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Decreased serum complement component 4 levels in patients with schizophrenia

Ji, Ruo-nan*,; Zhang, Li-li*,; Zhao, Meng-fei; He, Hui-fang; Bai, Wei; Duan, Rui-xin; Kou, Chang-gui

doi: 10.1097/YPG.0000000000000226
Brief Report

Dysregulation of the immune system in mental disease, particularly complement component 4 (C4), which may be associated with schizophrenia, has been repeatedly observed. This study investigated the association between the level of serum component 4 and schizophrenia. Data were derived from a case-control association study of 40 unrelated adult patients with schizophrenia and 40 matched healthy controls. The component 4 level in serum was measured for comparative analysis by a component 4 enzyme-linked immunosorbent assay kit. Our findings suggest that the serum component 4 level is lower in patients with schizophrenia than in the controls, and the results apply to both males and females. Our results will lay an important foundation for establishing diagnostic methods and provide feasible and reliable evidence for the clinical treatment of schizophrenia.

Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, China

* Ruo-nan Ji and Li-li Zhang contributed equally to this article.

Received 12 October 2018 Accepted 19 March 2019

Correspondence to Chang-gui Kou, PhD, Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, NO. 1163 Xinmin Street, Changchun, Jilin Province 130021, China, Tel: +86 431 85619173; fax: +86 431 85619451; e-mail:

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Schizophrenia (SZ) is a complicated and chronic psychiatric illness that is characterised by hallucinations, delusions, emotional disorders and cognitive impairments. SZ is a severe disorder of cerebral function, with patient thoughts, behaviors and feelings being influenced. Currently, more than 23 million individuals are afflicted by SZ globally (McIntyre, 2009). According to the WHO (World Health Organisation, 2008), it is estimated that SZ is the fifth leading cause of the global burden of disease in males and sixth among females, making up 2.8 and 2.6% of total years lived with disability, respectively (Millier et al., 2014). Researchers have not identified a single or specific factor that contributes to SZ. It is believed that the etiological mechanism is the consequence of multifactor-induced interactions between genetic and environmental risk factors.

Accumulating evidence (Patterson, 2009; Richard and Brahm, 2012; Horváth and Mirnics, 2014; Khandaker and Dantzer, 2016; Kopczynska et al., 2017) suggests that immune mechanisms are involved in the onset of mental illness because of the close relationship between the immune system and the nervous system. Researchers have identified 108 genetic loci that are significantly associated with SZ, many of which are located in immune system-related genes (Ripke et al., 2014). Recent genome-wide association studies have also demonstrated that a genetic polymorphism of complement component 4 (C4) plays a pivotal role in relation to the susceptibility to SZ (Ripke et al., 2011). There is a significant association between the human C4 gene and the risk of SZ, and the increased expression of C4A in the human adult brain correlates with an increased risk of SZ (Sekar et al., 2016). In a further study (Sekar et al., 2016) that thoroughly investigates the mechanism of action of C4 on SZ through a mouse model, researchers concluded that C4 reduces the number of synapses in the brains of individuals with SZ. These results suggest that the expression of C4 may contribute to SZ.

Despite strong evidence supporting the association between abnormalities in the complement system and the emergence of SZ in recent years, the association between the level of C4 in serum and SZ emergence is inconsistent (Wang et al., 1992, Fernandes et al., 2010, Santos Sória et al., 2012, Tao et al., 2017). For instance, some studies showed that there was no significant difference in the serum level of C4 between patients with SZ and healthy controls. However, Wang et al. (1992) found that the complement C4 level in serum was higher in patients with SZ than in healthy controls. Therefore, this study aims to explore the association between the level of serum C4 and the emergence of SZ by measuring the level of C4 in serum of individuals with disorder. The results will lay an important foundation for establishing diagnostic methods and provide feasible and reliable evidence for clinical treatment.

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Methods and subjects


A total of 40 hospital patients with first-episode SZ, diagnosed by at least two experienced psychiatrists in strict accordance with ICD-10 diagnostic criteria, were selected as the case group. The healthy controls consisted of 40 unrelated adults without a history of psychiatric illness according to a survey of chronic diseases in the community. All cases and controls with long-term chronic disease and the use of immunosuppressants were excluded. This study was approved by the Ethics Committee of the School of Public Health of Jilin University and complied with the Helsinki Declaration. Participant anonymity and privacy were completely guaranteed.

