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Keywords:

  • case-control study;
  • interleukin-1;
  • schizophrenia;
  • single nucleotide polymorphism;
  • variable number of tandem repeat

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Abstract  Interleukin-1 (IL1) is an inflammatory cytokine and exerts neurodegenerative effects in the brain. Several studies have indicated that IL1 is likely to be involved in the pathogenesis of schizophrenia. Recent genetic studies have revealed that the IL1 gene complex (IL,1 alpha, IL1, beta and IL1 receptor antagonist) was associated with schizophrenia, although contradictory findings have also been reported. To assess whether the IL1 gene complex was implicated in vulnerability to schizophrenia, the authors conducted a case-control association study (416 patients with schizophrenia and 440 control subjects) for nine polymorphisms in Japanese subjects. The authors found no association between the IL1 gene complex polymorphisms and schizophrenia using either single-marker or haplotype analyses. The results of the present study suggest that the IL1 gene complex does not play a major role in conferring susceptibility to schizophrenia in the Japanese population.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Schizophrenia is a complex genetic disorder and affects approximately 1% of the population worldwide. The pathogenesis of schizophrenia is still unclear, however, cytokines may be implicated in its etiology and/or pathology.1 Interleukin-1 (IL1) is an inflammatory cytokine and is expressed endogenously by brain cells such as microglia and astrocytes. IL1 exerts neurodegenerative effects in the brain and has been implicated in the modulation of synaptic plasticity.2 Subchronic peripheral IL1, alpha (IL1A) administration into neonatal rats and mice disrupted prepulse inhibition (PPI) in adulthood.3,4 Deficient PPI in patients with schizophrenia is noted in the loss of sensorimotor gating, and impaired PPI is also present in an animal model of schizophrenia.5 Chronic treatment with antipsychotics increased the mRNA levels of IL1, beta (IL1B) and IL1 receptor antagonist (IL1RN), an endogenous antagonist for the IL1 receptor, in various regions of the rat brain.6 Antipsychotics also have effects on human serum and cerebrospinal fluid (CSF) levels and in vitro production of IL1 as well as IL1RN.7–12 Furthermore, abnormal blood and CSF concentrations and in vitro production of IL1 and IL1RN have been observed in patients with schizophrenia,9,11,13–18 although some studies failed to find these changes.7,19–25 Recently, Toyooka et al. reported that both protein and mRNA expression levels of IL1RN were specifically decreased in the prefrontal cortex in patients with schizophrenia.18 Taken together, these findings suggest that disturbances in IL1A, IL1B and IL1RN are likely to be related to the pathogenesis of schizophrenia.

Genetic variants in the IL1 gene complex including IL1A, IL1B and IL1RN, located on chromosome 2q14, have been tested for their associations with schizophrenia. Specifically, the most extensively investigatedpolymorphisms in the IL1 gene complex are as follows: a single nucleotide polymorphism (SNP) at position −889 (relative to the transcriptional start site) in the 5′-flanking regulatory region of IL1A (C-889T); a SNP at position −511 of IL1B (C-511T); a SNP in the fifth exon of IL1B, which is a synonymous change (Phe105Phe); and a variable number of tandem repeats (VNTR) comprising two to six repeats of an 86 bp sequence [(86 bp)n] in the third intron of IL1RN. Interestingly, these polymorphisms influence the capacity to produce IL1A, IL1B and IL1RN, suggesting that these polymorphisms may be functional, although this remains controversial.26–31 Katila et al. reported that the frequencies of a single haplotype [−889T, −551C, (86 bp)4] were significantly higher in patients with schizophrenia than in the control subjects.32 Subsequently, studies replicating this work have provided confirmation that these polymorphisms and haplotypes consisting of these variants were associated with schizophrenia.33–35 However, contradictory results have also been reported,36–42 and these inconsistencies require further investigation. Therefore, the authors performed a case-control association study in Japanese subjects to assess whether the IL1 gene complex was implicated in vulnerability to schizophrenia. The authors tried to increase power by testing more markers and by increasing the sample size.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

The study population consisted of 416 patients with schizophrenia (224 men and 192 women; mean age, 40.5 [standard deviation (SD) 14.7] years) and 440 control subjects (230 men and 210 women: mean age, 38.0 [SD 10.4] years). No significant difference in gender ratio was observed between the two groups (χ2 = 0.21, d.f. = 1, P = 0.645). There was also no significant difference between the mean ages of the two groups (P = 0.054, Mann–Whitney U-test). All participants were unrelated Japanese living in the Niigata Prefecture or the Fukushima Prefecture. Patients meeting the Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV) criteria for schizophrenia were recruited from 14 hospitals. The diagnosis of schizophrenia had been assigned based on all available sources of information, including unstructured interviews, clinical observations and medical records, and was subsequently reassessed by an experienced psychiatrist. The mean age of the patients at onset of disease was 22.9 (SD 7.4) years. The control subjects were mainly recruited from the staff of the participating hospitals. Although these subjects were not assessed by a structured psychiatric interview, they all showed good social and occupational skills and reported that they had no history of psychiatric disorders. The present study was approved by the Ethics Committee on Genetics of the Niigata University School of Medicine, and written informed consent was obtained from all participants.

