The Influence of Rs6311 and Rs6313 Polymorphisms of Serotonin 2a Receptor Gene (HTR2A) on Its mRNA and Protein Levels in Peripheral Blood Leukocytes in Treatment with Antipsychotics

The 5-hydroxytrypamine (serotonin) 2A receptor (5-HTR_2A) is the key receptor involved in the monoaminergic regulation of the body, which determines the biological functions and behavior of a person, and the target of the action of atypical antipsychotics. Polymorphic variants of the HTR2А gene rs6311 (-1438 A>G) and rs6313 (102 T>C)), potentially associated with impairment of the effectiveness of posttranscriptional processes, are considered to be risk factors for neuropsychiatric and cognitive pathologies. In the present study, we performed genotyping of these allelic variants among patients with schizophrenia spectrum disorders on antipsychotic therapy (haloperidol or olanzapine) (n = 60) and in the control group (n = 106). High linkage disequilibrium of allelic variants rs6311 and rs6313 (D' = 0.98) was found, and significant differences between the distribution of control group genotypes and patients with schizophrenia spectrum disorders were not detected. The contribution of the carriage of homozygous genotype GG (CC) into the efficacy of haloperidol therapy (р = 0.048) was shown. The effect of single nucleotide polymorphic variants rs6311 and rs6313 of the HTR2A gene on the mRNA level of the gene and the amount of 5-HTR_2A in patients with mental disorders on the antipsychotic therapy was estimated for the first time. Before treatment, the level of the mRNA of the HTR2A gene was not different between the genotypes, whereas the amount of the 5-HTR_2A protein was significantly higher in carriers of the AA (TT) genotype (р = 0.004). While mRNA level of HTR2A gene (р = 0.034) was increased in carriers of the GG (CC) genotype on haloperidol therapy. Olanzapine therapy reduced the amount of 5-HTR_2A in the carriers of the wild-type “A” allele, apparently due to the pharmacological effect of the drug. Thus, the obtained data suggest that antipsychotic drugs, regardless of their affinity, modulate the transcription and/or translation of the HTR2A gene in the rs6311 (rs6313) genotype-dependent manner, and may affect the effectiveness of therapy.