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Blood collection and measurement

Under the informed consent of the participants or their families, 5 ml of venous blood was drawn from participants in the morning following a required fasting period. Blood was stored at room temperature for 2 hours before the supernatant was centrifuged and serum samples were extracted. Then, the serum samples were stored at −80°C. C4 was measured with an immunoassay technique on a HITACHI 7600 biochemistry analyser (Hitachi Crop., Tokyo, Japan) using a C4 enzyme-linked immunosorbent assay kit (Renjie Bio Company, Shanghai, China). All procedures were performed strictly in accordance with the instructions of the kit.

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Statistical analyses

SPSS software version 24.0 was used for analyses. The normality hypothesis was verified using Kolmogorov–Smirnov and Shapiro–Wilk tests. The level of C4 agreed with the normal distribution, and the distribution of the level of serum C4 was described as the mean ± SD. Intergroup comparisons were performed using Student’s t-test. All analyses used a two-sided 0.05 significance level.

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The case group consisted of 15 males and 25 females with a mean age of 28.68 ± 6.97 years. The control group consisted of 18 males and 22 females with a mean age of 30.38 ± 4.28 years. The distribution of age and sex matched between case and control groups. The serum C4 concentrations in the case group were lower than those in the control group (t = 3.72, P < 0.001). In addition, the level of serum C4 in male or female patients with SZ was significantly decreased compared to the level in the controls. The results are presented in Table 1 and Figure 1.

Table 1

Table 1

Fig. 1

Fig. 1

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In the present study, we explored the association between complement C4 levels and SZ and found that the complement C4 level in serum was lower among patients with SZ than among healthy controls. In addition, this study also demonstrated that the complement C4 level in the serum of male patients with SZ was lower than that in healthy controls, and similar results were observed in females. Our results indicate that abnormalities in C4 level are associated with the emergence of SZ in both males and females. Our finding of significantly reduced C4 levels in patients with SZ compared to healthy controls duplicates the discovery of Mayilyan et al. (2008), which suggested a similar outcome. In contrast, Maes et al. (1997) reported that C4 levels were significantly higher in patients with SZ. In the Maes et al. (1997) study, all cases were of the chronic or subchronic type, and they were all free of psychiatric illnesses or long-term chronic disease and the use of drugs that interfere with immune function, which may account for the inconsistency with our findings. Additionally, previous studies (Fernandes et al., 2010; Santos Sória et al., 2012) showed that there was no significant difference in the serum level of C4 between patients with SZ and healthy controls; however, an increased level of C3 was observed for cases, which may indicate that the activation of the complement system occurred through an alternative pathway. In addition, there are many other factors (Sopeña et al., 1996; Aral et al., 2006; El-Fatah Fahmy Hanno et al., 2014; Wakabayashi et al., 2016) that may influence the level of C4, such as a history of using drugs and suffering from other diseases, smoking and drinking habits and so on.

The complement system mediates innate and acquired immunity, and the activation of the complement component can remove damaged cells and autoantigens (Nimgaonkar et al., 2017). However, the mechanisms of how C4 affects SZ merit further investigation. Kopczynska et al. (2017) reported that select complement analyte measurements could be used to aid in the early diagnosis of SZ. The results of our study also suggest that serum C4 levels may be associated with SZ. Therefore, C4 has the potential to become a biomarker for the diagnosis and efficacy evaluation of SZ and other mental disorders.

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In conclusion, the level of serum C4 in patients with SZ was lower than that in healthy controls. Further investigations with a high quality and larger sample size are needed to validate our findings.

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This study was supported by the Innovation and Entrepreneurship Training Program Fund of Jilin University.

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Conflicts of interest

There are no conflicts of interest.

