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Updated: Oct 9, 2025
Candidate Gene Testing in Clinical Cohort Studies with Multiplexed Genotyping and Mass Spectrometry
Published on: June 21, 2018
17q12-21 risk-variants influence cord blood immune regulation and multitrigger-wheeze
Kristina Laubhahn1,2, Andreas Böck1,3, Kathrin Zeber1,3
1Pediatric Allergology, Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany.
Insights
Childhood wheeze, an early asthma symptom, is linked to 17q12-21 genetic variants. Gene expression at birth, particularly TLR2, influences wheeze risk, highlighting early immune development
Area of Science:
- Immunogenetics
- Pediatric Allergy
- Molecular Epidemiology
Background:
- Childhood wheeze is a primary indicator of asthma development.
- Early identification of at-risk children and underlying immunological mechanisms for 17q12-21 variants is crucial.
- The influence of specific genetic variants and gene expression at birth on wheeze development requires further investigation.
Purpose of the Study:
- To assess the impact of 17q12-21 genetic variants on wheeze development in children.
- To investigate the role of mRNA expression in cord blood at birth in relation to wheeze.
- To explore the immunological mechanisms linking genetic predisposition to childhood wheeze.
Main Methods:
- Utilized PAULINA/PAULCHEN birth cohorts (n=216) with genotyping (GSA-chip).
- Measured mRNA expression of 17q21 and innate/adaptive genes in cord blood mononuclear cells (qRT-PCR).
- Performed expression quantitative trait loci (eQTL) and mediation analyses, summarizing 17q12-21 asthma single nucleotide polymorphisms (SNPs) as principal component 1 (PC1).
Main Results:
- Core region risk variants (e.g., IKZF3, GSDMB) associated with multitrigger wheeze (OR: 3.05-5.43) and were locus-dependent eQTL SNPs, influencing GSDMA, TLR2, TLR5, and TGFB1 expression.
- Increased multitrigger wheeze risk with rs9303277 was partly mediated by TLR2 expression.
- Distinct cord blood immune signatures, including increased innate genes (TLR2, IPS1) for multitrigger wheeze and decreased NF-κB genes for viral wheeze, were identified.
Conclusions:
- Locus-dependent eQTL SNPs in the core region linked to elevated inflammatory genes (TLR2) at birth suggest early immune priming imbalance is critical for asthma.
- Locus-independent eQTL SNPs may influence dendritic cell activation and T cell interactions, potentially initiating asthma pathogenesis.
- Identifying early-life mechanistic pathways is key to understanding immune development and predisposition to asthma.
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 the 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 summarized 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, and 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). Identifying potential mechanistic pathways at birth may point to critical key points during early immune development predisposing to asthma.
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