Association of polymorphism in the dopamine receptors and transporter genes with hyperprolactinemia in patients with schizophrenia

Abstract

Association of polymorphism in the dopamine receptors and transporter genes with hyperprolactinemia in patients with schizophrenia D. Osmanova(1), A.S. Boiko(1), O.Y. Fedorenko(1), I.V. Pozhidaev(1), M.B. Freidin(2), E.G. Kornetova(3), S.A. Ivanova(1), B. Wilffert(4), A.J.M. Loonen(5) (1)Mental Health Research Institute- Tomsk NRMC, Laboratory of Molecular Genetics and Biochemistry, Tomsk, Russia (2)Research Institute of Medical Genetics, Tomsk NRMC, Laboratory of Population Genetics, Tomsk, Russia (3)Mental Health Research Institute- Tomsk NRMC, Department of Clinical and Social Psychiatry and Addiction, Tomsk, Russia (4)Groningen Research Institute of Pharmacy, Pharmacotherapy and Clinical Pharmacology, Groningen, The Netherlands (5)Groningen Research Institute of Pharmacy, Pharmacotherapy in Psychiatric Patients, Groningen, The Netherlands Background: Long-term antipsychotic drug use remains the mainstay of treatment for patients with schizophrenia. However, pharmacotherapy with these drugs is complicated by several troublesome side effects, including hyperprolactinemia (HP). Prolactin secretion is persistently inhibited by dopamine, and antipsychotic drugs are believed to increase prolactin release by blocking dopamine receptors in the pituitary gland. Genetic factors play an important role in the development of antipsychotic induced HP [1,2]. Genes coding for dopamine receptors and transporters are considered to be responsible for HP in schizophrenia [3]. The present study aimed to investigate the role of polymorphisms of the dopamine receptors and transporters genes (DRD1, DRD2, SLC6A3) in the pathogenesis of antipsychotic-related HP in patients with schizophrenia. Methods: 431 Russian patients with schizophrenia were examined. The average age of patients was 42.1 ± 1.4 years. Evaluation of serum prolactin level was performed by ELISA using reagents set PRL Test System (USA). Genotyping was carried out on 17 polymorphic variants of the dopamine receptors and transporters genes DRD1 (rs4532, rs936461), DRD2 (rs4245147, rs6279, rs2734842) and SLC6A3 (rs3756450, rs2550956, rs6347, rs2617605, rs3863145, rs250686, rs464049, rs4975646, rs1048953, rs11133767, rs27048, rs40184). The SPSS software was used for statistical analysis. The Hardy-Weinberg equilibrium (HWE) of genotypic frequencies was tested by the chi-square test. Results: We studied the association between HP and a set of SNPs from DRD1, DRD2 receptor genes and neurotransmitter transporter SLC6A3 in patients from Siberia with a clinical diagnosis of schizophrenia who were treated with classical and/or atypical antipsychotic drugs. All patients with schizophrenia were divided into two groups: those with and without HP. Physiological normal results for the serum prolactin levels are less than 20 ng/ml in men, and less than 25 ng/ml in women. Statistically significant result was obtained for polymorphic variant rs2550956 of the gene SLC6A3 (χ2 = 9.992; p = 0.007), which suggests its involvement in the development of HP. The heterozygous genotype TC of rs2550956 was significantly less common in patients with elevated levels of prolactin and it presumably has protective properties (OR 0.54; 95% CI: 0.36–0.81). We did not find any statistically significant associations for other polymorphisms DRD1 (rs4532, rs936461), DRD2 (rs4245147, rs6279, rs2734842) and SLC6A3 (rs3756450, rs6347, rs2617605, rs3863145, rs250686, rs464049, rs4975646, rs1048953, rs11133767, rs27048, rs40184). The group of dopamine receptors is heterogeneous and only some of them participate in the formation of psychotic symptoms and, accordingly, in the antipsychotic action of neuroleptics. The effect of neuroleptics on other groups of dopamine receptors leads to the development of different side effects including extrapyramidal disorders [4], and their role is extremely low in the formation of the actual therapeutic response. Conclusion: Our results indicate that genetic variants of SLC6A3 may have functional consequences on the modulation of prolactin secretion. Neurotransmitter systems are involved in the mechanisms of action of antipsychotic drugs; therefore, a further search for genetic markers associated with the development of antipsychotic-related hyperprolactinemia in schizophrenic patients is needed. References [1] Ivanova, S.A., Osmanova, D.Z., Boiko, A.S., Pozhidaev, I.V., Freidin, M.B., Fedorenko, O.Y., Semke, A.V., Bokhan, N.A., Kornetova, E.G., Rakhmazova, L.D., Wilffert, B., Loonen, A.J., 2016. Prolactin gene polymorphism (-1149G/T) is associated with hyperprolactinemia in patients with schizophrenia treated with antipsychotics. Schizophrenia Research Oct 21, pii: S0920-9964 (16)30473-X. doi: 10.1016/j.schres.2016.10.029. [2] Ivanova, S.A., Osmanova, D.Z., Freidin, M.B., Fedorenko, O.Y., Boiko, A.S., Pozhidaev, I.V., Semke, A.V., Bokhan, N.A., Agarkov, A.A., Wilffert, B., Loonen, A.J., 2017. Identification of 5-hydroxytryptamine receptor gene polymorphisms modulating hyperprolactinaemia in antipsychotic drug-treated patients with schizophrenia. World J Biol Psychiatry 18 (3), 239–246. [3] Miura, I., Zhang, J.P., Hagi, K., Lencz, T., Kane, J.M., Yabe, H., Malhotra, A.K., Correll, C.U., 2016. Variants in the DRD2 locus and antipsychotic-related prolactin levels: A meta-analysis. Psychoneuroendocrinology 72, 1–10. [4] Al Hadithy, A.F.Y., Ivanova, S.A., Pechlivanoglou, P., Semke, A., Fedorenko, O., Kornetova, E., Ryadovaya, L., Brouwers, J.R.B.J., Wilffert, B., Bruggeman, R., Loonen, A.J.M., 2009. Tardive dyskinesia and DRD3, HTR2A and HTR2C gene polymorphisms in Russian psychiatric inpatients from Siberia. Progress in NeuroPsychopharmacology and Biological Psychiatry 33, 475–481. Keywords: Dopamine Genetics / Molecular genetics Schizophrenia: basi