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Association of the histidine-triad nucleotide-binding protein-1 (HINT1) gene variants with nicotine dependence

The Pharmacogenomics Journal volume 11, pages 251–257 (2011)Cite this article

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Abstract

The histidine triad nucleotide-binding protein-1 gene (HINT1) is implicated in schizophrenia and in the behavioral effects of morphine and amphetamine. Because nicotine dependence (ND) is highly comorbid with schizophrenia and other substance abuse, we examined the association of HINT1 with ND. Association analyses from two independent samples show that HINT1 gene variants are associated with ND phenotypes. Furthermore, human postmortem mRNA expression shows that smoking status and genotype influence HINT1 expression in the brain. In animal studies, western blot analyses show an increase of HINT1 protein level in the mouse nucleus accumbens (NAc) after chronic nicotine exposure. This increase was reduced after treatment with the nicotinic-receptor antagonist mecamylamine, and 24 and 72 h after cessation of nicotine treatment. These results indicate a genetic association between HINT1 variants and ND, and indicate that nicotine-induced modulation of HINT1 level may be involved in mechanisms of excess smoking.

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Acknowledgements

This study was supported by grants DA-019498 to XC, and DA-011287 to KSK from the National Institute on Drug Abuse and by funds from the Virginia Tobacco Settlement Foundation through the Virginia Youth Tobacco Project to Virginia Commonwealth University (subcontracted to KSK, #5100004ST). Funding support for the GAIN subjects was provided by NIMH and the genotyping of samples was provided through the GAIN organization. The data set used for the analyses described in the paper was obtained from the GAIN Database found at http://view.ncbi.nlm.nih.gov/dbgap-controlled through dbGaP accession number phs000017.v1.p1. The samples and associated phenotype data for the Linking Genome-Wide Association Study of Schizophrenia were provided by Pablo Gejman.

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  1. Department of Psychiatry and Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

    K J Jackson, Q Chen, J Chen, S H Aggen, K S Kendler & X Chen

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  1. K J Jackson
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  2. Q Chen
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Correspondence to X Chen.

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Jackson, K., Chen, Q., Chen, J. et al. Association of the histidine-triad nucleotide-binding protein-1 (HINT1) gene variants with nicotine dependence. Pharmacogenomics J 11, 251–257 (2011). https://doi.org/10.1038/tpj.2010.41

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