Asthma-associated polymorphisms in 17q21 influence cord blood ORMDL3 and GSDMA gene expression and IL-17 secretion

J Allergy Clin Immunol. 2011 Jun;127(6):1587-94.e6. doi: 10.1016/j.jaci.2011.03.015. Epub 2011 May 4.


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).

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Asthma / blood
  • Asthma / genetics*
  • Asthma / immunology*
  • Chromosomes, Human, Pair 17 / genetics*
  • Fetal Blood / cytology
  • Fetal Blood / immunology
  • Fetal Blood / metabolism
  • Gene Expression
  • Genome-Wide Association Study
  • Homozygote
  • Humans
  • Infant, Newborn
  • Interleukin-17 / blood*
  • Membrane Proteins / genetics*
  • Neoplasm Proteins / genetics*
  • Polymorphism, Single Nucleotide*
  • RNA, Messenger / blood
  • RNA, Messenger / genetics
  • Risk Factors
  • T-Lymphocyte Subsets / immunology


  • GSDMA protein, human
  • Interleukin-17
  • Membrane Proteins
  • Neoplasm Proteins
  • ORMDL3 protein, human
  • RNA, Messenger