Asthma-associated polymorphisms in 17q21 influence cord blood ORMDL3 and GSDMA gene expression and IL-17 secretion - 11/08/11
, Michaela Schedel, PhD b, , Jing Liu, MD a, c, Sabina Illi, PhD a, Martin Depner, MSc a, Erika von Mutius, MD a, Michael Kabesch, MD b, Bianca Schaub, MD a, ⁎ 
Reprint requests: Bianca Schaub, MD, University Children’s Hospital Munich, Dr von Haunersches Kinderspital, Lindwurmstr 4, 80337 Munich, Germany.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 Th2/Th1/Th17 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/Th2/Th1 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.
Le texte complet de cet article est disponible en PDF.Key words : Chromosome 17q21 locus, cord blood, cytokines, GSDMA, IL-17, ORMDL3, polymorphism, T-cells
Abbreviations used : CBMC, CT, GMR, GSDMA, GSDMB, GWAS, LD, LpA, ORMDL3, PSMD3, SNP, ZNFN1A3, ZPBP2
Plan
| Supported by the Bavarian Research Association PIZ-140-08 (B.S., J.L.), a Marie Curie research grant (MEST-CT-2005-020524-GALTRAIN, A.L.), National Genome Research Network research grant NGFN 01GS 0810, and the German Research Foundation as part of the transregional collaborative research program TR22 “Allergic Immune Responses of the Lung,” A22 (B.S., A.L.), and grant Z3 (M.S., M.K.). |
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| Disclosure of potential conflict of interest: E. von Mutius has consultant arrangements with GlaxoSmithKline, UCB, Protectimmun, and Novartis and receives research support from Airsonett AB. M. Kabesch has financial interests in Roxall, Glaxo Wellcome, Novartis, Sanofi Aventis, and Allergopharma and receives research support from the German Research Foundation, Bundesministerium fur Bildung und Forschung, and the European Union. B. Schaub receives research support from the German Research Foundation and the European Union. The rest of the authors have declared that they have no conflict of interest. |
Vol 127 - N° 6
P. 1587 - juin 2011 Retour au numéro
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