title: Asthma-associated polymorphisms in 17q21 influence cord blood ORMDL3 and GSDMA gene expression and IL-17 secretion.
abstract: BACKGROUND
  In a genome-wide association study, genetic variants on chromosome 17q21 were strongly associated with childhood asthma and orosomucoid 1-like 3 (ORMDL3) gene expression. Regulation of the 17q21 locus and its immunologic relevance early in life have not been well characterized.
  
  
  OBJECTIVE
  We investigated the relation between polymorphisms and mRNA expression of 17q21 locus genes and their influence on T-cell subsets in cord blood.
  
  
  METHODS
  In 200 children of our cord blood study, 17q21 polymorphisms were genotyped by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Gene expression was assessed for ORMDL3; gasdermin A (GSDMA, alias GSDM1); gasdermin B (GSDMB, alias GSDML); Ikaros family zinc finger 3 (ZNFN1A3), zona pellucida binding protein 2 (ZPBP2); and proteasome (prosome, macropain) 26S subunit, non-ATPase, 3 (PSMD3), in cord blood mononuclear cells (CBMCs) and for ORMDL3 in peripheral blood (real-time RT-PCR). Mononuclear cells were assessed before and after microbial (lipid A/peptidoglycan), phytohemagglutinin, or allergen (Der p 1) stimulation. Regulatory T-associated markers (forkhead box protein 3, glucocorticoid-induced TNF receptor, lymphocyte activation gene 3 mRNA expression) and T(h)2/T(h)1/T(h)17 cytokines were examined.
  
  
  RESULTS
  In CBMCs, single genetic risk variants within 17q21 were associated with increased ORMDL3 (Der p 1 stimulation; P ≤ .01) and GSDMA expression (phytohemagglutinin/Der p 1 stimulation; P ≤ .05). Children homozygous for all 4 risk alleles for 17q21 tagging single nucleotide polymorphisms showed increased expression for ORMDL3 (Der p 1; P = .002) and GSDMA (phytohemagglutinin; P = .0009/Der p 1; P = .004). CBMC ORMDL3 expression was lower compared with PBMCs (P ≤ .0003) and increased in both CBMC and PBMC after stimulation (phytohemagglutinin/lipid A/peptidoglycan/Der p 1; P ≤ .006 and phytohemagglutinin/peptidoglycan; P < .05, respectively). No correlation between 17q21 polymorphisms and regulatory T/T(h)2/T(h)1 lineages was detectable. However, 17q21 risk allele carriers showed significantly increased IL-17 secretion (unstimulated, phytohemagglutinin-stimulated).
  
  
  CONCLUSIONS
  Our results suggest an association of 17q21 polymorphisms with ORMDL3, GSDMA expression, and IL-17 secretion early in life. These observations may imply a functional role of the 17q21 locus affecting T-cell development during immune maturation.
authors.affiliation: University Children's Hospital Munich, Department of Pulmonary and Allergy, LMU Munich, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Lluis
authors.forename: Michaela
authors.initials: M
authors.lastname: Schedel
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Sabina
authors.initials: S
authors.lastname: Illi
authors.forename: Martin
authors.initials: M
authors.lastname: Depner
authors.forename: Erika
authors.initials: E
authors.lastname: von Mutius
authors.forename: Michael
authors.initials: M
authors.lastname: Kabesch
authors.forename: Bianca
authors.initials: B
authors.lastname: Schaub
mesh_terms: D000483:Alleles; D001249:Asthma / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D055106:Genome-Wide Association Study; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D020381:Interleukin-17 / Q000097:blood*; D008565:Membrane Proteins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics; D012307:Risk Factors; D016176:T-Lymphocyte Subsets / Q000276:immunology; D000094524:Gasdermins
chemical_list: D020381:Interleukin-17; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; C485887:GSDMA protein, human; D000094524:Gasdermins; C464399:ORMDL3 protein, human