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Susceptibility polymorphisms for drug abuse
Heroin addiction and variants of the DRD4 gene in a Chinese population
Edward R. Winstead

The dopamine D4 receptor (DRD4) gene is active in the region of the brain associated with reward and dependence, and the gene contains a large number of variable sequences, or polymorphisms. In the field of psychiatric genetics, DRD4 variants have been the focus of numerous association studies, including several on heroin addiction.

Published data suggest that forms of DRD4 contribute to overall vulnerability to heroin abuse. In 1997, an association was reported between a polymorphism in the DRD4 gene and heroin abuse in a population of Chinese addicts. David A. Collier, of the Institute of Psychiatry, London, led the study, which was based on a study of Israeli heroin addicts.

Collier's group recently returned to their original sample population in Sichuan Province, Southwest China. In an expanded sample of addicts and controls, the researchers examined two DRD4 polymorphisms—a repeat of 48-letters within the gene and a single nucleotide polymorphism, or SNP, in the gene's regulatory region. An analysis of the data revealed that neither variant was a risk factor for heroin abuse in that population.

‘The association between inhalers and the DRD4 polymorphism is difficult to interpret’

An unexpected association was found, however, when the data were sorted according to inhalers of the drug and injectors of the drug. Injection of heroin is a more severe form of addiction than nasal inhalation, and the researchers thought genetic effects might be more apparent from this perspective.

The significant difference turned out to be between inhalers and controls rather than between injectors and controls. "The association observed between inhalers and the [48-letter] DRD4 polymorphism is difficult to interpret," the authors write in a recent issue of the American Journal of Medical Genetics. They speculate that the association is related to personality differences, some of which may involve dopamine-related genes. Although the data are controversial, differences in the psychological domain of novelty seeking have been attributed to variation in DRD4.

The 48-letter polymorphism is a 'VNTR,' or variable number of tandem repeats. The VNTR is repeated up to seven times in the gene in different ethnic populations. The 7-repeat motif, which occurs less frequently in Asia, is considered a risk factor for some psychiatric conditions such as attention deficit hyperactivity disorder. Here, too, the data are inconsistent.

"Overall, there is no clear consensus in the field over the role of the DRD4 VNTR in personality, psychiatric illness, and alcohol/substance abuse," the researchers write in their paper.

The initial study of the Chinese population included 121 heroin addicts and 154 controls. The addict group had an excess of the 'long' variants (five to seven repeats) of the DRD4 polymorphism compared to the control group. The researchers concluded that the long variants might be susceptibility polymorphisms for drug abuse.

The current study attempted to replicate the initial findings. This time, the sample included 405 heroin-abusing subjects recruited from inpatients in four psychiatric hospitals and 304 controls. The researchers do not rule out the possibility that further analysis will reveal that DRD4 has a modest effect on overall vulnerability to heroin abuse.

See related GNN article
»The DRD4 Gene: Psychiatry's Repeat Offender

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Li, T. et al. Association analysis of polymorphisms in the DRD4 gene and heroin abuse in Chinese subjects. Am J Med Genet (Neuropsychiatr Genet) 96, 616-621 (October 9, 2000).
Li, T. et al. Association analysis of the dopamine D4 gene exon III VNTR and heroin abuse in Chinese subjects. Mol Psychiatry 5, 413-416 (September 1997).

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