Mediated Mendelian randomization analysis to determine the role of immune cells in regulating the effects of plasma metabolites on childhood asthma

Abstract

Childhood asthma is a chronic inflammatory disease of the airways, the pathogenesis of which involves multiple factors including genetic predisposition, environmental exposure, and immune system regulation. To date, the causal relationships between immune cells, plasma metabolites, and childhood asthma remain undetermined. Therefore, we aim to utilize the Mendelian randomization approach to assess the causal relationships among immune cells, plasma metabolites, and childhood asthma. This study employed the Mendelian randomization approach to investigate how immune cells influenced the risk of childhood asthma by modulating the levels of plasma metabolites. Five Mendelian randomization methods-inverse variance weighted, weighted median, Mendelian randomization-Egger, simple mode, and weighted mode-were utilized to explore the causal relationships among 731 types of immune cells, 1400 plasma metabolites, and childhood asthma. The instrumental variables for the 731 immune cells and 1400 plasma metabolites were derived from a genome-wide association study meta-analysis. Additionally, sensitivity analyses were conducted to examine the robustness of the results, potential heterogeneity, and pleiotropy. The inverse variance weighted results indicated that HLA DR on dendritic cells (DC) is a risk factor for childhood asthma (OR: 1.08, 95% CI: 1.02-1.14). In contrast, HLA DR on DC acts as a protective factor against elevated catechol glucuronide levels (OR: 0.94, 95% CI: 0.91-0.98), while catechol glucuronide levels themselves serve as a protective factor for childhood asthma (OR: 0.73, 95% CI: 0.60-0.89). Thus, HLA DR on DC can exert a detrimental effect on childhood asthma through the negative regulation of catechol glucuronide levels. The mediating effect was 0.018, accounting for a mediation effect proportion of 23.4%. This study found that HLA DR on DC can exert a risk effect on childhood asthma through the negative regulation of catechol glucuronide levels, providing new strategies for the prevention and treatment of childhood asthma and guiding future research and clinical practice.

Figure 1.

Flowchart.

Figure 2.

Mendelian Randomization (MR) results of immune cells on plasma metabolites. (A) Scatter plot of MR for HLA DR on DC with catechol glucuronide levels. (B) Forest plot of MR for HLA DR on DC with catechol glucuronide levels. (C) Leave-one-out analysis of MR for HLA DR on DC with catechol glucuronide levels. (D) Funnel plot of MR for HLA DR on DC with catechol glucuronide levels.

Figure 3.

Mendelian Randomization (MR) results of catechol glucuronide levels on childhood asthma. (A) Scatter plot of MR for catechol glucuronide levels on childhood asthma. (B) Forest plot of MR for catechol glucuronide levels on childhood asthma. (C) Leave-one-out analysis of MR for catechol glucuronide levels on childhood asthma. (D) Funnel plot of MR for catechol glucuronide levels on childhood asthma.

Figure 4.

Mendelian randomization (MR) results of HLA DR on DC on childhood asthma. (A) Scatter plot of MR for HLA DR on DC on childhood asthma. (B) Forest plot of MR for HLA DR on DC on childhood asthma. (C) Leave-one-out analysis of MR for HLA DR on DC on childhood asthma. (D) Funnel plot of MR for HLA DR on DC on childhood asthma.

Figure 5.

Forest plot depicting the causal relationship between HLA DR on DC, Catechol glucuronide levels, and childhood asthma.