Genetically predicted blood metabolites mediate the association between circulating immune cells and severe COVID-19: A Mendelian randomization study.

Investigating the causal relationship between circulating immune cells, blood metabolites, and severe COVID-19 and revealing the role of blood metabolite-mediated circulating immune cells in disease onset and progression. Genetic variation data of 731 circulating immune cells, 1400 blood metabolites, and severe COVID-19 from genome-wide association study open-access database (https://gwas.mrcieu.ac.uk) were used as instrumental variables for bidirectional and two-step Mendelian randomization analysis. The study identified 11 circulating immune cells with unidirectional causality to severe COVID-19. Two-step Mendelian randomization analysis showed 10 blood metabolites were causally associated with severe COVID-19, and blood Myristate and Citrulline to phosphate ratio mediated the association of circulating effector memory double negative % DN and CD8dim natural killer T cell % T cells, respectively, with severe COVID-19 (Myristate mediated effect ratio was 10.20%, P = .011; Citrulline to phosphate ratio mediated effect ratio was -9.21%, P = .017). This study provides genetic evidence assessing the causal relationship between circulating immune cells, blood metabolites, and severe COVID-19, elucidates the role of blood metabolite-mediated circulating immune cells in severe COVID-19 development, and offers new insights into severe COVID-19 etiology and related preventive and targeted therapeutic strategies.