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Possible association between Interleukin-1beta gene and schizophrenia in a Japanese population

Possible association between Interleukin-1beta gene and schizophrenia in a Japanese population Background: Several lines of evidence have implicated the pro-inflammatory cytokine interleukin-1beta (IL-1b)in the etiology of schizophrenia. Although a number of genetic association studies have been reported, very few have systematically examined gene-wide tagging polymorphisms. Methods: A total of 533 patients with schizophrenia (302 males: mean age ± standard deviation 43.4 ± 13.0 years; 233 females; mean age 44.8 ± 15.3 years) and 1136 healthy controls (388 males: mean age 44.6 ± 17.3 years; 748 females; 46.3 ± 15.6 years) were recruited for this study. All subjects were biologically unrelated Japanese individuals. Five tagging polymorphisms of IL-1b gene (rs2853550, rs1143634, rs1143633, rs1143630, rs16944) were examined for association with schizophrenia. Results: Significant difference in allele distribution was found between patients with schizophrenia and controls for rs1143633 (P = 0.0089). When the analysis was performed separately in each gender, significant difference between patients and controls in allele distribution of rs1143633 was observed in females (P = 0.0073). A trend towards association was also found between rs16944 and female patients with schizophrenia (P = 0.032). Conclusions: The present study shows the first evidence that the IL-1b gene polymorphism rs1143633 is associated with schizophrenia susceptibility in a Japanese population. The results suggest the possibility that the influence of IL-1b gene variations on susceptibility to schizophrenia may be greater in females than in males. Findings of the present study provide further support for the role of IL-1b in the etiology of schizophrenia. Background only in schizophrenia patients but also in their siblings, Several lines of evidence suggest that pro-inflammatory suggesting the involvement of the hereditary factors. cytokine interleukin-1beta (IL-1b) is implicated in the Furthermore, previous findings suggested that IL-1b may etiology and pathophysiology of schizophrenia. Although be involved in the possible link between prenatal exposure studies investigating peripheral levels of IL-1b in schizo- to infection and schizophrenia [10,11]. phrenic patients have reported inconsistent results [1-6], a The IL-1b gene is located in a region on 2q14. This study examining the cerebrospinal fluid has shown a region has consistently shown positive linkage findings in marked elevation of IL-1b in patients with first-episode schizophrenia. Many studieshavereported this region schizophrenia compared to healthy controls [7]. Kowalski among their largest results [12,13]. Furthermore, Lewis et et al [8] reported that the release of IL-1b by peripheral al [14] have shown in their meta-analysis of 20 genome scans that 2p12-q22.1 was associated with a genomewide monocytes was increased before treatment and then nor- malized by antipsychotic medication in patients with schi- significant P value. Linkage of this region with schizo- zophrenia. Recently, Liu et al. [9] showed that IL-1b in the phrenia in an Asian population has also been reported peripheral blood mononuclear cells was overexpressed not [15]. A number of genetic association studies have sug- gested that genetic variation of the IL-1b gene might * Correspondence: sasayama@shinshu-u.ac.jp Department of Mental Disorder Research, National Institute of Neuroscience, confer susceptibility to schizophrenia. Three studies in National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8502, Caucasian populations reported a significant association Japan of schizophrenia with an IL-1b gene polymorphism Full list of author information is available at the end of the article © 2011 Sasayama et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Sasayama et al. Behavioral and Brain Functions 2011, 7:35 Page 2 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/35 rs16944 [16-18]. However, this association was not con- using Japanese and Chinese population in the HapMap firmed in other studies [19,20]. Furthermore, none of SNP set (version 22), at an r threshold of 0.80 with a the previous studies in Asian populations have obtained minor allele frequency greater than 0.1. Genomic DNA evidence for an association between IL-1b gene and was prepared from the venous blood according to stan- schizophrenia [21-23]. All of the aforementioned asso- dard procedures. The SNPs were genotyped using the ciation studies, except for that of Shirts, et al. [19], TaqMan 5’-exonuclease allelic discrimination assay. examined only rs16944 and/or rs1143634. Therefore, Thermal cycling conditions for polymerase chain reac- theroleofother IL-1b gene polymorphisms remains to tion were 