We found that variation in FKBP5 was associated with nicotine withdrawal severity, the acute behavioral and physiological effects of nicotine, and cortisol regulation during nicotine withdrawal. FKBP5 genotype was associated with withdrawal severity in subjects both in a laboratory study and in an independent larger cohort of current EA and AA smokers. FKBP5 genotype and RNA expression were associated with differences in the acute negative subjective effects of IV nicotine, while FKBP5 RNA expression was associated with HR response to IV nicotine. FKBP5 mRNA expression was positively correlated with cortisol levels during nicotine withdrawal, but not after IV nicotine administration. Our investigation of effects at the RNA level provided convergent support for some of the genotype effects. For example, FKBP5 mRNA expression and genotype were both associated with the “negative” drug effects domain of the DEQ. Combined, these findings reaffirm the importance of HPA-axis regulation via FKBP5 and show that FKBP5 variation at the DNA and RNA levels contributes to some inter-individual differences in nicotine-related behavior.
