Family-based association study of interleukin 10 (IL10) and interleukin 10 receptor alpha (IL10RA) functional polymorphisms in schizophrenia in Polish population
Graphical abstract
Introduction
Schizophrenia is a heterogeneous disorder and its etiology remains incompletely elucidated. Among the possible causes, immunological factors have been implicated in its pathogenesis and course. The inflammatory system may trigger or modulate the course of schizophrenia through complex mechanisms influencing neurodevelopment, neuroplasticity and neurotransmission (Na et al., 2014). A concept of the relationship between psychiatric symptoms and immunological abnormalities was formed over a hundred years ago (Drzyzga et al., 2006). In the last three decades a range of cytokine alterations has been found in acute and chronic schizophrenia patients (Altamura et al., 2013, Benros et al., 2012, Drexhage et al., 2010, Ganguli et al., 1994, Gibney and Drexhage, 2013, Mansur et al., 2012). Cytokines are supposed to play a critical role in infectious and inflammatory processes, mediating the cross-talk between the brain and the immune system (Mansur et al., 2012).
Interleukin 10 (IL10) is a cytokine mainly produced by immune cells and exhibits diverse activities in various organs. It has been detected in the brain and human glia cells are considered a major source of IL10 (Chabot et al., 1999). IL10 may play an important role for immunological aspects in etiologies of major psychiatric disorders including schizophrenia (Eskdale et al., 1997, Jun et al., 2003). IL10 is biologically active as a homodimer and activates the IL10RA and IL10RB receptor complex. IL10 helps to downregulate the inflammatory immune response (Muller et al., 2013). IL10 suppresses the expression of other inflammatory molecules and is an extremely important anti-inflammatory and immunosuppressive cytokine in humans (Brocker et al., 2010). IL10 activity suppresses cell-mediated immune responses by hindering T cell proliferation and by altering the activation potential of professional antigen presenting cells, such as dendritic cells and macrophages (O'Garra et al., 2008). IL10 also promotes the proliferation of B cells and thereby enhances humoral immunity (Freudenreich et al., 2010). IL10 prevents glutamate and N-methyl-d-aspartate (NMDA)-mediated cell death in vitro (Bachis et al., 2001). It also attenuates the degeneration of dopaminergic neurons (Qian et al., 2006). There is the evidence that an altered functionality of IL10 may influence the dopamine balance (Platzer et al., 2000, Shibata et al., 1997).
Increased IL10 serum levels in schizophrenia were detected (Cazzullo et al., 1998, de Witte et al., 2014, Kunz et al., 2011, Maes et al., 2002, Rothermundt et al., 1996). However, other studies on patients with schizophrenia reported decreased serum IL10 levels (Kaminska et al., 2001, Xiu et al., 2014). Also recent meta-analysis showed that blood IL10 level was significantly lower in acutely relapsed schizophrenics (Miller et al., 2011). Paranoid patients produce less IL10 than other chronic schizophrenia patients (Cazzullo et al., 1998). Another meta-analysis conducted by Potvin et al. (2008) shows no significant effect sizes in the in vitro secretion of IL10 by peripheral blood leukocytes from schizophrenia patients (Potvin et al., 2008). No differences in IL10 gene expression in peripheral blood cells were also observed in patients with schizophrenia (Freudenreich et al., 2010).
Numerous studies reported that treatment with antipsychotic drugs affects the cytokine network (Pollmacher et al., 1996). Chlorpromazine increases the release and the circulating levels of IL10 and this effect was partly associated with the protective activity of chlorpromazine against endotoxic shock (Drzyzga et al., 2006). Increases in the levels of IL10 were found in the in vitro study with chlorpromazine, haloperidol, and clozapine (Szuster-Ciesielska et al., 2004) as well as in plasma of schizophrenic patients during treatment with risperidone (Cazzullo et al., 1998) and aripiprazole (Sobis et al., 2015). Sobis et al. (2015) also observed that the improvement in psychopathological symptoms (PANSS positive, negative and total scores) after 28 days of aripiprazole treatment was closely related to a significant increase in the IL10 level (Sobis et al., 2015). However, de Witte et al. (2014) found that the levels of IL10 were decreased in 32 antipsychotic-naïve first-episode schizophrenia patients who had been followed up and treated for 6 weeks with atypical antipsychotics, and noticed that the changes in IL10 levels were significantly correlated with the improvements in negative, general and total symptom scores in PANSS (de Witte et al., 2014). Maes et al. (2002) reported an increased serum level of IL10 in patients with schizophrenia resistant to treatment who received clozapine (Maes et al., 2002). Another study of IL10 plasma level in schizophrenic patients showed no significant changes compared to those of baseline after antipsychotic treatment with olanzapine, risperidone and quetiapine (Pae et al., 2006).