1 cycle at 95°C for 10 minutes followed by 50 be determined. We here examined 5 tagging polymorph- cycles of 92°C for 15 seconds and 60°C for 1 minute. isms of the IL-1b gene for an association with schizo- The allele-specific fluorescence was measured with ABI phrenia in a Japanese sample. PRISM 7900 Sequence Detection Systems (Applied Bio- systems, Foster city, CA, USA). Genotype data were Methods read blind to the case-control status. Ambiguous geno- Subjects type data were not included in the analysis. The call Subjects were 533 patients with schizophrenia (302 rates for each SNP ranged from 97.7% to 98.6%. The males: mean age ± standard deviation 43.4 ± 13.0 years; genotyping failure rate for all SNPs combined was < 2%. 233 females; mean age 44.8 ± 15.3 years) and 1136 In 92 subjects, all 5 SNPs were genotyped in duplicate healthy controls (388 males: mean age 44.6 ± 17.3 years; to ensure genotyping accuracy, and the concordance 748 females; 46.3 ± 15.6 years). The mean age at onset rate of called genotypes was over 99%. was 23.9 ± 8.0 and 25.8 ± 9.8 years for male and female patients, respectively. All subjects were biologically unre- Statistical analysis lated Japanese individuals, based on their self-reports, Deviations of genotype distributions from the Hardy- and were recruited from the outpatient clinic of the Weinberg equilibrium (HWE) were assessed with the National Center of Neurology and Psychiatry Hospital, exact test described by Wigginton et al [32]. Genotype Tokyo, Japan or through advertisements in free local and allele distributions were compared between patients information magazines and by our website announce- and controls by using the c test for independence or ment. Consensus diagnosis by at least two psychiatrists with Fisher’s exact test. The above statistical analyses was made for each patient according to the Diagnostic were performed using PLINK version 1.07 [33]. th and Statistical Manual of Mental Disorders, 4 edition Haploview 4.2 [31] was used to estimate haplotype fre- criteria [24], on the basis of unstructured interviews and quencies and linkage disequilibrium (LD) coefficients. information from medical records. The controls were Haplotypes with frequencies > 1% were included in the healthy volunteers with no current or past history of psy- association analysis. Permutation procedure (10,000 repli- chiatric treatment, and were screened using the Japanese cations) was used to determine the empirical significance. version of the Mini International Neuropsychiatric Inter- Statistical tests were two tailed and statistical signifi- view (M.I.N.I.) [25,26] by a research psychiatrist to rule cance was considered when P < 0.05. Significance level out any axis I psychiatric disorders. Participants were corrected for multiple comparisons of 5 SNPs was set at excluded if they had prior medical histories of central P <0.013 by amethodproposedbyLietal[34],which nervous system disease or severe head injury, or if they was calculated using SNPSpD (SNP Spectral Decompo- met the criteria for substance abuse or dependence, or sition) software [35]. mental retardation. The study protocol was approved by Power calculations were performed using the Power the ethics committee at the National Center of Neurol- Calculator for Two Stage Association Studies (http:// ogy and Psychiatry, Japan. After description of the study, www.sph.umich.edu/csg/abecasis/CaTS/). Power was cal- written informed consent was obtained from every sub- culated under prevalence of 0.01 using an allelic model ject. Most of the subjects had participated in our previous with an alpha level of 0.05. Assuming disease allele fre- genetic association studies [27,28]. Some of the control quencies of 0.20 and 0.40, our sample had 80% statistical subjects had also participated in our previous studies power to detect relative risks of 1.28 and 1.23, respec- which examined IL-1b gene polymorphisms [29,30]. tively. Similarly, we had 90% power to detect relative risks of 1.33 and 1.27. Genotyping Since several aspects of immunity have marked sex Five tagging single nucleotide polymorphisms (SNPs) differences [36], analyses were performed not only for (rs2853550, rs1143634, rs1143633, rs1143630, rs16944) the entire sample but also for each gender separately. in a region 1 kilobase (kb) upstream to 1 kb down- Assuming allele frequency of 0.40, male and female stream of the IL-1b gene (chromosome 2: 113,302,808 - samples each had 80% statistical power to detect relative risks of 1.35 and 1.34, respectively. 