Prolactin gene polymorphism (− 1149 G/T) is associated with hyperprolactinemia in patients with schizophrenia treated with antipsychotics

Abstract

Background

Antipsychotic drugs can cause hyperprolactinemia. However, hyperprolactinemia was also observed in treatment-naive patients with a first schizophrenic episode. This phenomenon might be related to the role of prolactin as a cytokine in autoimmune diseases. Extrapituitary prolactin production is regulated by an alternative promoter, which contains the functional single nucleotide polymorphism − 1149 G/T (rs1341239). We examined whether this polymorphism was associated with hyperprolactinemia in patients with schizophrenia.

Method

We recruited 443 patients with schizophrenia and 126 healthy controls. The functional polymorphism − 1149 G/T (rs1341239) in the prolactin gene was genotyped with multiplexed primer extension, combined with MALDI-TOF mass spectrometry. Genotype and allele frequencies were compared between groups with the χ² test and logistic regression models adjusting for covariates.

Results

The frequency of genotypes and alleles in patients with schizophrenia did not differ from those in control subjects. A comparison between patients with schizophrenia with and without hyperprolactinemia revealed significantly higher frequency of the G allele in patients with hyperprolactinemia than in patients without it (χ² = 7.25; p = 0.007; OR = 1.44 [1.10–1.89]). Accordingly, patients with hyperprolactinemia carried the GG genotype more frequently than patients without hyperprolactinemia (χ² = 9.49; p = 0.009). This association remained significant after adjusting the estimates for such covariates as sex, age, duration of the diseases and the dose of chlorpromazine equivalents.

Conclusion

This study revealed a significant association between the polymorphic variant rs1341239 and the development of hyperprolactinemia in patients with schizophrenia. The serum prolactin concentration in patients with schizophrenia treated with antipsychotics may provide an indication of the activity of the gene that regulates extrapituitary prolactin production which is believed to play a role in the immune system.

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.