Heritability estimates of the interleukin levels based on twin studies range from 50 to 75% for IL10 (Tekola Ayele et al., 2012). The IL10 gene is located on chromosome region 1q31–32 (Eskdale et al., 1997), a locus that has been reported to be linked to genetic susceptibility to schizophrenia (Gurling et al., 2001, Hovatta et al., 1999).
The human IL10 receptor (IL10R) is a heterotetramer composed of two receptor chains (IL10RA and IL10RB). The IL10RA chain plays a dominant role in mediating high-affinity ligand binding and signal transduction, whereas the IL10RB subunit is thought to be required for signaling only (Moore et al., 2001).
Section snippets
Material and methods
The study was performed on a group of 146 trios (patients diagnosed with schizophrenia and their healthy parents). There were 65 males (mean age 24.3; SD 6.7) and 81 females (mean age 26.9; SD 6.8) in the patients' group. Mean age of onset of the first psychotic episode was 22.9 years. In 21 patients family history of schizophrenia and in 42 patients family history of other psychiatric disorders have been confirmed. Mean age of parents at the recruitment time was: fathers 55.9 (SD 8.44), mothers
Theory/calculation
A total of 7 polymorphisms of the IL10 and IL10RA genes, each selected on the basis of molecular evidence for functionality, were investigated in this study. The SNPs investigated in the IL10 gene (− 592C/A, rs1800872; − 819C/T, rs1800871; − 1082A/G, rs1800896; − 3575T/A, rs1800890; and − 6752A/T, rs6676671) have been characterized as promoter region regulatory variants (Misener et al., 2008, Yilmaz et al., 2005). Two single nucleotide polymorphisms (SNPs) of the IL10 receptor 1 (IL10RA) caused a
Results
All polymorphisms did not deviate from the Hardy–Weinberg equilibrium.
No association of the polymorphisms from IL10 (rs1800872, rs1800871, rs1800896, rs1800890, and rs6676671) and IL10RA (rs3135932 and rs2229113) genes with schizophrenia were found. Results are presented in Table 1.
All five studied SNPs within IL10 were in strong linkage disequilibrium (Fig. 1). We also performed haplotype analysis of haplotype block in the IL10 gene (consisting of − 592C/A, rs1800872; − 819C/T, rs1800871; −
Discussion
The mutations in IL10 gene promoter sequences might alter IL10 protein production in vitro (Kube et al., 2001). Three biallelic polymorphisms (− 1082G/A, − 819C/T, and − 592C/A) may have a functional effect on IL10 transcription activation and cytokine production (Turner et al., 1997) and have been found to be strongly connected with schizophrenia in the Caucasian population (Paul-Samojedny et al., 2010).
A modest increase in frequency of the − 592A allele and − 592A/A genotype in the schizophrenic
Conclusions
Our results do not support the theory that polymorphisms of IL10 and IL10RA genes are involved in the pathogenesis of schizophrenia, but they should be interpreted very carefully. Although the present study showed a negative association of IL10 and IL10RA gene polymorphisms with schizophrenia, it does not mean an exclusion of IL10 and IL10RA genes for the etiologic factors in this disease. Probably an increase in the number of patients studied would not alter our conclusion, but negative
Role of the funding source
This study was supported by the grant of the Polish Ministry of Science and High Education number NN 402407339. The funding source had no involvement in study design, in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
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