113,311,827 bp) were selected by Haploview 4.2 [31] Sasayama et al. Behavioral and Brain Functions 2011, 7:35 Page 3 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/35 Table 1 Association analysis of the 5 SNPs in both genders combined Males SNP name Allele 1/2 N Genotype Allele P-value HWE P-value 1/1 1/2 2/2 1 2 Genotype Allele rs2853550 A/G Schizophrenia 531 9 128 394 146 916 0.23 0.088 0.86 (0.02) (0.24) (0.74) (0.14) (0.86) Controls 1115 14 232 869 260 1970 0.88 (0.01) (0.21) (0.78) (0.12) (0.88) (a) rs1143634 A/G Schizophrenia 525 1 41 483 43 1007 0.97 0.90 0.59 (0.00) (0.08) (0.92) (0.04) (0.96) Controls 1121 2 90 1029 94 2148 1.00 (0.00) (0.08) (0.92) (0.04) (0.96) rs1143633 C/T Schizophrenia 524 111 249 164 471 577 0.035 0.0089 0.38 (0.21) (0.48) (0.31) (0.45) (0.55) Controls 1123 188 525 410 901 1345 0.38 (0.17) (0.47) (0.37) (0.40) (0.60) rs1143630 T/G Schizophrenia 520 13 140 367 166 874 0.88 0.66 1.00 (0.03) (0.27) (0.71) (0.16) (0.84) Controls 1119 24 296 799 344 1894 0.65 (0.02) (0.26) (0.71) (0.15) (0.85) rs16944 A/G Schizophrenia 521 123 253 145 499 543 0.18 0.060 0.54 (0.24) (0.49) (0.28) (0.48) (0.52) Controls 1111 226 534 351 986 1236 0.39 (0.20) (0.48) (0.32) (0.44) (0.56) (a) Calculated using Fisher’s exact test. SNP: single nucleotide polymorphism; HWE: Hardy-Weinberg Disequilibrium Numbers in parentheses represent the frequencies of genotypes and alleles. Results Discussion Genotype and allele distributions of the examined SNPs To our knowledge, the present study is the largest study for the entire sample, males, and females are shown in to date that examined the IL-1b gene polymorphisms for Table 1, 2, and 3, respectively. The genotype distributions association with schizophrenia. The results provide the did not significantly deviate from the HWE in any of the first evidence suggesting that the C allele of rs1143633 is SNPs examined. Significant differences in genotype and associated with schizophrenia. allele distributions were found between the patients with The study in a United States population by Shirts et al schizophrenia and controls for rs1143633. The C allele [19] was the only one that previously examined the asso- wassignificantlymore commoninpatientsthanincon- ciation of schizophrenia with rs1143633, in which no sig- trols (odds ratio 1.22, 95% confidence interval (CI) 1.05 nificant difference was found in allele frequencies to 1.41, P = 0.0089). This association remained significant between patients and controls. Although Watanabe et al after correcting for multiple testing of 5 SNPs (corrected [23] have also examined 9 SNPs of the IL-1 gene complex P = 0.013). When the analysis was performed separately in Japanese subjects, none of the SNPs examined in their in each gender, significant difference between patients study was in remarkable linkage disequilibrium with and controls in allele distribution of rs1143633 was rs1143633 or rs16944 (all r <0.1 basedonHapMap observed only in females (odds ratio 1.34, 95% CI 1.08 to Japanese and Han Chinese population data, release 22). 1.66, P = 0.0073). The A allele of rs16944 also showed a The inconsistent results regarding the effect of rs1143633 trend towards association with schizophrenia in female between Shirts, et al [19] and our study may be attributa- subjects (odds ratio 1.26, 95% CI 1.02 to 1.56, P = 0.032). ble to ethnic difference. Indeed, a recent meta-analysis Linkage disequilibrium (LD) coefficients (D’ and r ) has shown a significant association of the G allele of and haplotype blocks are shown in Figure 1. Results of rs16944 and the G allele carrier status of rs1143634 with the haplotype association analyses are shown in Table 4. a risk of schizophrenia in Caucasian, but not in Asian, No significant difference in haplotype distribution was populations [37]. Our samples provided sufficient power found between patients with schizophrenia and controls to detect relatively small relative risks, and therefore sug- (all P > 0.05 by permutation test). gest that rs16944 and rs1143634 have no major effect on Sasayama et al. Behavioral and Brain Functions 2011, 7:35 Page 4 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/35 Table 2 Association analysis of the 5 SNPs in males Males SNP name Allele 1/2 N Genotype Allele P-value HWE P-value 1/1 1/2 2/2 1 2 Genotype Allele (a) rs2853550 A/G Schizophrenia 300 4 74 222 82 518 0.68 0.69 0.62 (0.01) (0.25) (0.74) (0.14) (0.86) Controls 383 7 85 291 99 667 0.82 (0.02) (0.22) (0.76) (0.13) (0.87) (a) rs1143634 A/G Schizophrenia 298 0 24 274 24 572 0.81 0.82 1.00 (0.00) (0.08) (0.92) (0.04) (0.96) Controls 383 1 27 355 29 737 0.42 (0.00) (0.07) (0.93) (0.04) (0.96) rs1143633 C/T Schizophrenia 299 59 145 95 263 335 0.43 0.47 0.81 (0.20) (0.48) (0.32) (0.44) (0.56) Controls 383 77 168 138 322 444 0.059 (0.20) (0.44) (0.36) (0.42) (0.58) rs1143630 T/G Schizophrenia 295 7 81 207 95 495 0.75 0.73 1.00 (0.02) (0.27) (0.70) (0.16) (0.84) Controls 383 6 106 271 118 648 0.32 (0.02) (0.28) (0.71) (0.15) (0.85) rs16944 A/G Schizophrenia 295 66 143 86 275 315 0.92 0.67 0.64 (0.22) (0.48) (0.29) (0.47) (0.53) Controls 385 82 186 117 350 420 0.61 (0.21) (0.48) (0.30) (0.45) (0.55) (a) Calculated using Fisher’s exact test. SNP: