Immunocytes Play a Crucial Role as Mediators in the Protective Effects of D-β-Hydroxybutyrate Dehydrogenase 1 against Type 2 Diabetes Mellitus: A Mendelian Randomization Study

Abstract

Background: Observational studies suggest an association between the immune system and type 2 diabetes. The present study sought to ascertain the causal relationship between BDH1 and type 2 diabetes and investigate whether immunocytes mediate this relationship.

Methods: Appropriate single nucleotide polymorphisms (SNPs) were carefully selected from publicly available GWAS databases based on rigorous criteria to ensure the validity of the Mendelian randomization (MR) analysis. Inverse variance weighting (IVW) was employed as the primary approach for assessing effect sizes, supplemented by four sensitivity analysis techniques: weighted median, simple mode, weighted mode, and MR-Egger regression tests, all aimed at ensuring the robustness and reliability of the IVW results. Reverse MR was conducted to confirm the feasibility of the mediation analysis. Lastly, Cochran's Q test, MR Egger intercept regression, and MR-PRESSO analysis were utilized to examine heterogeneity and horizontal pleiotropy.

Results: The expression of BDH1 is inversely associated with the risk of type 2 diabetes, with an odds ratio of 0.97 (95% CI: 0.95-0.99). IgD+ CD38+ B cell absolute count (20.7%), HLA DR on dendritic cell (18.7%), BAFF-R on CD20- CD38- B cell (9.5%), CD25 on IgD+ CD24+ B cell (4.1%), and BAFF-R on IgD+ B cell (3.4%), all exhibit certain mediating effects, whereas IgD+ CD38+ B cell absolute count, activated and resting CD4 regulatory T cell %, CD4+ T cell, transitional B cell absolute count, CD28- CD8 dim T cell absolute count, CD45 on HLA DR+ CD8+ T cell, FSC-A on HLA DR+ natural killer, and SSC-A on plasmacytoid dendritic cell exert masking effects.

Conclusion: The findings indicate that immunocytes could serve as a crucial mediating mechanism through which BDH1 exerts its protective effect against type 2 diabetes, offering novel insights for the prevention and therapeutic management of the disease.

Keywords: D-β-hydroxybutyrate dehydrogenase; immunocyte; mediation.; mendelian randomization; type 2 diabetes.