Abstract
PURPOSE: This study aimed to investigate causal relationships between gut microbiota, blood metabolites, immune cell traits, circulating inflammatory proteins, and myopia through Mendelian randomization (MR) analysis. DESIGN: Mendelian randomization study. SUBJECTS: Genome-wide association study (GWAS) data of 412 gut microbiota, 1400 blood metabolites/metabolite ratios, 731 immune cell traits, and 91 circulating inflammatory proteins from the public GWAS database. Genome-wide association study data of myopia from the public GWAS database and FinnGen consortium. METHODS: Two-sample MR analysis and meta-analysis were employed using 4 methods, with inverse-variance weighted as the primary approach, to investigate potential causal links. Metabolic pathway analysis was conducted to explore metabolic pathways. The Cochran Q-test, MR-Egger intercept test, and MR-PRESSO were used for sensitivity analyses. Mediation and reverse MR analyses were also carried out to identify potential mediation relationships and modification effects of myopia. MAIN OUTCOME MEASURES: Causal relationships between gut microbiota, blood metabolites, immune cell traits, circulating inflammatory proteins, and myopia. RESULTS: We identified causal effects of 34 and 22 gut microbiota/bacterial pathways, 131 and 98 blood metabolites/metabolite ratios, 60 and 37 immune cell traits, and 5 and 2 circulating inflammatory proteins on myopia (ukb-b-6353 and R10_H7_MYOPIA, respectively). Overlapping causal relationships were found for 1 gut bacterial pathway, 10 blood metabolites/metabolite ratios, and 2 immune cell traits across both outcomes; however, none of these overlaps reached significance after meta-analysis. The Small Molecule Pathway Database and Kyoto Encyclopedia of Genes and Genomes database enriched 14 significant pathways. Flavin adenine dinucleotide was involved in 8 pathways in both databases. Furthermore, the causal effect of glycochenodeoxycholate glucuronide on myopia was mediated by acetyl-CoA fermentation to butanoate lI, with mediation proportion of 19.03% (ukb-b-6353) and 19.48% (R10_H7_MYOPIA). Reverse MR analysis identified modification effects of myopia (ukb-b-6353) on gut microbiota, blood metabolites, and circulating inflammatory proteins. CONCLUSIONS: These findings demonstrated significant causal relationships between gut microbiota, blood metabolites, immune cell traits, circulating inflammatory proteins, and myopia. Gut microbiota pathway may mediate the causal effects of blood metabolite on myopia. This may provide researchers with a new perspective in exploring the biological mechanisms of myopia and may lead to the exploration of earlier treatment strategies. FINANCIAL DISCLOSURES: The author(s) have no proprietary or commercial interest in any materials discussed in this article.