engleski

Intronic polymorphism of tryptophan hydroxylase and serotonin transporter : indication for combined effect in predisposition to suicide

Recent epidemiological studies revealed the role of genetic factors in the predisposition to suicide, which is now considered a disorder sui generis, independent of concomitant psychiatric disorders. Indices of disturbed serotonergic neurotransmission are the most robust biological findings in suicide. Serotonergic neurotransmission is controlled by the two main mechanisms: synthesis of the transmitter, regulated by the rate limiting tryptophan hydroxylase (TPH), and termination of transmission, mediated by 5-hydroxytryptamine transporter (5HTt). Intronic polymorphisms have been identified in both TPH (218AC in intron 7) and 5HTt (VNTR, with 12 and 10 repeats) genes. In the present work, we investigated whether the concurrence of two suspected, allegedly transcriptionally less active, variants (TPH allele C and 5HTt allele 10) represented the increased risk for suicidal behaviour. Frequencies of concurrence of the TPH and 5HTt genotypes containing "lower activity" alleles (CC and 1010, respectively) were investigated in 192 suicide victims and 377 controls. Target sequences encompassing the polymorphic site (218AC in TPH and intron-2 VNTR in 5HTt gene, respectively) were amplified by polymerase chain reaction. For 218AC polymorphism, PCR products were digested with BfaI and digests were electrophoresed on 2% agarose gels stained with ethidium bromide. PCR products of 5HTt VNTR polymorphism were separated on 3% agarose. Significant differences in frequencies of 5HTt and TPH genotype combinations were found between suicide victims and control subjects (p=0.0156), with a clear dose-effect of the suspected ("lower activity") genotypes (p=0.0046). Concurrent presence of the two, allegedly transcriptionally less active, variants of these genes seems to be somehow in relation to the increased susceptibility to suicide.

tryptophan hydroxylase; serotonin transporter; intron; gene polymorphism; suicide

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