Proteomic analysis reveals potential therapeutic targets for childhood asthma through Mendelian randomization

Abstract

Background: Asthma is the most common chronic disease among children and poses a significant threat to their health. This study aims to assess the relationship between various plasma proteins and childhood asthma, thereby identifying potential therapeutic targets.

Methods: Based on publicly available genome-wide association study summary statistics, we employed a two-sample Mendelian randomization (MR) approach to elucidate the causal relationship between plasma proteins and asthma. Mediation analysis was then conducted to evaluate the indirect influence of plasma proteins on childhood asthma mediated through risk factors. Comprehensive analysis was also conducted to explore the association between plasma proteins and various phenotypes using the UK Biobank dataset.

Results: MR analysis uncovered a causal relationship between 10 plasma proteins and childhood asthma. Elevated levels of seven proteins (TLR4, UBP25, CBR1, Rac GTPase-activating protein 1 [RGAP1], IL-21, MICB, and PDE4D) and decreased levels of three proteins (GSTO1, LIRB4 and PIGF) were associated with an increased risk of childhood asthma. Our findings further validated the connections between reported risk factors (body mass index, mood swings, hay fever or allergic rhinitis, and eczema or dermatitis) and childhood asthma. Mediation analysis revealed the influence of proteins on childhood asthma outcomes through risk factors. Furthermore, the MR analysis identified 73 plasma proteins that exhibited causal associations with at least one risk factor for childhood asthma. Among them, RGAP1 mediates a significant proportion (25.10%) of the risk of childhood asthma through eczema or dermatitis. Finally, a phenotype-wide association study based on these 10 proteins and 1403 diseases provided novel associations between these biomarkers and multiple phenotypes.

Conclusion: Our study comprehensively investigated the causal relationship between plasma proteins and childhood asthma, providing novel insights into potential therapeutic targets.

Keywords: Mendelian randomization; childhood asthma; plasma proteome; risk factors; therapeutic targets.

FIGURE 1

Overview of MR analyses. This study employed two‐sample MR, mediation MR analysis, and PheWAS to investigate the association between plasma proteins and childhood asthma. Initially, we assessed the potential causal role of 4489 plasma proteins in mediating childhood asthma. Subsequently, four risk factors associated with childhood asthma were identified and their causal relationship with childhood asthma was assessed using MR analysis. Mediation analyses were subsequently conducted to evaluate the indirect effect of plasma proteins on childhood asthma through the identified risk factors. Lastly, comprehensive phenotypic association studies of plasma proteins were conducted using the UK Biobank dataset. MR, Mendelian randomization; PheWAS, phenome‐wide association studies.

FIGURE 2

Association between plasma proteins and childhood asthma. MR analysis of the causal effects of 10 plasma proteins on childhood asthma outcome. CI, confidence interval; MR, Mendelian randomization; OR, odds ratio.

FIGURE 3

Association between identified risk factors and childhood asthma. MR analysis of the causal effects of risk factors on childhood asthma outcome. CI, confidence interval; MR, Mendelian randomization; OR, odds ratio.

FIGURE 4

Indirect effects of plasma proteins on childhood asthma through risk factors. Mediation analysis to assess the indirect effects of plasma proteins on childhood asthma through risk factors. β _EM, effects of exposure on mediator; β _EO, effects of exposure on outcome; β _MO, effects of mediator on outcome.

FIGURE 5

Associations between childhood asthma‐associated proteins and other disease outcomes revealed by PheWAS analysis.