FKBP5 variation is associated with the acute and chronic effects of nicotine.
- Authors
- Jensen, K P; Herman, A I; Morean, M E; Kranzler, H R; Gelernter, J; Sofuoglu, M
- Year
- 2015
- Journal
- The pharmacogenomics journal
- PMID
- 25532758
- DOI
- 10.1038/tpj.2014.76
- PMCID
- PMC4599366
Stress and hormones released in response to stress influence the effects of nicotine and the severity of nicotine withdrawal. Here, we systematically examine the contribution of a stress response gene, FKBP5, to the acute and chronic behavioral effects of nicotine in smokers. Subjects were European- and African-American (EA and AA) heavy smokers who participated in an intravenous (IV) nicotine administration study (total n=169). FKBP5 rs3800373 genotype was analyzed for association to several outcomes, including nicotine withdrawal and the acute subjective, heart rate (HR), blood pressure and plasma cortisol responses to IV nicotine. Nicotine withdrawal was also examined in relation to rs3800373 allele frequencies in an independent cohort of EA and AA current smokers (n=3821). For a subset of laboratory subjects FKBP5 mRNA (n=48) expression was explored for an association to the same outcomes. The rs3800373 minor allele was associated with less severe nicotine withdrawal in laboratory subjects and the independent cohort of smokers. The rs3800373 minor allele was also associated with lower subjective ratings of negative drug effects in response to IV nicotine. Low FKBP5 mRNA expression was associated lower cortisol levels, lower subjective ratings of negative drug effects and a blunted HR response to nicotine. Stress hormone regulation via FKBP5 warrants further investigation as a potential contributor to the effects of nicotine withdrawal, which occurs commonly, and has an important role in the maintenance of smoking behavior and relapse following a quit attempt.
FK506 binding protein 5 (FKBP5) rs3800373 is associated with nicotine withdrawal. A. Mean Minnesota Nicotine Withdrawal Scale scores for laboratory participants at the pre- and post-nicotine conditions and B. Mean DSM-IV symptom count for any withdrawal symptom (left) or symptom lasting 24 hours (right) in an independent cohort of current smokers. Rs3800373*C carriers reported lower MNWS scores at the pre-nicotine condition (*P=0.007) and fewer DSM-IV withdrawal symptoms. Error bars are ± s.e.m.
FK506 binding protein 5 (FKBP5) genotype and mRNA expression are associated with the acute response to IV nicotine. The association of FKBP5 rs3800373 genotype (left panels) and FKBP5 mRNA (right panels) to subjective reports of “negative” drug effects (A) and heart rate (B). For the graph, subjects were grouped as having high (n=24) or low (n=24) FKBP5 expression based on a median split. The mean value for each experimental condition is presented (±s.e.m.) and main effects of FKBP5 mRNA or genotype and interactive effects with dose are shown. Nic = nicotine.
FK506 binding protein 5 (FKBP5) mRNA expression is positively correlated with cortisol levels. Effects were tested for (A) rs3800373 genotype (AA versus C-carrier) and (B) FKBP5 mRNA (graphed as high or low based on a median split). Time points are, 1. Post-IV line insertion; 2. Pre-saline injection; 3. Pre-nicotine (0.5 mg/70 kg) injection; 4. Pre-nicotine (1.0 mg/70 kg) injection and 5. Post-infusions. FKBP5 mRNA levels were obtained prior to time point 2. The mean value is presented (±s.e.m.) and main effects of FKBP5 mRNA or genotype and interactive effects with time point are shown. *Pairwise p <0.005. Nic=nicotine.
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| Examining racial differences in smoking outcomes among smokers enrolled in an intravenous nicotine infusion study. | Schwartz EKC et al. | — | 2023 | → |
| Threshold for the pleasurable effects of nicotine are lower than its reinforcing effects during self-administration. | MacLean RR et al. | — | 2023 | → |
| Impact of delivery rate on the acute response to intravenous nicotine: A human laboratory study with implications for regulatory science. | De Aquino JP et al. | — | 2022 | → |
| Threshold dose for intravenous nicotine self-administration in young adult non-dependent smokers. | MacLean RR et al. | — | 2021 | → |
| Differential effects of nicotine delivery rate on subjective drug effects, urges to smoke, heart rate and blood pressure in tobacco smokers. | Jensen KP et al. | — | 2020 | → |
| Examining sex differences in pleiotropic effects for depression and smoking using polygenic and gene-region aggregation techniques. | Schmitz LL et al. | — | 2019 | → |
| Biochemical, demographic, and self-reported tobacco-related predictors of the acute heart rate response to nicotine in smokers. | Jensen KP et al. | — | 2018 | → |
| A protocadherin gene cluster regulatory variant is associated with nicotine withdrawal and the urge to smoke. | Jensen KP et al. | — | 2017 | → |
| Examining FKBP5 mRNA expression in human iPSC-derived neural cells. | Lieberman R et al. | — | 2017 | → |
| FK506 binding protein 51 integrates pathways of adaptation: FKBP51 shapes the reactivity to environmental change. | Rein T | — | 2016 | → |
| FKBP5 genotype interacts with early life trauma to predict heavy drinking in college students. | Lieberman R et al. | — | 2016 | → |
| Gene-Stress-Epigenetic Regulation of FKBP5: Clinical and Translational Implications. | Zannas AS et al. | — | 2016 | → |
| Intravenous Nicotine Self-Administration in Smokers: Dose-Response Function and Sex Differences. | Jensen KP et al. | — | 2016 | → |
| Stress response genes and the severity of nicotine withdrawal. | Jensen KP et al. | — | 2016 | → |
| A CHRNA5 Smoking Risk Variant Decreases the Aversive Effects of Nicotine in Humans. | Jensen KP et al. | — | 2015 | → |
| Co-occurring tobacco use and posttraumatic stress disorder: Smoking cessation treatment implications. | Kelly MM et al. | — | 2015 | → |