Genetic Causal Association between Treg Subtypes and Acute Respiratory Distress Syndrome: A Mendelian Randomization...

Observational research has indicated a link between regulatory T-cells (Tregs) and the risk of acute respiratory distress syndrome (ARDS). However, establishing a definitive causal relationship has been challenging. This study aimed to clarify this connection using a two-sample Mendelian randomization (MR) approach.

The summary datasets of genome-wide association studies (GWAS) were utilized, identifying 716 instrumental variables (IVs) related to Tregs. The inverse-variance weighted (IVW) method served as the primary analysis, supplemented by weighted median, MR-Egger, and weighted mode methods. Sensitivity analyses included Cochran's Q, leave-one-out analysis, MR-Egger intercept, and MR pleiotropy residual sum and outlier (MR-PRESSO) tests.

A genetically-predicted 1-SD increase in the absolute count of CD39+ CD4+ Tregs was associated with a 23.2% reduction in the odds of ARDS (OR = 0.768, 95% CI: 0.612 - 0.963, P = 0.022). Conversely, a 1-SD increase in the absolute count of CD127- CD8br Tregs was associated with a nearly threefold increase in the odds of developing ARDS (OR = 2.894, 95% CI: 1.511 - 5.543, P = 0.001). Sensitivity tests revealed no heterogeneity or horizontal pleiotropy.

Our findings suggested a dual and opposing role for Treg subtypes in ARDS. The protective effect of CD39+ CD4+ Tregs is biologically plausible, likely mediated by the immunosuppressive adenosine pathway. In contrast, the unexpected risk-increasing effect of CD127- CD8br Tregs may reflect their functional plasticity or a dysregulated, insufficient response within the severe inflammatory lung microenvironment, rather than a direct pathogenic role.

This study has provided compelling evidence for a genetic causal link between specific Tregs subtypes and ARDS risk, highlighting their potential as biomarkers for ARDS diagnosis and treatment.