Genetically supported causality between alcohol dependence, immune cells and opioids tolerance: A two-sample...

Previous studies indicate a link between alcohol consumption, immune cells, and opioid tolerance, but causality is unclear. We use two-sample Mendelian randomization to explore this causal relationship and the impact of alcohol dependence and immune cells on opioid tolerance.

Mendelian randomization was used to analyze the causal association between alcohol dependence, immune cells, and opioid tolerance. Inverse variance weighting (IVW) was used as the main analysis method. In addition, Cochran's q test was used to evaluate the heterogeneity of the results, and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and MR-Egger regression were used to evaluate the horizontal pleiotropy of the results. In addition, leave-one sensitivity analysis was used to analyze whether the causal association was driven by a single SNP. At the same time, we performed reverse MR to assess whether there was interference with reverse causal association.

Alcohol-dependent populations may contribute to opioid tolerance (IVW, OR = 1.057, P = 0.008). In addition, there is a causal relationship between 33 types of immune cells and opioid tolerance (P < 0.05). Additionally, there is a causal relationship between alcohol dependence and monocyte (IVW, OR = 1.092, P = 0.038), indicating that alcohol dependence is the promoting factor of the increase of monocyte absolute count. Moreover, there is a causal relationship between monocyte absolute count and opioids tolerance (IVW, OR = 1.020, P = 0.047). The MR-Egger regression and MR PRESSO methods revealed no horizontal pleiotropy (P > 0.05). For data with heterogeneity, we used the random effects model of IVW for analysis. Leave-one-out sensitivity analysis further indicated the robustness of the results. We used multivariate Mendelian randomization to perform mediation analysis and found that absolute monocyte count can be regarded as a mediator between alcohol dependence and opioid tolerance (OR = 1.002, P = 0.044), and the proportion of mediation was 3.6%.

This study provides genetic evidence suggesting that alcohol dependence may promote opioid tolerance, potentially mediated by increased monocyte counts. While the observed effect sizes were modest, these findings highlight the immune system as a relevant biological target, offering new insights for future prevention strategies.