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Article

DNA Sequence Variations Affecting Serotonin Transporter Transcriptional Regulation and Activity: Do They Impact Alcohol Addiction?

by
Giampiero Ferraguti
1,*,
Silvia Francati
1,
Claudia Codazzo
2,
Giovanna Blaconà
1,
Giancarlo Testino
1,
Antonio Angeloni
1,
Marco Fiore
3,
Mauro Ceccanti
4 and
Marco Lucarelli
1,5
1
Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
2
UOSD Genetica Medica, Asl Roma1, 00193 Roma, Italy
3
Institute of Biochemistry and Cell Biology, IBBC-CNR, 00161 Rome, Italy
4
SITAC, Società Italiana Per il Trattamento Dell’alcolismo e le Sue Complicanze, 00185 Rome, Italy
5
Pasteur Institute, Cenci Bolognetti Foundation, Sapienza University of Rome, 00161 Rome, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(15), 8089; https://doi.org/10.3390/ijms25158089
Submission received: 4 June 2024 / Revised: 17 July 2024 / Accepted: 23 July 2024 / Published: 25 July 2024
(This article belongs to the Special Issue Genetic and Epigenetic Control of Disease Occurrence)
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Abstract

Genetic features of alcohol dependence have been extensively investigated in recent years. A large body of studies has underlined the important role of genetic variants not only in metabolic pathways but also in the neurobiology of alcohol dependence, mediated by the neuronal circuits regulating reward and craving. Serotonin transporter (5-HTT), encoded by the SLC6A4 gene (Solute carrier family 6-neurotransmitter transporter-member 4), is targeted by antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs) and plays a pivotal role in serotoninergic transmission; it has been associated with psychiatric diseases and alcohol dependence. Transcriptional regulation and expression of 5-HTT depend not only on epigenetic modifications, among which DNA methylation (CpG and non-CpG) is primarily involved, but also on sequence variations occurring in intron/exon regions and in untranslated regions in 5′ and 3′, being the first sequences important for the splicing machinery and the last for the binding of transcription factors and micro RNAs. This work intends to shed light on the role of sequence variations known to affect the expression or function of 5-HTT in alcohol-dependent individuals. We found a statistically significant difference in the allelic (p = 0.0083) and genotypic (p = 0.0151) frequencies of the tri-allelic polymorphism, with higher function alleles and genotypes more represented in the control population. Furthermore, we identified three haplotypes more frequent in subjects with AUD (p < 0.0001) and one more frequent in the control population (p < 0.0001). The results obtained for the tri-allelic polymorphism in alcohol dependence confirm what is already present in part of the literature. The role of haplotypes requires further studies to be clarified.
Keywords: alcohol dependence; serotonin transporter; polymorphisms; molecular biology; gene expression alcohol dependence; serotonin transporter; polymorphisms; molecular biology; gene expression

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MDPI and ACS Style

Ferraguti, G.; Francati, S.; Codazzo, C.; Blaconà, G.; Testino, G.; Angeloni, A.; Fiore, M.; Ceccanti, M.; Lucarelli, M. DNA Sequence Variations Affecting Serotonin Transporter Transcriptional Regulation and Activity: Do They Impact Alcohol Addiction? Int. J. Mol. Sci. 2024, 25, 8089. https://doi.org/10.3390/ijms25158089

AMA Style

Ferraguti G, Francati S, Codazzo C, Blaconà G, Testino G, Angeloni A, Fiore M, Ceccanti M, Lucarelli M. DNA Sequence Variations Affecting Serotonin Transporter Transcriptional Regulation and Activity: Do They Impact Alcohol Addiction? International Journal of Molecular Sciences. 2024; 25(15):8089. https://doi.org/10.3390/ijms25158089

Chicago/Turabian Style

Ferraguti, Giampiero, Silvia Francati, Claudia Codazzo, Giovanna Blaconà, Giancarlo Testino, Antonio Angeloni, Marco Fiore, Mauro Ceccanti, and Marco Lucarelli. 2024. "DNA Sequence Variations Affecting Serotonin Transporter Transcriptional Regulation and Activity: Do They Impact Alcohol Addiction?" International Journal of Molecular Sciences 25, no. 15: 8089. https://doi.org/10.3390/ijms25158089

APA Style

Ferraguti, G., Francati, S., Codazzo, C., Blaconà, G., Testino, G., Angeloni, A., Fiore, M., Ceccanti, M., & Lucarelli, M. (2024). DNA Sequence Variations Affecting Serotonin Transporter Transcriptional Regulation and Activity: Do They Impact Alcohol Addiction? International Journal of Molecular Sciences, 25(15), 8089. https://doi.org/10.3390/ijms25158089

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