title: FKBP5 variation is associated with the acute and chronic effects of nicotine.
abstract: 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.
authors.affiliation: 1] Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA [2] VA Connecticut Healthcare System, West Haven, CT, USA.
authors.forename: K P
authors.initials: KP
authors.lastname: Jensen
authors.affiliation: 1] Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA [2] VA Connecticut Healthcare System, West Haven, CT, USA.
authors.forename: A I
authors.initials: AI
authors.lastname: Herman
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Morean
authors.affiliation: 1] Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA [2] The VISN4 MIRECC, Philadelphia VA Medical Center, Philadelphia, PA, USA.
authors.forename: H R
authors.initials: HR
authors.lastname: Kranzler
authors.affiliation: 1] Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA [2] VA Connecticut Healthcare System, West Haven, CT, USA [3] Department of Genetics, Yale University School of Medicine, New Haven, CT, USA [4] Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gelernter
authors.affiliation: 1] Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA [2] VA Connecticut Healthcare System, West Haven, CT, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sofuoglu
mesh_terms: D001741:Black or African American; D000483:Alleles; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005787:Gene Frequency; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007275:Injections, Intravenous; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012907:Smoking / Q000235:genetics*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology; D022021:Tacrolimus Binding Proteins / Q000235:genetics*; D044465:White People; D000099159:Tacrolimus Binding Protein 5
chemical_list: D006854:Hydrocortisone; D009538:Nicotine; D018722:Nicotinic Agonists; D012313:RNA; D012333:RNA, Messenger; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5