single nucleotide polymorphism; HWE: Hardy-Weinberg Disequilibrium Numbers in parentheses represent the frequencies of genotypes and alleles. Table 3 Association analysis of the 5 SNPs in females Males SNP name Allele 1/2 N Genotype Allele P-value HWE P-value 1/1 1/2 2/2 1 2 Genotype Allele rs2853550 A/G Schizophrenia 231 5 54 172 64 398 0.18 0.096 0.78 (0.02) (0.23) (0.74) (0.14) (0.86) Controls 732 7 147 578 161 1303 0.57 (0.01) (0.20) (0.79) (0.11) (0.89) (a) rs1143634 A/G Schizophrenia 227 1 17 209 19 435 0.46 0.84 0.32 (0.00) (0.07) (0.92) (0.04) (0.96) Controls 738 1 63 674 65 1411 1.00 (0.00) (0.09) (0.91) (0.04) (0.96) rs1143633 C/T Schizophrenia 225 52 104 69 208 242 0.013 0.0073 0.29 (0.23) (0.46) (0.31) (0.46) (0.54) Controls 740 111 357 272 579 901 0.76 (0.15) (0.48) (0.37) (0.39) (0.61) rs1143630 T/G Schizophrenia 225 6 59 160 71 379 0.97 0.83 0.80 (0.03) (0.26) (0.71) (0.16) (0.84) Controls 736 18 190 528 226 1246 0.89 (0.02) (0.26) (0.72) (0.15) (0.85) rs16944 A/G Schizophrenia 226 57 110 59 224 228 0.11 0.032 0.69 (0.25) (0.49) (0.26) (0.50) (0.50) Controls 726 144 348 234 636 816 0.50 (0.20) (0.48) (0.32) (0.44) (0.56) (a) Calculated using Fisher’s exact test. SNP: single nucleotide polymorphism; HWE: Hardy-Weinberg Disequilibrium Numbers in parentheses represent the frequencies of genotypes and alleles. Significant P-values (< 0.013) are shown in boldface. Sasayama et al. Behavioral and Brain Functions 2011, 7:35 Page 5 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/35 the opposite direction to that of the Caucasians, with schizophrenia susceptibility in female subjects. Therefore, there remains a possibility that a larger study would yield a significant difference between Japanese female schizo- phrenic patients and controls in the allele frequency of rs16944. A number of genome-wide association studies (GWAS) have searched for polymorphisms associated with schizo- phrenia [38-43]. Although no evidence of association with IL-1b gene has been reported, common risk alleles in the major histocompatibility region on chromosome 6, a. SNPs in the promoter region which is involved in the immune response, have shown b. Intronic SNPs statistically significant evidence of association [38-40]. c. Synonymous SNPs Furthermore, a genome-wide pharmacogenomic study has shown that IL-1a rs11677416, which is in weak LD Figure 1 Haplotype block structure of the IL-1b gene.Genomic with rs1143633 (r = 0.094, D’ = 0.809 based on HapMap organization and linkage disequilibrium (LD) structure of the IL-1b Japanese and Han Chinese population data, release 22), gene are shown. Exons are shown as boxes. Shades of red represent extent of LD (darker red denotes D’ = 1). Numbers in was associated with response of neurocognitive symp- squares give r values multiplied by 100. toms to antipsychotic treatment [44]. These findings, together with ours, suggest genetic influence on immune alterations in schizophrenia. schizophrenia susceptibility in Asian populations, which A shift towards the T helper type 2 (Th2) system has is consistent with the previous Asian findings [21-23]. been indicated in schizophrenia [45-47]. IL-1b stimulates However, there was a trend of association of rs16944, in Table 4 Haplotype analysis of IL-1b gene polymorphisms Males Females Block Haplotype Diagnosis Carrier Non- c2 Nominal P Permutation Carrier Non- c2 Nominal P Permutation carrier value P value carrier value P value GT Schizophrenia 336.3 265.7 0.557 0.456 0.957 251.0 213.0 6.240 0.0125 0.118 (0.559) (0.441) (0.541) (0.459) Controls 447.9 326.1 901.0 585.0 (0.579) (0.421) (0.606) (0.394) 1 GC Schizophrenia 183.1 418.9 0.216 0.642 0.995 149.0 315.0 2.298 0.130 0.691 (0.304) (0.696) (0.321) (0.679) Controls 226.4 547.6 422.5 1063.5 (0.293) (0.707) (0.284) (0.716) AC Schizophrenia 82.6 519.4 0.215 0.643 0.995 63.7 400.3 3.281 0.0701 0.461 (0.137) (0.863) (0.137) (0.863) Controls 99.6 674.4 158.5 1327.5 (0.129) (0.871) (0.107) (0.893) GG Schizophrenia 321.4 280.6 0.154 0.694 0.996 231.2 228.8 5.012 0.0252 0.207 (0.534) (0.466) (0.503) (0.497) Controls 422.6 353.4 837.4 652.6 (0.545) (0.455) (0.562) (0.438) 2 GA Schizophrenia 183.5 418.5 0.040 0.841 1.00 156.4 303.6 5.326 0.0210 0.178 (0.305) (0.695) (0.340) (0.660) Controls 232.7 543.3 422.8 1067.2 (0.300) (0.700) (0.284) (0.716) TA Schizophrenia 97.1 504.9 0.081 0.776 0.999 72.4 387.6 0.027 0.869 1.00 (0.161) (0.839) (0.157) (0.843) Controls 120.7 655.3 229.8 1260.2 (0.156) (0.844) (0.154) (0.846) Numbers in parentheses represent the frequencies of haplotypes. Permutation P values were based on 10,000 permutations. Sasayama et al. Behavioral and Brain Functions 2011, 7:35 Page 6 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/35 the production of prostaglandin E2, which is an impor- Furthermore, in vitro stimulation of lymphocytes with tant cofactor for the induction of T-helper