"ARTICLE (see meta-analysis by GENDEP Investigators, 2013). Besides ethnicity, etiological heterogeneity, high complexity of the clinically defined phenotype, environmental factors, low statistical power of the individual studies and random error in the absence of a true effect, another potential confounder of the presently available pharmacogenetic studies might be epigenetic processes such as methylation of the cytosine pyrimidine ring in CpG dinucleotides, which are flexible, temporally dynamic and functionally highly relevant mechanisms suggested to shape disease risk as well as treatment response in MDD (Menke et al., 2012; Schroeder et al., 2012; Frieling and Tadic, 2013). The 5-HTT transcriptional control region contains a CpG island, which has been found to be variably methylated and to functionally influence 5-HTT mRNA levels with increased methylation, resulting in decreased 5-HTT expression depending on the 5-HTTLPR (Philibert et al., 2007). "
[Show abstract][Hide abstract] ABSTRACT: Variation in the serotonin transporter gene (5-HTT; SERT; SLC6A4) has been suggested to pharmacogenetically drive interindividual differences in antidepressant treatment response. In the present analysis, a 'pharmaco-epigenetic' approach was applied by investigating the influence of DNA methylation patterns in the 5-HTT transcriptional control region on antidepressant treatment response. Ninety-four patients of Caucasian descent with major depressive disorder (MDD) (f = 61) were analysed for DNA methylation status at nine CpG sites in the 5-HTT transcriptional control region upstream of exon 1A via direct sequencing of sodium bisulfite treated DNA extracted from blood cells. Patients were also genotyped for the functional 5-HTTLPR/rs25531 polymorphisms. Clinical response to treatment with escitalopram was assessed by intra-individual changes of HAM-D-21 scores after 6 wk of treatment. Lower average 5-HTT methylation across all nine CpGs was found to be associated with impaired antidepressant treatment response after 6 wk (p = 0.005). This effect was particularly conferred by one individual 5-HTT CpG site (CpG2 (GRCh37 build, NC_000017.10 28.563.102; p = 0.002). 5-HTTLPR/rs25531 haplotype was neither associated with 5-HTT DNA methylation nor treatment response. This analysis suggests that DNA hypomethylation of the 5-HTT transcriptional control region - possibly via increased serotonin transporter expression and consecutively decreased serotonin availability - might impair antidepressant treatment response in Caucasian patients with MDD. This pharmaco-epigenetic approach could eventually aid in establishing epigenetic biomarkers of treatment response and thereby a more personalized treatment of MDD.
The International Journal of Neuropsychopharmacology 03/2014; 17(08):1-10. DOI:10.1017/S146114571400039X · 4.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Molecular medicine is moving beyond genomics to encompass the new scientific field of epigenetics. First described as a conceptual model of how genes might interact with their surroundings to produce a phenotype, epigenomic research currently investigates mechanisms of nongenetic modification contributing to gene regulation and examines the impact of these changes on human health and behavior.
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