Influences of smoking behaviors on human immune signatures: large observational studies and Mendelian randomization analyses

Abstract Introduction Although exposure to cigarette smoking is known to impair immune function, the specific immune components involved remain unclear. Methods We conducted multiple regression analyses to assess associations between smoking behaviors and immune markers—including white blood cell counts, pathogen-specific antibodies, and SARS-CoV-2 antibody seropositivity post-vaccination, by using data from the UK Biobank (n=499,244) and the National Health and Nutrition Examination Survey (n=66,947). We further used two-sample Mendelian randomization analysis to reveal the causal relationships between smoking and different immune cell phenotypes, and plasma antibodies against various pathogens. Results Observational studies revealed that ever-smokers had elevated white blood cell, and neutrophil counts compared to never-smokers, with current smokers also showing a higher increase in white blood cell, neutrophil counts and a decrease in lymphocyte percentage and monocyte percentage. Current smokers had greater seropositivity for Epstein-Barr Virus, herpes simplex virus-2, and Chlamydia trachomatis (Definition I). Additionally, current smokers had reduced SARS-CoV-2 antibody seropositivity following both first and second vaccine doses. MR analyses demonstrated that smoking initiation, age of initiation, cigarettes per day, cessation, and lifetime smoking causally influenced 73, 25, 44, 36, and 17 immune cell phenotypes, respectively. Notably, smoking initiation and lifetime smoking reduced anti-SARS-CoV-2 spike IgG seropositivity after the second vaccination. Conclusions Our findings demonstrate that smoking significantly alters leukocyte composition, impairs immune cell populations, and influences pathogen-specific antibody responses—most notably diminishing the humoral response to SARS-CoV-2 vaccination. These results suggest smoking may compromise both innate and adaptive immunity.