lymphocyte phytohemagglutinin has shown that females produce activity towards Th2 direction. Significant increase in cir- more Th2 cytokines than males [58]. Thus, future studies culating mRNA expression levels of IL-1b has been investigating associations of immune-related genes with observed in schizophrenic patients [9]. The changes in schizophrenia should take into consideration the possible mRNA levels may reflect the genetic variation in IL-1b gender differences. There are some limitations to this study. The ethnicity gene. The findings on biological roles of IL-1b poly- of the participants was based on self-reports and was morphisms, however, have not been consistent across not confirmed by genetic analyses. Our positive results studies. A/A genotype of rs16944 has been associated with higher gastric mucosa IL-1b levels in H. pylori posi- might be derived from sample bias due to population tive population [48]. On the other hand, subjects with stratification, although the Japanese are a relatively G/G genotype showed an increased release of IL-1b from homogeneous population. Furthermore, structured inter- mononuclear cells after stimulation with lipopolysacchar- view such as SCID (Structured Clinical Interview for ide [49]. Recent studies suggest that the functional role of DSM) was not used for diagnosis in this study. Finally, rs16944 may depend on the IL-1b promoter region hap- the function of the IL-1b gene SNPs are unclear. Future lotypes including rs16944 and rs1143627 [50-53]. studies are necessary to elucidate the function and its Although the findings are inconsistent, these previous relationship with the pathogenesis of schizophrenia. studies suggest that rs16944 could affect the expression levels of IL-1b. On the other hand, the influence of Conclusions rs1143633 on IL-1b expression levels has not been pre- Our results suggest that rs1143633 of IL-1b gene is viously reported. associated with schizophrenia susceptibility in a Japanese Intriguingly, rs1143633 and rs16944 have also been population and that the influence of IL-1b gene varia- associated with cortisol response to dexamethasone in tions on susceptibility to schizophrenia may be greater healthy subjects [30]. Alleles associated with increased in females than in males. We obtained no significant cortisol response to dexamethasone were shown to be evidence for a well-studied polymorphism rs16944 being associated with schizophrenia in the present study. associated with schizophrenia, which is consistent with Higher rates of non-suppression to dexamethasone com- previous studies in Asian populations. However, a trend pared to healthy subjects have been reported in schizo- of higher A allele frequency of rs16944 in female phrenia [54] and schizotypy [55]. On the other hand, patients with schizophrenia leaves open a possibility that Ismail et al [56] reported that less than 2% of their schi- a larger study may yield a significant difference. The zophrenic patients were non-suppressors. Although the results of the present study provide further support for findings are inconsistent, these studies indicate that the role of IL-1b in the etiology of schizophrenia. Future schizophrenia may be associated with alteration in studies are warranted to replicate the present findings hypothalamic- pituitary- adrenal (HPA) axis. Taken and to reveal the functional role of IL-1b gene in patho- together, our findings suggest that IL-1b gene poly- physiology of schizophrenia. morphisms may play a role in the HPA axis alteration in schizophrenic patients. Acknowledgements Our results showed significant association of rs1143633 This study was supported by Health and Labor Sciences Research Grants with schizophrenia in only females. Although our male (Comprehensive Research on Disability, Health, and Welfare), Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science sample was not large enough to detect a small relative (JSPS), Core Research of Evolutional Science & Technology (CREST), Japan risk, our data suggest that susceptibility to schizophrenia Science and Technology Agency (JST), the Strategic Research Program for is more influenced by the IL-1b gene variation in females. Brain Sciences by the Ministry of Education, Culture, Sports, Science and Technology of Japan (Understanding of molecular and environmental bases To our knowledge, no previous studies have examined for brain health), and Intramural Research Grant for Neurological and the gender differences in the association between IL-1b Psychiatric Disorders of NCNP (H.K.). gene polymorphisms and schizophrenia. However, gen- Author details der differences have been reported in the association Department of Mental Disorder Research, National Institute of Neuroscience, between schizophrenia and RELA gene [27] encoding the National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8502, major component