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Serotonin transporter promoter (5-httlpr) and intron 2 (vntr-2) polymorphisms: relationship between allelic variants and gene expression in schizophrenic patients

Serotonin transporter (5-hydroxytryptamine transporter, 5HTt) plays a central role in regulation of 5HT synaptic function and represents an interesting candidate for association studies in neuropsychiatric disorders. Two polymorphic regions of the 5HTt gene, which seem to modulate its transcription in allele-dependent manner, have been identified: 44 bp insertion/deletion in the promoter region (5-HTTLPR), and 17 bp variable number of tandem repeats in second intron of the gene (VNTR-2). In this study, separate and combined effects of VNTR-2 and 5-HTTLPR on the rate of peripheral 5HTt transcription were investigated in a sample of offspring from the families, multiply affected by schizophrenia, in which association with 5HTt gene has been previously demonstrated. Relative 5HTt mRNA levels were determined in 53 permanent lymphoblast cell lines by semi-quantitative real time PCR, using beta-actin as a reference. Since the low expressing alleles (S and 10) appeared to act in a dominant manner, genotypes were grouped as "high expressing" (LL, 1212) vs. "low expressing" (S, 10). At both loci, differences in 5HTt mRNA levels, of about 30%, between "high" and "low" expressing genotypes were indicative but non-significant. In order to search for potential combined effect of 5-HTTLPR and VNTR-2, levels of 5HTt mRNA were compared among three groups of samples having "low expressing" genotype at none, one or both loci. Increase in the number of "low expressing" genotypes significantly reduced relative 5HTt gene expression (p=0.0158). Our results indicate weak individual influence, but possible combined effect of 5-HTTLPR and VNTR-2 polymorphisms on 5HTt gene expression.

serotonin transporter; gene polymorphism; gene expression; intron; promoter

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