Prolactin gene polymorphism (− 1149 G/T) is associated with hyperprolactinemia in patients with schizophrenia treated with antipsychotics
Introduction
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 metabolic, endocrine, cardiovascular, and movement disorders (Lally and MacCabe, 2015, Staller, 2006). One of these side effects may be hyperprolactinemia (Ajmal et al., 2014, Peuskens et al., 2014). Prolactin secretion is persistently inhibited by dopamine (Fitzgerald and Dinan, 2008, Peuskens et al., 2014), and antipsychotic drugs are believed to increase prolactin release by blocking dopamine receptors.
Prolactin, also called the lactotrophin hormone, is a 199 amino-acid hormone synthesized and secreted in a pulsatile manner (~ 10 peaks per day in young adults) by the lactotroph cells of the anterior lobe of the pituitary gland (i.e., the adenohypophysis) (Fitzgerald and Dinan, 2008, Peuskens et al., 2014). The gene that encodes prolactin (PRL) has been mapped to chromosome 6p21 (Evans et al., 1989, Owerbach et al., 1981). The 6p21 region has been identified as a susceptibility locus that harbors genes associated with schizophrenia (Roig et al., 2007, Schwab et al., 2003, Tochigi et al., 2004). A recent genome-wide analysis (Stefansson et al., 2009) also found that this region was significantly associated with schizophrenia. In humans, the PRL locus consists of a single gene that contains five coding exons, which is controlled by a pituitary-specific promoter, and a non-coding exon, which is controlled by an alternative promoter. The latter promoter drives expression in non-pituitary tissues (Featherstone et al., 2012). Thus, apart from its role as a pituitary hormone, prolactin is also produced as a cytokine by immune cells; its receptor belongs to the family of cytokine receptors type 1 (Peeva et al., 2003). Stevens et al. (2001) identified a functional polymorphism in the PRL gene, − 1149 G/T (rs1341239). They showed that the G allele was associated with increased extrapituitary promoter activity and increased levels of lymphocyte prolactin mRNA. This polymorphism was previously associated with autoimmune diseases, such as systemic sclerosis (Fojtíková et al., 2010), rheumatoid arthritis (Lee et al., 2015, Reyes-Castillo et al., 2013), and systemic lupus erythematosus (SLE) (Lee et al., 2015, Stevens et al., 2001, Treadwell et al., 2015).
The immune system is believed to be involved in the pathogenesis of schizophrenia (DeLisi and Crow, 1986, Leboyer et al., 2016). Indeed, SLE was positively associated with schizophrenia (Tiosano et al., 2016). Moreover, stress is an important activator of the immune response (Leonard, 2006), and psychosocial stress has been shown to trigger the outbreak of psychotic symptoms and activate prolactin secretion (Riecher-Rössler et al., 2013). Additionally, Rybakowski et al. (2012) found that the − 1149 G allele was associated with schizophrenia, and others showed that the − 1149 TT genotype was correlated with high levels of serum prolactin (Treadwell et al., 2015).
In a collaborative Tomsk-Groningen research project, we measured serum prolactin levels (among other things) in patients with schizophrenia treated with antipsychotic drugs (Ivanova et al., 2016). In the present study, we investigated the possible role of the prolactin gene polymorphic variant, rs1341239, in the development of hyperprolactinemia in patients with schizophrenia.
Section snippets
Patients
This study was carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki 1975, revised in Fortaleza, Brazil, 2013), established for experiments involving humans. We recruited patients from three psychiatric hospitals located in the Tomsk, Kemerovo, and Chita oblasts (regions) of Siberia, Russia. Each patient provided written informed consent, after the study was approved (protocol N63/7.2014) by the Local Bioethics Committee of the Mental Health
Results
The total sample comprised 446 patients with schizophrenia (Table 1). Of these, 227 patients exhibited hyperprolactinemia (98 males/129 females), according to predefined criteria (Kelly et al., 2013, Peuskens et al., 2014).
The prevalence of genotypes in both the schizophrenic and healthy groups was consistent with Hardy-Weinberg equilibrium. The frequency of genotypes and alleles in patients with schizophrenia did not differ from those in control subjects (Table 2). Table 3 shows the
Discussion
We studied the association between the − 1149 G/T (rs1341239) variant of the PRL gene and antipsychotic drug-induced hyperprolactinemia in 443 white patients with schizophrenia from Siberia. We excluded patients with physiological or pathological conditions that might have affected prolactin secretion, and we corrected for variables related to prolactin secretion. The size of our reference group of healthy volunteers was limited; this limitation might explain the lack of significant differences
Acknowledgments
Author contributions: SI and AL instigated, designed, coordinated, and supervised the study. MF designed and performed the statistical analysis and contributed to writing the paper. SI wrote the study protocol and selected the SNP. DO, IP, EK, LR, and OF monitored the study, collected clinical data, and isolated DNA. DO and IP genotyped the samples and recorded all data in an Excel database. AB analyzed the prolactin samples. NB and AS supervised the clinical work. SI, AL, and BW supervised the
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2019, Journal of Affective DisordersCitation Excerpt :Stevens et al. (2001) identified a functional polymorphism in the PRL gene, − 1149 G/T (rs1341239), demonstrating the G allele was associated with increased extra-pituitary promoter activity and increased levels of lymphocyte PRL mRNA. Ivanova and colleagues revealed the existence of a significant association between the polymorphic variant rs1341239 and the development of hyperprolactinemia in patients with schizophrenia (Ivanova et al., 2017). Within the brain, prolactin acts as a neuropeptide to promote physiological responses related to reproduction, stress adaptation, neurogenesis, and neuroprotection (Torner, 2016).
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