Substance abuse is a major worldwide public health and social problem. A study in Taiwan [1] reported that heroin dependence may cause significant economic costs and affect the quality of life. The authors also indicated that the economic cost of heroin dependency was comparable to that for schizophrenia. Heroin-dependent subjects also had a poorer quality of life than healthy normal controls.
Environmental and genetic risk factors influence substance dependence [2]. Previous studies have demonstrated clusters of heroin dependence in families [3]. The results of a genetic epidemiologic study [4] supported a high degree of heritable vulnerability for heroin dependence. Among relatives of the controls, the drug dependence rate was 3.5%, compared to 20.5% among relatives of heroin-dependent individuals. Other studies [5] support the importance of the genetic influence on substance dependence in general, and on heroin dependence in particular. Twin epidemiological studies showed that genetic factors accounted for approximately 30–60% of the overall variance in the risk of drug addiction [6–8]. While the influences of environmental or genetic factors may vary at different stages [2], specific vulnerability to heroin has a major genetic component, greater than that of other types of substance abuse [6].
The neural-biochemical mechanisms of substance use disorders include dopamine (DA), 5-hydroxytryptamine, serotonin (5-HT), and norepinephrine (NE) neurotransmitter systems. Therefore, the receptor, transporter, and metabolic enzyme genes related to these neurotransmitter systems may be associated with substance use disorders. The serotonergic system, specifically the serotonin transporter (5-HTT) and postsynaptic activation of the serotonin 2A receptor (5-HT 2A), may play a relevant role in this substance dependence [2].
The serotonin transporter gene (SLC6A4) encodes the serotonin transporter which controls serotonin reuptake and inactivation from the synapse. A previous meta-analysis study [9] found a significant association in the combined studies of heroin dependence/abuse and 5-HTTLPR, which was more significant in European populations. They showed a weak association between STin2 variable number tandem repeat (VNTR) and heroin dependence/abuse in European studies of heroin dependence. However, Asian subjects with the STin2 VNTR 10 allele had a higher ratio of heroin dependence/abuse subjects than subjects with the STin2 VNTR 12 allele.
The promoter of the serotonin transporter gene is a repeat variant (5-HTTLPR) with either a short (S) or a long (L) form [10]. Recently, a variant (rs25531) was identified within the repeat which alters the transcriptional activity of the serotonin transporter gene. Combining this variant with the repeat yields a triallelic polymorphism which can be classified as a high transcriptional activity L_ or a low activity S_ allele [11].
Another study [12] observed an interaction between A-1438G (rs6311) of 5-HT2A and 5-HTT polymorphisms. The association between 5-HT2A A-1438G (rs6311) AA and AG/GG genotypes and heroin dependence was enhanced in the presence of 12-repeat 5-HTT VNTR (Stin2) and short-form 5-HTTLPR alleles. Their findings support the contribution of the 5-HT 2A gene to susceptibility to heroin dependence as well as a possible synergistic effect of 5-HT 2A and 5-HTT genes on susceptibility to heroin dependence.
Despite the serotonin transporter, the availability of serotonin for postsynaptic activity also requires tryptophan hydroxylase (TPH). Both genes coding for these proteins have functional variants which may make lower levels of serotonin available in the synapse. TPH is the rate-limiting enzyme in the biosynthesis of serotonin [13] and is expressed in TPH2 in the brain [14]. Serotonin is involved in the regulation of various aspects of mood and impulsivity [15, 16]. Concentrations of cerebral spinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA), a degradation product of serotonin, are low in depressed patients with a family history of alcoholism [17] and in those with behaviours characterised by a deficit in impulse control, such as aggression [18, 19] and impulsivity [20]. The synonymous variant 1125A > T (rs4290270) in exon 9 of the TPH2 gene is a marker for allelic expression imbalance [21]. The T allele is expressed at approximately two-fold the levels of the A allele in heterozygous subjects. A allele carriers may produce less serotonin than those with a TT genotype.
Therefore, we explored the association of 5-HTTLPR, STin2, 5-HT2A, and TPH2 variants with heroin dependence by comparing the different distributions of these gene polymorphisms in the case and control groups. Using case-control methods to study associations between these gene polymorphisms and heroin use disorders is important to identify genetic predispositions to heroin dependence and genetic predispositions to heroin co-occurring disorders. We also wanted to understand the impact of 5-HTTLPR, STin2, 5-HT2A, and TPH2 on heroin use conditions, such as dose, duration of use, and age of first use.