Analysis of genetic polymorphisms of the dopaminergic and the serotonergic systems in drug dependent patients (Hungarian text)

Substance dependence is a major social and health problem worldwide. It is generally accepted that genetic and environmental risk factors contribute to the development of drug addiction, however, at present, little is known about the exact nature and effects of its genetic components. The aim of the molecular genetic researches is to identify the genetic risk factors. One of the most widely used methods is the candidate gene association study.; Neurobiological models emphasize the key role of the reward system through the dopaminergic mesocorticolimbic pathway, which is modulated by a number of other neurotransmitters, such as serotonin. Genetic polymorphisms of several components of reward system (receptors, metabolizing enzymes, transporters) have been widely studied for association with various personality traits, as well as psychiatric disorders including substance dependence.; The present theses describe the elaboration [1] and the application [3,4] of a simplified, non invasive DNA sampling method; the genotyping of polymorphic regions including the coding region (DRD4 48 by VNTR) and the 5' upstream region (-521 C/T SNP [2]) and 120 by duplication) of the DRD4 gene; the investigation of the 5' upstream region (5HTTLPR), and the intron 2 polymorphism (STin2) of the SERT gene and the analysis of DRD4 and SERT gene polymorphisms as possible risk factors for substance dependence, in a case-control association study of 73 substance dependent subjects and 362 healthy Caucasian (Hungarian) controls [3,4].; Our results indicate significant association between the -521 C/T SNP of the DRD4 promoter region and heroin dependence (p = 0.044) and an interaction between the dopaminergic and serotonergic system at molecular level. Association between the -521 CC vs. CT or TT genotypes and heroin dependence was enhanced in the presence of 14-repeat 5HTTLPR allele (p < 0.01). The observed odds ratio of 2.14 for the -521 CC genotype increased to 4.82 in case of the double homozygotes (i.e. -521 CC and 5HTTLPR 14/14), emphasizing the importance of combined analysis of polymorphisms in the dopaminergic and serotonergic systems in heroin dependence.