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Aral M, Ekerbicer HC, Celik M, Ciragil P, Gul M. Comparison of effects of smoking and smokeless tobacco ‘maras powder’ use on humoral immune system parameters. Mediators Inflamm. 2006; 2006:85019.
El-Fatah Fahmy Hanno A, Mohiedeen KM, Deghedy A, Sayed R. Serum complements C3 and C4 in chronic HCV infection and their correlation with response to pegylated interferon and ribavirin treatment. Arab J Gastroenterol. 2014; 15:58–62.
Fernandes BS, Cereser KM, Zortea K, Fries GR, Colpo G, Moreira L, et al. Complement system in bipolar disorders and schizophrenia: C3 and C4 (conference abstract). Bipolar Disord. 2010; 12:18–19.
Horváth S, Mirnics K. Immune system disturbances in schizophrenia. Biol Psychiatry. 2014; 75:316–323.
Khandaker GM, Dantzer R. Is there a role for immune-to-brain communication in schizophrenia? Psychopharmacology (Berl). 2016; 233:1559–1573.
Kopczynska M, Zelek W, Touchard S, Gaughran F, Di Forti M, Mondelli V, et al. Complement system biomarkers in first episode psychosis. Schizophr Res. 2017; S0920-9964:30764–30768.
Maes M, Delange J, Ranjan R, Meltzer HY, Desnyder R, Cooremans W, et al. Acute phase proteins in schizophrenia, mania and major depression: modulation by psychotropic drugs. Psychiatry Res. 1997; 66:1–11.
Mayilyan KR, Dodds AW, Boyajyan AS, Soghoyan AF, Sim RB. Complement C4B protein in schizophrenia. World J Biol Psychiatry. 2008; 9:225–230.
McIntyre RS. Understanding needs, interactions, treatment, and expectations among individuals affected by bipolar disorder or schizophrenia: the UNITE global survey. J Clin Psychiatry. 2009; 70Suppl 35–11.
Millier A, Schmidt U, Angermeyer MC, Chauhan D, Murthy V, Toumi M, Cadi-Soussi N. Humanistic burden in schizophrenia: a literature review. J Psychiatr Res. 2014; 54:85–93.
Nimgaonkar VL, Prasad KM, Chowdari KV, Severance EG, Yolken RH. The complement system: a gateway to gene-environment interactions in schizophrenia pathogenesis. Mol Psychiatry. 2017; 22:1554–1561.
Patterson PH. Immune involvement in schizophrenia and autism: etiology, pathology and animal models. Behav Brain Res. 2009; 204:313–321.
Richard MD, Brahm NC. Schizophrenia and the immune system: pathophysiology, prevention, and treatment. Am J Health Syst Pharm. 2012; 69:757–766.
Ripke S, Sanders AR, Kendler KS, Levinson DF, Sklar P, Holmans PA, et al. Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011; 43:969–976.
Ripke S, Neale BM, Corvin A, Walters JT, Farh KH, Holmans PA, et al. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014; 511:421–427.
Santos Sória Ld, Moura Gubert Cd, Ceresér KM, Gama CS, Kapczinski F. Increased serum levels of C3 and C4 in patients with schizophrenia compared to eutymic patients with bipolar disorder and healthy. Braz J Psychiatry. 2012; 34:119–120.
Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, et al. Schizophrenia Working Group of the Psychiatric Genomics ConsortiumSchizophrenia risk from complex variation of complement component 4. Nature. 2016; 530:177–183.
Sopeña B, Martínez-Vázquez C, Fernández-Rodríguez CM, de la Fuente J, Rivera A, Rodríguez M, et al. Serum angiotensin converting enzyme and C4 protein of complement as a combined diagnostic index in alcoholic liver disease. Liver. 1996; 16:303–308.
Tao H, Chen F, Luo H, Yang X, Liu Y, Tang Y. The levels of complement component 3, complement component 4, high sensitivity C reactive protein, and uric acid in serum of schizophrenia. Chinese J Nerv Ment Dis. 2017; 43:544–548.
Wakabayashi I, Marumo M, Nonaka D, Shimomura T, Eguchi R, Lee LJ, et al. Potential biomarker peptides associated with acute alcohol-induced reduction of blood pressure. PLoS One. 2016; 11:e0147297.
Wang C, Jian BX, Jiang XD, Zhao XZ. Investigation of allotypes of HLA class III (C2, BF and C4) in patients with schizophrenia. Chin Med J (Engl). 1992; 105:316–318.
World Health Organisation. The Global Burden of Disease: 2004 Update. 2008. Geneva: World Health Organization Press.

    complement component 4; schizophrenia; serum

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