The authors examined eight SNP and a VNTR in the IL1 gene complex (Fig. 1). The authors tested three SNP, C-889T (rs1800587), Phe105Phe (rs1143634) and C-511T (rs16944), and a VNTR [(86 bp)n], which were investigated in previous studies.32–42 The remaining five SNP, JST006818 (rs2071376), JST006815 (rs2071373), JST075040 (rs3213448), JST006948 (rs2071459) and JST006488 (rs315952), were selected from the JSNP database (http://snp.ims.u-tokyo.ac.jp/index_ja.html).43 All SNP were genotyped using the TaqMan 5′-exonuclease assay, as described previously.44 A VNTR [(86 bp)n] was analyzed as described erlier.32

image

Figure 1. Genomic structure of the interleukin-1 gene complex and locations of the nine polymorphisms analyzed in the present study. Rectangles indicate exons. Arrows indicate transcriptional orientation. The lower bar indicates the distance (in kb) from interleukin-1 aplha.

Download figure to PowerPoint

Deviation from Hardy–Weinberg equilibrium (HWE) was tested by using the χ2 test for goodness-of-fit. Allele and genotype frequencies between the patients and control subjects were compared using the χ2 test or Fisher's exact test. Haplotype frequencies were estimated using the expectation maximization algorithm with SNPAlyze v3.5 (DYNACOM, Yokohama, Japan). Pair-wise linkage disequilibrium (LD) indices, D′ and r2, were calculated in the patients and control subjects. Case-control haplotype analyses were performed using the χ2 test. In these analyses, very rare haplotypes with frequencies of less than 0.01 were not assessed. A probability level of P < 0.05 was considered to indicate statistical significance.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Table 1 shows the genotype and allele frequencies of nine polymorphisms in the IL1 gene complex among the patients and control subjects. The genotype distributions of the polymorphisms did not deviate significantly from HWE in either group (P > 0.05), except for rs1800587 in the control subjects (P = 0.023). The alleles 2, 3 and 4 of (86 bp)n were considered as a single allele due to their low frequencies (5.3%, 0.6%, and 0.8%, respectively, in the control subjects). The genotype and allele frequencies of none of the nine polymorphisms in the patients differed significantly from those in the control subjects (P > 0.05). The values of absolute D′ and r2 for the control subjects are presented in Table 2. The authors observed intermediate to strong LD among rs2071376, rs2071373, rs1800587, rs1143634 and rs16944, and among rs3213448, rs2071459 (86 bp)n and rs315952. The pair-wise LD pattern in the patients was similar to that in the control subjects (data not shown). No associations between schizophrenia and the common haplotypes of these LD blocks (P > 0.05, Table 3) were found.

Table 1.  Genotype and allele frequencies of nine polymorphisms of the interleukin-1 gene complex in patients with schizophrenia and control subjects
MarkerPatientsControlsP
nHWE (P)GenotypeMAFnHWE (P)GenotypeMAF
1/11/11/22/21/22/2GenotypeAllele
  •  

    Calculated using Fisher's exact test.

  •  

    Alleles 2, 3 and 4 were considered as a single allele.

  • § 

    The frequencies of alleles 1, 2, 3 and 4 were 775 (0.93), 40 (0.05), 10 (0.01), 5 (0.01), respectively.

  •  

    The frequencies of alleles 1, 2, 3 and 4 were 821 (0.93), 47 (0.05), 5 (0.01), 7 (0.01), respectively.

  • HWE, Hardy–Weinberg equilibrium; MAF, minor allele frequency; 1, major allele; 2, minor allele.

rs20713764160.109221173220.264400.799242170280.260.5990.850
rs20713734160.123222172220.264400.848243169280.260.6000.852
rs18005874160.3183397520.104400.0233656780.090.1140.964
rs11436344160.3803902510.034400.4594103000.030.6260.850
rs169444160.370134212700.424400.083128235770.440.6120.429
rs32134484160.799160194620.384400.380172213550.370.5860.517
rs20714594160.837161194610.384400.380172213550.370.6410.585
(86 bp)n4150.1483605500.07§4400.1323815900.071.0000.948
rs3159524140.533165188610.374400.327176212520.360.4230.512
Table 2.  Linkage disequilibrium indices in the control subjects
Markerrs2071376rs2071373rs1800587rs1143634rs16944rs3213448rs2071459(86 bp)nrs315952
  1. Values at upper right show D′ and those at lower left show r2.

