Stress-related genes and heroin addiction: a role for a functional FKBP5 haplotype.
BACKGROUND
Stress is a critical risk factor affecting both the development of and the relapse to drug addictions. Drug addictions are caused by genetic, environmental and drug-induced factors. The objective of this hypothesis-driven association study was to determine if genetic variants in stress-related genes are associated with heroin addiction.


METHODS
112 selected genetic variants in 26 stress-related genes were genotyped in 852 case subjects and 238 controls of predominantly European ancestry. The case subjects are former heroin addicts with a history of at least one year of daily multiple uses of heroin, treated at a methadone maintenance treatment program (MMTP). The two most promising SNPs were subsequently tested in an African-American sample comprising of 314 cases and 208 control individuals.


RESULTS
Nineteen single nucleotide polymorphisms (SNPs) in 9 genes (AVP, AVPR1A, CRHR1, CRHR2, FKBP5, GAL, GLRA1, NPY1R and NR3C2) showed nominally significant association with heroin addiction. The associations of two FKBP5 SNPs that are part of one haplotype block, rs1360780 (intron 2) and rs3800373 (the 3' untranslated region), remained significant after correction for multiple testing (Pcorrected=0.03; OR=2.35, Pcorrected=0.0018; OR=2.85, respectively). The two SNPs also showed nominally significant association (P<0.05) with heroin addiction in an independent African-American cohort. FKBP5 is a co-chaperone that regulates glucocorticoid sensitivity. These FKBP5 SNPs were previously associated with diverse affective disorders and showed functional differences in gene expression and stress response. This study also supports our and others' previous reports of association of the GAL SNP rs694066 and the AVPR1A SNPs rs11174811, rs1587097 and rs10784339 with heroin and general drug addiction, respectively.


CONCLUSIONS
This study suggests that variations in the FKBP5 gene contribute to the development of opiate addiction by modulating the stress response. These findings may enhance the understanding of the interaction between stress and heroin addiction.
The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA. Electronic address: levrano@rockefeller.edu.
O
O
Levran
Dr. Miriam and Sheldon G. Adelson Clinic for Drug Abuse Treatment and Research, Tel Aviv Elias Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
E
E
Peles
The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA.
M
M
Randesi
The School of Statistics, Shanxi University of Finance & Economics, Shanxi, China.
Y
Y
Li
VA New York Harbor Healthcare System and NYU School of Medicine, New York, NY, USA.
J
J
Rotrosen
Institute of Psychology, Chinese Academy of Sciences, Beijing, China; The Laboratory of Statistical Genetics, The Rockefeller University, New York, NY, USA.
J
J
Ott
The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA; Dr. Miriam and Sheldon G. Adelson Clinic for Drug Abuse Treatment and Research, Tel Aviv Elias Sourasky Medical Center, Tel Aviv, Israel; Dr. Miriam and Sheldon G. Adelson Clinic for Drug Abuse Treatment and Research, Las Vegas, NV, USA.
M
M
Adelson
The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA.
M J
MJ
Kreek
D000328:Adult; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006556:Heroin Dependence / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013315:Stress, Psychological / Q000453:epidemiology / Q000235:genetics*; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000502:physiology*; D000099159:Tacrolimus Binding Protein 5
D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5
AVPR1A; Association study; FKBP5; GAL; Genetic variants; Glucocorticoid sensitivity; HPA axis; Heroin addiction; Stress