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Abstract Premenstrual syndrome (PMS) is characterized by recurrent psychologic, somatic and/or behavioral symptoms that occur specifically during the luteal phase of the menstrual cycle, and resolve by menstruation. The symptoms are severe enough to affect the quality of life. At the end of the PMS spectrum comes the Premenstrual dysphoric disorder (PMDD) with predominant psychologic symptoms. PMDD is estimated to occur in 3% to 8% of women with PMS.1 Although the exact cause of PMDD is unknown, however, there is evidence implicate an underlying dysregulation of serotonergic pathway. Evidence from epidemiologic studies suggests genetic factor contribution to PMDD.9-Most investigations have focused on the serotonin transporter gene (SLC6A4), which encodes a membrane-bound serotonin transporter responsible for active reuptake of serotonin from the synaptic cleft. It is also the site of action of selective serotonin reuptake inhibitors (SSRIs) which proved to be effective in the treatment of up to 70% of women suffering from PM DD.The most frequently studied polymorphism of SLC6A4 is the serotonin transporter long promoter region which comprises a complex of 20 to 23 base-pair (bp) repeat elements. A 43 bp insertion/deletion that produces a long (L) or a short (S) allele. The S variant has been associated with lower transcriptional activity of SLC6A4 and has a been linked to major depressive disorders and SSRI response in Caucasian subjects. A functional A/G single nucleotide polymorphism (SNP rs25531) that is located immediately upstream of the 43 bp insertion/deletion site further classify the L allele to La and Lg .23-24 The later has been shown to lower 5-HTT expression in vitro. Because the SNP is very rare to be found in the S alleles. Many studies currently consider 5-HTTLPR as a triallelic marker: LA, LG and S(A or G). Functionally, both alleles LG and S(A or G) are associated with low expression of the transporter protein. Objective: To investigate whether the function serotonin transporter long promoter region (5-HTTLPR) / rs25531 promoter polymorphism in the serotonin transporter gene is associated with premenstrual dysphoric disorder.Materials and Methods: The study included 53 women with clinically diagnosed premenstrual dysphoric disorder and 52 healthy control subjects. The 5-HTTLPR promoter polymorphism was genotyped in both groups by PCR and gel electrophoreses. The rs25531 single nucleotide polymorphism was also genotyped in both groups by doing PCR and digestion with the restriction enzyme MspI which recognizes and cut the G variant only. Genotyping was done by two independent researchers that were unaware of the clinical group status. Genotype and allele frequencies for the composite 5-HTTLPR/rs25531 marker were analyzed by Chisquare test. Statistical analysis Genotype distribution was tested regarding conformity to Hardy-Weinberg equilibrium. Fisher exact probability tests were used to test any specific genotype distribution between the PMDD and control group with the use of StatXact version 4.0.1 (Cytel Corp, Cambridge, MA). The test is considered statistically significant if the exact p value is less than 0.05. Results: Genotype distribution has shown conformity to Hardy- Weinberg equilibrium. There was no significant association between any of rs25531 SNP or the 5-HTTLPR/rs25531 composite marker and either the premenstrual dysphoric disorder or the control groups. Neither the triallelic classification nor the functional classification of the genotypes proved any association with any of the two groups of the study. |