Unveiling causal relationships between addiction phenotypes and inflammatory cytokines: insights from bidirectional...

Observational studies have suggested associations between multiple inflammatory factors and tobacco and alcohol use, but establishing causation is challenging in epidemiological investigations. We employed genetic association data about the circulating levels of 41 cytokines obtained from the genome-wide association study (GWAS), which contained 8293 Finnish participants. Genetic data on 5 substance use phenotypes were obtained from the GWAS dataset containing 1.2 million European subjects. Then, we conducted a bidirectional mendelian randomization (MR) study. The forward results indicated that smoking cessation was positively correlated with hepatocyte growth factor (HGF), interleukin-10 (IL-10), and stem cell factor (SCF); cigarettes per day was a risk factor associated with high expression in stromal cell-derived factor 1α (SDF-1 A), interferon-γ (IFN-G), IL-4, and granulocyte colony-stimulating factor (G-CSF); drinks per week and smoking initiation were risk factors respectively correlated with reduced HGF and IL-2RA levels. During inverse MR analysis, the findings revealed that both IL-16 and IL-18 increased the risk of cigarettes per day; macrophage inflammatory protein-1β (MIP-1B) and tumor necrosis factor-β (TNF-B) inhibited and promoted smoking cessation, respectively; macrophage colony-stimulating factor (M-CSF) elevated the risk of drinks per week, while interferon inducible protein 10 (IP-10) had a contrary role; IL-7 and M-CSF respectively prolonged and shortened age of initiation of regular smoking. This study provides genetic proof supporting a causal relationship between various inflammatory factors and addiction phenotypes. Further comprehensive investigations are required to uncover underlying biological mechanisms. In addition, bibliometric studies have shown that oxidative stress is one of the most important orientations in alcohol and tobacco addiction research, where an in-depth investigation of its pro-inflammatory mechanisms would facilitate the development of potential therapeutic biological targets and drugs.