Causal relationships of metabolites with allergic diseases: a trans-ethnic Mendelian randomization study

Abstract

Background: Allergic diseases exert a considerable impact on global health, thus necessitating investigations into their etiology and pathophysiology for devising effective prevention and treatment strategies. This study employs a Mendelian randomization (MR) analysis and meta-analysis to identify metabolite targets potentially associated with allergic diseases.

Methods: A two-sample MR analysis was conducted to explore potential causal relationships between circulating and urinary metabolites and allergic diseases. Exposures were derived from a genome-wide association study (GWAS) of 486 circulating metabolites and a GWAS of 55 targeted urinary metabolites. Outcome data for allergic diseases, including atopic dermatitis (AD), allergic rhinitis (AR), and asthma, were obtained from the FinnGen biobank in Europe (cohort 1) and the Biobank Japan in Asia (cohort 2). MR results from both cohorts were combined using a meta-analysis.

Results: MR analysis identified 50 circulating metabolites and 6 urinary metabolites in cohort 1 and 54 circulating metabolites and 2 urinary metabolites in cohort 2 as potentially causally related to allergic diseases. A meta-analysis of the MR results revealed stearoylcarnitine (OR 8.654; 95% CI 4.399-17.025; P = 4.06E-10) and 1-arachidonoylglycerophosphoinositol (OR 2.178; 95% CI 1.388-3.419; P = 7.15E-04) as the most reliable causal circulating metabolites for asthma and AR, respectively. Further, histidine (OR 0.734; 95% CI: 0.594-0.907; P = 0.004), tyrosine (OR 0.601; 95% CI: 0.380-0.952; P = 0.030), and alanine (OR 0.280; 95% CI: 0.125-0.628; P = 0.002) emerged as urinary metabolites with the greatest protective effects against asthma, AD, and AR, respectively.

Conclusions: Imbalances in numerous circulating and urinary metabolites may be implicated in the development and progression of allergic diseases. These findings have significant implications for the development of targeted strategies for the prevention and treatment of allergic diseases.

Keywords: Allergic diseases; Allergic rhinitis; Asthma; Mendelian randomization; Metabolites.

Fig. 1

(A) Mendelian randomization key assumptions diagram. (B) Schematic design and overview flowchart of the hypothesis

Fig. 2

This forest plot displays the results of the subgroup meta-analyses conducted on shared circulating metabolites indicative of allergic diseases associations in both cohorts (P value < 0.05 in both cohorts), examining their potential links to the allergic disease risk. CIs: confidence intervals

Fig. 3

This forest plot displays the results of the subgroup meta-analyses conducted on shared urinary metabolites indicative of allergic diseases associations in both cohorts (P value < 0.05 in both cohorts), examining their potential links to the allergic disease risk. CIs: confidence intervals

Fig. 4

Bubble plot of the pathway enrichment analysis for the circulating and urinary metabolites based on a full meta-analysis of the MR analysis results. (A-C). Bubble plot of the pathway enrichment analysis for the circulating metabolites in asthma (A), AD (B), AR (C). (D-F). Bubble plot of the pathway enrichment analysis for the urinary metabolites in asthma (D), AD (E), and AR (F)

Fig. 5

This illustration highlights the causal metabolites and their interconnected metabolic pathways related to allergic diseases