LMU Munich, University Children's Hospital, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Böck
authors.affiliation: Children's Hospital, and Christine Kühne-Center for Allergy Research and Education, University of Zurich, Zurich, Switzerland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Roduit
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.|Christine Kühne-Center for Allergy research and Education, Hochgebirgsklinik Davos-Wolfgang, Davos, Switzerland.
authors.forename: Remo
authors.initials: R
authors.lastname: Frei
authors.affiliation: National Jewish Health, Denver, CO, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Lluis
authors.affiliation: Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany.
authors.forename: Jon
authors.identifier: 0000-0001-5764-1528
authors.initials: J
authors.lastname: Genuneit
authors.affiliation: Department of Clinical Chemistry and Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Pfefferle
authors.affiliation: Living Environment and Health Unit, National Institute for Health and Welfare, Kuopio, Finland.
authors.forename: Marjut
authors.initials: M
authors.lastname: Roponen
authors.affiliation: LMU Munich, University Children's Hospital, Munich, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Weber
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Braun-Fahrländer
authors.affiliation: Children's Hospital Schwarzach, Schwarzach, Austria.
authors.forename: Josef
authors.initials: J
authors.lastname: Riedler
authors.affiliation: Christine Kühne-Center for Allergy research and Education, Hochgebirgsklinik Davos-Wolfgang, Davos, Switzerland.|Children's Hospital of Eastern Switzerland, St. Gallen, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Lauener
authors.affiliation: University Hospital of Besançon, the Research Unit Health and Rural Environment, University of Franche-Comté, Besançon, France.
authors.forename: Dominique Angèle
authors.initials: DA
authors.lastname: Vuitton
authors.affiliation: University Hospital of Besançon, the Research Unit Health and Rural Environment, University of Franche-Comté, Besançon, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Dalphin
authors.affiliation: Living Environment and Health Unit, National Institute for Health and Welfare, Kuopio, Finland.|Department of Public health, University of Helsinki, Helsinki, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Pekkanen
authors.affiliation: LMU Munich, University Children's Hospital, Munich, Germany.
authors.forename: Erika
authors.initials: E
authors.lastname: von Mutius
authors.affiliation: Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.|Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kabesch
authors.affiliation: LMU Munich, University Children's Hospital, Munich, Germany. Bianca.Schaub@med.uni-muenchen.de.
authors.forename: Bianca
authors.initials: B
authors.lastname: Schaub
mesh_terms: D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005858:Germany; D006801:Humans; D000067596:Interleukin-33 / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D006255:Rhinitis, Allergic, Seasonal / Q000235:genetics*; D012306:Risk; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D000067596:Interleukin-33; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein
keywords: 
  IL-33
  ; Tregs; childhood; hay fever; polymorphisms