of NF-B, which is activated by IL-1b. Japan. Department of Psychiatry, Shinshu University School of Medicine, Matsumoto, 390-8621, Japan. Core Research of Evolutional Science & Taken together with our results, the influence of IL-1b Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, on susceptibility to schizophrenia may differ between 102-0075, Japan. Department of Medical Genetics, Majors of Medical genders. Indeed, gender differences in immunity have Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, 305-8577, Japan. Yokohama Shinryo Clinic, Yokohama, been reported in previous studies [36]. IL-1 release from 221-0835, Japan. National Center of Neurology and Psychiatry, Kodaira, mononucleated cells has been shown to be menstrual Tokyo, 187-8502, Japan. phase dependent in females and lower in males [57]. Sasayama et al. Behavioral and Brain Functions 2011, 7:35 Page 7 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/35 18. Zanardini R, Bocchio-Chiavetto L, Scassellati C, Bonvicini C, Tura GB, Rossi G, Authors’ contributions Perez J, Gennarelli M: Association between IL-1beta -511C/T and IL-1RA DS and HK designed the study and DS wrote the draft of the manuscript. (86bp)n repeats polymorphisms and schizophrenia. J Psychiatr Res 2003, DS, HH, TT, KH, MO, MT, and HK made the diagnosis according to DSM-IV 37:457-462. criteria. DS, HH, TT, KH, MO, and HK screened the healthy participants using 19. Shirts BH, Wood J, Yolken RH, Nimgaonkar VL: Association study of IL10, the Mini International Neuropsychiatric Interview (M.I.N.I.). DS and YI IL1beta, and IL1RN and schizophrenia using tag SNPs from a performed the genotyping. HK supervised the data analysis and writing of comprehensive database: suggestive association with rs16944 at the paper. TH and NA also supervised the writing of the paper and gave IL1beta. Schizophr Res 2006, 88:235-244. critical comments on the manuscript. All authors contributed to and have 20. Betcheva ET, Mushiroda T, Takahashi A, Kubo M, Karachanak SK, approved the final manuscript. Zaharieva IT, Vazharova RV, Dimova II, Milanova VK, Tolev T, et al: Case- control association study of 59 candidate genes reveals the DRD2 SNP Competing interests The authors declare that they have no competing interests. rs6277 (C957T) as the only susceptibility factor for schizophrenia in the Bulgarian population. J Hum Genet 2009, 54:98-107. Received: 27 April 2011 Accepted: 16 August 2011 21. 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Possible association between Interleukin-1beta gene and schizophrenia in a Japanese population

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Copyright © 2011 by Sasayama et al; licensee BioMed Central Ltd.
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Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
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Abstract

Background: Several lines of evidence have implicated the pro-inflammatory cytokine interleukin-1beta (IL-1b)in the etiology of schizophrenia. Although a number of genetic association studies have been reported, very few have systematically examined gene-wide tagging polymorphisms. Methods: A total of 533 patients with schizophrenia (302 males: mean age ± standard deviation 43.4 ± 13.0 years; 233 females; mean age 44.8 ± 15.3 years) and 1136 healthy controls (388 males: mean age 44.6 ± 17.3 years; 748 females; 46.3 ± 15.6 years) were recruited for this study. All subjects were biologically unrelated Japanese individuals. Five tagging polymorphisms of IL-1b gene (rs2853550, rs1143634, rs1143633, rs1143630, rs16944) were examined for association with schizophrenia. Results: Significant difference in allele distribution was found between patients with schizophrenia and controls for rs1143633 (P = 0.0089). When the analysis was performed separately in each gender, significant difference between patients and controls in allele distribution of rs1143633 was observed in females (P = 0.0073). A trend towards association was also found between rs16944 and female patients with schizophrenia (P = 0.032). Conclusions: The present study shows the first evidence that the IL-1b gene polymorphism rs1143633 is associated with schizophrenia susceptibility in a Japanese population. The results suggest the possibility that the influence of IL-1b gene variations on susceptibility to schizophrenia may be greater in females than in males. Findings of the present study provide further support for the role of IL-1b in the etiology of schizophrenia. Background only in schizophrenia patients but also in their siblings, Several lines of evidence suggest that pro-inflammatory suggesting the involvement of the hereditary factors. cytokine interleukin-1beta (IL-1b) is implicated in the Furthermore, previous findings suggested that IL-1b may etiology and pathophysiology of schizophrenia. Although be involved in