Immune Cells Mediate the Causal Pathway Linking Multisite Chronic Pain to Asthma: A Mediation Mendelian Randomization Study.

Background: Cumulative evidence from observational studies has revealed associations between chronic pain (CP) and asthma. However, it remains unclear whether these associations indicate a causal relationship. In this study, we aimed to assess the causal relationships between CP and asthma.

Methods: First, linkage disequilibrium score regression (LDSC) analysis was used to estimate the genetic correlations between 9 types of CP (including multisite chronic pain, knee, back, neck/shoulder, headaches, hip, stomach/abdominal, facial, and general CP) and asthma. Conventional Mendelian randomization (MR) approaches and a new MR method, Causal Analysis Using Summary Effect estimates (CAUSE), were performed to test bidirectional causal relationships between genetically predicted CP and asthma. Finally, mediation analysis was conducted to establish whether immune cells and inflammatory cytokines causally mediate any associations.

Results: For the LDSC analysis, several significant genetic correlations (rg) were observed, such as multisite chronic pain (MCP) and asthma (rg = 0.442, P = 7.23×10^-52). For the MR analysis, we identified that genetically determined MCP (odds ratio [OR] 2.34, 95% confidence interval [CI] 1.84-2.97, P = 3.51×10^-12) was significantly associated with a higher risk of asthma. For the mediation analysis, the three immune-cell phenotypes (including CD3 on activated CD4 regulatory T cells, CD3 on activated and secreting CD4 regulatory T cells, and CD3 on CD39+ CD4+ T cells) were each found to mediate 4.6-5.0% of the total effect linking MCP to asthma, underscoring their partial mediating role in this causal pathway. Unexpectedly, other types of pain showed no correlation with asthma risk.

Conclusion: Our findings revealed that MCP is significantly associated with a higher risk of asthma, which is partially mediated by immune cells.