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Laubhahn, K.* ; Böck, A.* ; Zeber, K.* ; Unterschemmann, S.* ; Kunze, S. ; Schedel, M.* ; Schaub, B.*

17q12-21 risk-variants influence cord blood immune regulation and multitrigger-wheeze.

Pediatr. Allergy Immunol. 33:e13721 (2022)
DOI PMC
Creative Commons Lizenzvertrag
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
BACKGROUND: Childhood wheeze represents a first symptom of asthma. Early identification of children at risk for wheeze related to 17q12-21 variants and their underlying immunological mechanisms remain unknown. We aimed to assess the influence of 17q12-21 variants and mRNA-expression at birth on development of wheeze. METHODS: Children were classified as multitrigger-/viral-/no-wheeze until six years of age. The PAULINA/PAULCHEN birth cohorts were genotyped (n=216; GSA-chip). mRNA-expression of 17q21 and innate/adaptive genes was measured (qRT-PCR) in cord blood mononuclear cells. Expression quantitative trait loci (eQTL) and mediation analyses were performed. Genetic-variation of 17q12-21 asthma-single nucleotide polymorphisms (SNPs) was summarised as the first principal component (PC1) and used to classify single SNP effects on gene expression as (locus)-dependent/independent eQTL-SNPs. RESULTS: Core-region risk-variants (IKZF3,ZPBP2,GSDMB,ORMDL3) were associated with multitrigger-wheeze (OR:3.05-5.43) and were locus-dependent eQTL-SNPs with higher GSDMA,TLR2,TLR5 and lower TGFB1-expression. Increased risk of multitrigger-wheeze with rs9303277 was in part mediated by TLR2-expression. Risk-variants distal to the core-region were mainly locus-independent eQTL-SNPs with decreased CD209,CD86,TRAF6,RORA,IL-9-expression. Distinct immune signatures in cord blood were associated either with multitrigger-wheeze (increased innate genes e.g. TLR2,IPS1,LY75) or viral-wheeze (decreased NF-κB genes e.g. TNFAIP3 and TNIP2). CONCLUSION: Locus-dependent eQTL-SNPs (core-region) associated with increased inflammatory genes (primarily TLR2) at birth and subsequent multitrigger-wheeze indicate that early priming and imbalance may be crucial for asthma pathophysiology. Locus-independent eQTL-SNPs (mainly distal-region:rs1007654) may be involved in the initiation of dendritic-cell activation/maturation (TRAF6) and interaction with T-cells (CD209,CD86). This identification of potential mechanistic pathways at birth may point to critical key-points during early immune-development predisposing to asthma.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Childhood Wheeze And Asthma ; Chromosome 17 ; Cord Blood ; Eqtl ; Mrna Expression ; Mediation Analyses ; Single Nucleotide Polymorphisms; Genome-wide Association; Genetic Association; Childhood-onset; Asthma; Ormdl3; Cells; Susceptibility; Polymorphisms; Transcriptome; Children
ISSN (print) / ISBN 0905-6157
e-ISSN 1399-3038
Zeitschrift Pediatric Allergy and Immunology
Quellenangaben Band: 33, Heft: 2, Seiten: , Artikelnummer: e13721 Supplement: ,
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Epidemiology II (EPI2)
Förderungen Deutsches Zentrum fur Lungenforschung, Comprehensive Pneumology Center (DZL CPC-M)
Hauner Verein
Else Kroner-Fresenius-Stiftung
DFG
Deutsche Forschungsgemeinschaft (DFG)
Bundesministerium fur Bildung und Forschung (BMBF)