the possible link between prenatal exposure studies investigating peripheral levels of IL-1b in schizo- to infection and schizophrenia [10,11]. phrenic patients have reported inconsistent results [1-6], a The IL-1b gene is located in a region on 2q14. This study examining the cerebrospinal fluid has shown a region has consistently shown positive linkage findings in marked elevation of IL-1b in patients with first-episode schizophrenia. Many studieshavereported this region schizophrenia compared to healthy controls [7]. Kowalski among their largest results [12,13]. Furthermore, Lewis et et al [8] reported that the release of IL-1b by peripheral al [14] have shown in their meta-analysis of 20 genome scans that 2p12-q22.1 was associated with a genomewide monocytes was increased before treatment and then nor- malized by antipsychotic medication in patients with schi- significant P value. Linkage of this region with schizo- zophrenia. Recently, Liu et al. [9] showed that IL-1b in the phrenia in an Asian population has also been reported peripheral blood mononuclear cells was overexpressed not [15]. A number of genetic association studies have sug- gested that genetic variation of the IL-1b gene might * Correspondence: sasayama@shinshu-u.ac.jp Department of Mental Disorder Research, National Institute of Neuroscience, confer susceptibility to schizophrenia. Three studies in National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8502, Caucasian populations reported a significant association Japan of schizophrenia with an IL-1b gene polymorphism Full list of author information is available at the end of the article © 2011 Sasayama et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Sasayama et al. Behavioral and Brain Functions 2011, 7:35 Page 2 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/35 rs16944 [16-18]. However, this association was not con- using Japanese and Chinese population in the HapMap firmed in other studies [19,20]. Furthermore, none of SNP set (version 22), at an r threshold of 0.80 with a the previous studies in Asian populations have obtained minor allele frequency greater than 0.1. Genomic DNA evidence for an association between IL-1b gene and was prepared from the venous blood according to stan- schizophrenia [21-23]. All of the aforementioned asso- dard procedures. The SNPs were genotyped using the ciation studies, except for that of Shirts, et al. [19], TaqMan 5’-exonuclease allelic discrimination assay. examined only rs16944 and/or rs1143634. Therefore, Thermal cycling conditions for polymerase chain reac- theroleofother IL-1b gene polymorphisms remains to tion were 1 cycle at 95°C for 10 minutes followed by 50 be determined. We here examined 5 tagging polymorph- cycles of 92°C for 15 seconds and 60°C for 1 minute. isms of the IL-1b gene for an association with schizo- The allele-specific fluorescence was measured with ABI phrenia in a Japanese sample. PRISM 7900 Sequence Detection Systems (Applied Bio- systems, Foster city, CA, USA). Genotype data were Methods read blind to the case-control status. Ambiguous geno- Subjects type data were not included in the analysis. The call Subjects were 533 patients with schizophrenia (302 rates for each SNP ranged from 97.7% to 98.6%. The males: mean age ± standard deviation 43.4 ± 13.0 years; genotyping failure rate for all SNPs combined was < 2%. 233 females; mean age 44.8 ± 15.3 years) and 1136 In 92 subjects, all 5 SNPs were genotyped in duplicate healthy controls (388 males: mean age 44.6 ± 17.3 years; to ensure genotyping accuracy, and the concordance 748 females; 46.3 ± 15.6 years). The mean age at onset rate of called genotypes was over 99%. was 23.9 ± 8.0 and 25.8 ± 9.8 years for male and female patients, respectively. All subjects were biologically unre- Statistical analysis lated Japanese individuals, based on their self-reports, Deviations of genotype distributions from the Hardy- and were recruited from the outpatient clinic of the Weinberg equilibrium (HWE) were assessed with the National Center of Neurology and Psychiatry Hospital, exact test described by Wigginton et al [32]. Genotype Tokyo, Japan or through advertisements in free local and allele distributions were compared between patients information magazines and by our website announce- and controls by using the c test for independence or ment. Consensus diagnosis by at least two psychiatrists with Fisher’s exact test. The above statistical analyses was made for each patient according to the Diagnostic were performed using PLINK version 1.07 [33]. th and Statistical Manual of Mental Disorders, 4 edition Haploview 4.2 [31] was used to estimate haplotype fre- criteria [24], on the basis of unstructured interviews and quencies and linkage disequilibrium (LD) coefficients. information from medical records. The controls were Haplotypes with frequencies > 1% were included in the