rs2071376 1.001.000.940.430.240.230.260.21
rs20713730.99 1.000.940.420.250.240.270.21
rs18005870.300.30 0.960.270.000.030.250.09
rs11436340.090.090.31 0.800.000.080.120.18
rs169440.080.080.010.02 0.230.230.430.16
rs32134480.030.040.000.000.04 1.000.730.84
rs20714590.030.030.000.000.040.99 0.770.84
(86 bp)n0.010.010.000.010.020.070.07 0.27
rs3159520.030.030.000.000.020.690.690.01 
Table 3.  Haplotype analyses of polymorphisms of the interleukin-1 gene complex in patients with schizophrenia and control subjects
MarkersGlobal P
Two markersThree markersFour markersFive markers
rs2071376    
 0.854   
rs2071373 0.960  
 0.961 0.986 
rs1800587 0.987 0.088
 0.906 0.087 
rs1143634 0.674  
 0.690   
rs16944    
rs3213448    
 0.565   
rs2071459 0.817  
 0.826 0.963 
(86 bp)n 0.974  
 0.774   
rs315952    

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

The authors found no significant association between the IL1 gene complex polymorphisms and schizophrenia in their Japanese subjects. Among the polymorphisms examined in the present study, rs16944 (C-511T) has been the most extensively investigated. Zanardini et al. reported that the frequency of the major C allele was significantly increased in Italian patients with schizophrenia as compared to the control subjects.33 However, other studies, including the present study, failed to find an association.37–39,41 The sample size of the present study (416 patients and 440 controls) is larger than that of Zanardini et al. (169 patients and 177 controls),33 and the present sample group has a post-hoc power of >0.8 to detect even a small effect size of ω of 0.2, with α of 0.05, using G*Power (http://www.psycho.uni-duesseldorf.de/aap/projects/gpower/).45 Accordingly, the likelihood of type II error with the present sample size appears to be comparatively low.

The (86 bp)n repeat has also been an extensively investigated polymorphism. Zanardini et al. reported that the frequency of allele 1 was significantly higher in Italian patients with schizophrenia than in the control subjects,33 while Kim et al. found that allele 2 was associated with schizophrenia in a Korean population.34 However, other studies, including the present study, failed to find an association.32,35,38,42 The allele 1 frequencies in Caucasian control subjects (65–71%)32,33,35,42 are lower than those in Asian control subjects (86–96%).34,38 Indeed, the allele 1 frequency in the present Japanese control subjects was 93%. This ethnic heterogeneity may be one of the reasons for poor replication of the association between the (86 bp)n repeat and schizophrenia.

Katila et al. found that the T-C-1 haplotype for rs1800587-rs16944-(86 bp)n was significantly higher in the Finnish patients with schizophrenia than in the control subjects.32 Papiol et al. showed an association between the C-2 haplotype for rs16944-(86 bp)n and schizophrenia in the Spanish population.35 However, single-marker analysis did not provide evidence for association in either study. Pair-wise LD indices, D′ and r2, were not shown in these two previous studies, although Papiol et al. indicated that there was significant linkage between this pair of loci in the control subjects, but not in the patients.35 In the present study, the authors did not perform haplotype analyses of these polymorphisms, because they observed only weak LD between these polymorphisms (D′ = 0.25–0.43).

The genotype distributions of rs1800587 in the control subjects deviated from HWE (P = 0.026). However, the P-value for the difference did not exceed the level of significance after Bonferroni correction for multiple testing (corrected P > 0.05). All the subjects in the present study were unrelated Japanese individuals living in a restricted area of Japan. Accordingly, the likelihood of population stratification appears to be low. Nevertheless, to eliminate population stratification, it is important to use a family-based analysis with internal controls as in the study of Rosa et al.41 because case-control studies have potential problems of population stratification.

The authors conclude that the IL1 gene complex does not play a major role in conferring susceptibility to schizophrenia in the Japanese population. Further case-control as well as family-based association studies with larger sample groups for the IL1 gene complex polymorphisms should be performed in several other ethnic populations.

ACKNOWLEDGMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

The authors wish to thank the patients, the patients' families and healthy volunteers for their participation; and Mr H. Kusano and Ms T. Yamada, Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, for excellent technical assistance. This work was supported by Health and Labour Sciences Research Grants for Research on Psychiatric and Neurological Diseases and Mental Health (to TS), a Grant-in-Aid for Scientific Research (to YW) and a Grant from the Research Group for Schizophrenia, Japan (to YW).

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES
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