Genetic variation in ABCA1 significantly affects HDL levels and atherosclerotic risk. The aim of this study was to examine lifestyle factors influencing ABCA1 expression in human leukocytes and skeletal muscle. A fasting venous blood sample and a vastus lateralis muscle biopsy were taken from 30 volunteers (53+/-1 years; mean+/-S.E.M.). Levels of ABCA1 mRNA were measured in blood leukocytes and muscle biopsies. Plasma-induced cholesterol efflux from THP-1 human macrophages as well as plasma lipids and lipid-related parameters were also measured. The amount of alcohol consumed per week correlated strongly with both muscle ABCA1 expression (r(2)=+0.37, p<0.001) and cholesterol efflux (r(2)=+0.41, p<0.001). Higher levels of physical exercise were associated with higher leukocyte ABCA1 expression (p<0.005), and higher concentrations of plasma apoA-I (p<0.05) and pre beta(1)-HDL (p<0.001). All these relationships were independent of diabetic status on multivariate analysis. ABCA1 expression in leukocytes and skeletal muscle was not related, suggesting different regulatory mechanisms. In conclusion, ABCA1 expression in human leukocytes and muscle is associated with physical activity and alcohol consumption, respectively.