Association study of a functional promoter polymorphism of the X-box binding protein 1 gene in Japanese patients with schizophrenia

Authors


Tatsuyuki Muratake, MD, PhD, Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Asahimachi-dori 1-757, Niigata 951–8510, Japan. Email: mura@med.niigata-u.ac.jp

Abstract

Abstract  The functional promoter polymorphism −116C/G of the X-box binding protein 1 (XBP1) gene was found to be associated with schizophrenia in Han Chinese and Japanese subjects, although contradictive negative findings were also reported in European populations. To confirm this association in a Japanese population, the authors conducted a case-control association study. There was no significant difference in both genotype and allele frequencies between the patients and control subjects, suggesting that the XBP1 –116C/G polymorphism might not confer increased susceptibility for schizophrenia in a Japanese population. However, further studies using a larger sample with detailed clinical data should be performed in several populations.

INTRODUCTION

X-box binding protein 1 (XBP1) is a transcription factor and plays important roles in endoplasmic reticulum (ER) stress response.1 Kakiuchi et al. identified a C to G substitution at position −116 in the XBP1 gene, loosing the binding motif of the gene, which impaired the XBP1 loop in ER stress response.2 They found that this functional promoter polymorphism of the XBP1 gene was associated with bipolar disorder,2 whereas two other studies failed to find this association.3,4 The XBP1 gene is located on 22q12.1, one of the common susceptibility loci for schizophrenia and bipolar disorder.5 Accordingly, association studies between the XBP1 –116C/G polymorphism and schizophrenia were also performed. Chen et al. reported that this polymorphism was associated with schizophrenia in Han Chinese subjects.6 Kakiuchi et al. found that the C/C genotype was significantly less common in the patients compared with the controls in Japanese subjects, suggesting that the C/C genotype is a protective factor for schizophrenia.7 In contrast, Jönsson et al. recently found no association between the −116C/G polymorphism and schizophrenia in three European samples comprising 2182 German, Polish and Swedish subjects.8 This inconsistency requires further investigations, and there is the possibility that this polymorphism could be implicated in vulnerability to schizophrenia in Asian but not Caucasian populations. Therefore, the authors performed a case-control study to examine whether the XBP1 –116C/G polymorphism is associated with schizophrenia in a Japanese population.

METHODS

The participants included 347 patients with schizophrenia (186 male; mean age, 41.4 [standard deviation (SD) 15.0] years) and 420 control subjects (217 male; mean age, 38.3 [SD 10.5] years). All participants were unrelated Japanese living in Niigata Prefecture or 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 was 23.1 (SD 7.4) years, and the mean duration of illness was 18.0 (SD 12.9) years. A total of 22 patients met criteria for paranoid, 141 for disorganized, 10 for catatonic, 171 for undifferentiated, and three for residual subtype of schizophrenia. The patients with family history of schizophrenia within their first degree relatives were 115 (33.1%). The control subjects were mainly recruited from the staffs 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 Ethics Committee on Genetics of Niigata University School of Medicine approved the present study, and written informed consent was obtained from all participants.

The authors genotyped the XBP1 –116C/G polymorphism (rs2269577) using the TaqMan 5′-exonuclease assay. The primer and probe set was designed and synthesized by Applied Biosystems (Foster City, CA, USA). The authors carried out polymerase chain reaction amplification using TaqMan 2× Universal Master Mix, No AmpErase UNG (Applied Biosystems), 5 ng of DNA, 0.9 µM of each primer and 200 nM of each probe in total volume of 5 µL. The thermal cycling conditions were 95°C for 10 min, followed by 40 cycles of 92°C for 15 s and 60°C for 1 min. Fluorescence and allelic discrimination were measured using an ABI PRISM 7900HT Sequence Detection System and SDS 2.0 software (Applied Biosystems).

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 Fisher’s exact test. A probability level of P < 0.05 was considered statistically significant.

RESULTS

Table 1 shows the genotype and allele frequencies of the XBP1 –116C/G polymorphism in the patients and control subjects. The genotype distribution was within HWE in both groups (P > 0.05). There was no significant difference in both genotype and allele frequencies between the patients and controls among all subjects (P = 0.29 for genotype and P = 0.15 for allele); men (P = 0.65 for genotype and P = 0.40 for allele), and women (P = 0.41 for genotype and P = 0.26 for allele).

Table 1.  Genotype and allele frequencies of the −116C/G polymorphism in the cases and controls
GroupGenotype (%)  PAllele (%) P
All subjectsC/CC/GG/G CG 
 Cases41 (11.8)145 (41.8)161 (46.4)0.29227 (32.7)467 (67.3)0.15
 Controls36 (8.6)174 (41.4)210 (50.0) 246 (29.3)594 (70.7) 
MaleC/CC/GG/G CG 
 Cases21 (11.3)78 (41.9)87 (46.8)0.65120 (32.3)252 (67.7)0.40
 Controls19 (8.7)90 (41.5)108 (49.8) 128 (29.5)306 (70.5) 
FemaleC/CC/GG/G CG 
 Cases20 (12.4)67 (41.6)74 (46.0)0.41107 (33.2)215 (66.8)0.26
 Controls17 (8.4)84 (41.4)102 (50.2) 118 (29.1)288 (70.9) 

DISCUSSION

In the present study, the authors found no association between the functional promoter polymorphism −116C/G of the XBP1 gene and schizophrenia in their Japanese sample. Recently, Jönsson et al. reported that this polymorphism was not associated with schizophrenia in European subjects.8 In contrast, two other previous case-control studies using Asian samples showed significant associations between the XBP1 –116C/G polymorphism and schizophrenia. Chen et al. reported that the G allele and the G/G genotype were significantly higher in the patients than in the controls in Han Chinese subjects,6 and Kakiuchi et al. found that the C/C genotype was significantly less common in the patients compared with the controls in Japanese subjects.7 This discrepancy might stem from differences in the clinical backgrounds including the age of the patients at onset, duration of illness, subtypes of schizophrenia, and family history of schizophrenia, which influence the results of genotype analyses between the current sample and that of Chen et al. or Kakiuchi et al. Nevertheless, they did not describe the clinical backgrounds of their samples, and the authors do not have any precise ideas about this point. The current sample size (347 cases and 420 controls) is similar to that of Chen et al. (374 cases and 371 controls) or Kakiuchi et al. (234 cases and 451 controls), but has only a power of 0.26 to replicate the effects reported by Kakiuchi et al. (the genotypic relative risk of 2.18 for C/G and of 2.12 for G/G) with an α of 0.05, assuming a disease prevalence of 0.01 and the risk allele frequency of 0.71 using the Genetic Power Calculation.9 Therefore, the authors could not exclude the possibility of type II error due to an insufficient statistical power. When the authors pooled their sample with that of Kakiuchi et al., however, the results were also negative (P = 0.59 for genotype and P = 0.69 for allele). Further studies using a larger sample with detailed clinical data should be performed in several populations to evaluate the association between the XBP1 –116C/G polymorphism and schizophrenia.

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