healthy volunteers with no current or past history of psy- association analysis. Permutation procedure (10,000 repli- chiatric treatment, and were screened using the Japanese cations) was used to determine the empirical significance. version of the Mini International Neuropsychiatric Inter- Statistical tests were two tailed and statistical signifi- view (M.I.N.I.) [25,26] by a research psychiatrist to rule cance was considered when P < 0.05. Significance level out any axis I psychiatric disorders. Participants were corrected for multiple comparisons of 5 SNPs was set at excluded if they had prior medical histories of central P <0.013 by amethodproposedbyLietal[34],which nervous system disease or severe head injury, or if they was calculated using SNPSpD (SNP Spectral Decompo- met the criteria for substance abuse or dependence, or sition) software [35]. mental retardation. The study protocol was approved by Power calculations were performed using the Power the ethics committee at the National Center of Neurol- Calculator for Two Stage Association Studies (http:// ogy and Psychiatry, Japan. After description of the study, www.sph.umich.edu/csg/abecasis/CaTS/). Power was cal- written informed consent was obtained from every sub- culated under prevalence of 0.01 using an allelic model ject. Most of the subjects had participated in our previous with an alpha level of 0.05. Assuming disease allele fre- genetic association studies [27,28]. Some of the control quencies of 0.20 and 0.40, our sample had 80% statistical subjects had also participated in our previous studies power to detect relative risks of 1.28 and 1.23, respec- which examined IL-1b gene polymorphisms [29,30]. tively. Similarly, we had 90% power to detect relative risks of 1.33 and 1.27. Genotyping Since several aspects of immunity have marked sex Five tagging single nucleotide polymorphisms (SNPs) differences [36], analyses were performed not only for (rs2853550, rs1143634, rs1143633, rs1143630, rs16944) the entire sample but also for each gender separately. in a region 1 kilobase (kb) upstream to 1 kb down- Assuming allele frequency of 0.40, male and female stream of the IL-1b gene (chromosome 2: 113,302,808 - samples each had 80% statistical power to detect relative risks of 1.35 and 1.34, respectively. 113,311,827 bp) were selected by Haploview 4.2 [31] Sasayama et al. Behavioral and Brain Functions 2011, 7:35 Page 3 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/35 Table 1 Association analysis of the 5 SNPs in both genders combined Males SNP name Allele 1/2 N Genotype Allele P-value HWE P-value 1/1 1/2 2/2 1 2 Genotype Allele rs2853550 A/G Schizophrenia 531 9 128 394 146 916 0.23 0.088 0.86 (0.02) (0.24) (0.74) (0.14) (0.86) Controls 1115 14 232 869 260 1970 0.88 (0.01) (0.21) (0.78) (0.12) (0.88) (a) rs1143634 A/G Schizophrenia 525 1 41 483 43 1007 0.97 0.90 0.59 (0.00) (0.08) (0.92) (0.04) (0.96) Controls 1121 2 90 1029 94 2148 1.00 (0.00) (0.08) (0.92) (0.04) (0.96) rs1143633 C/T Schizophrenia 524 111 249 164 471 577 0.035 0.0089 0.38 (0.21) (0.48) (0.31) (0.45) (0.55) Controls 1123 188 525 410 901 1345 0.38 (0.17) (0.47) (0.37) (0.40) (0.60) rs1143630 T/G Schizophrenia 520 13 140 367 166 874 0.88 0.66 1.00 (0.03) (0.27) (0.71) (0.16) (0.84) Controls 1119 24 296 799 344 1894 0.65 (0.02) (0.26) (0.71) (0.15) (0.85) rs16944 A/G Schizophrenia 521 123 253 145 499 543 0.18 0.060 0.54 (0.24) (0.49) (0.28) (0.48) (0.52) Controls 1111 226 534 351 986 1236 0.39 (0.20) (0.48) (0.32) (0.44) (0.56) (a) Calculated using Fisher’s exact test. SNP: single nucleotide polymorphism; HWE: Hardy-Weinberg Disequilibrium Numbers in parentheses represent the frequencies of genotypes and alleles. Results Discussion Genotype and allele distributions of the examined SNPs To our knowledge, the present study is the largest study for the entire sample, males, and females are shown in to date that examined the IL-1b gene polymorphisms for Table 1, 2, and 3, respectively. The genotype distributions association with schizophrenia. The results provide the did not significantly deviate from the HWE in any of the first evidence suggesting that the C allele of rs1143633 is SNPs examined. Significant differences in genotype and associated with schizophrenia. allele distributions were found between the patients with The study in a United States population by Shirts et al schizophrenia and controls for rs1143633. The C allele [19] was the only one that previously examined the asso- wassignificantlymore commoninpatientsthanincon- ciation of schizophrenia with rs1143633, in which no sig- trols (odds ratio 1.22, 95% confidence interval (CI) 1.05 nificant difference was found in allele frequencies to 1.41, P = 0.0089). This association remained significant between patients and controls. Although Watanabe et al after correcting for multiple testing of 5 SNPs (corrected [23] have also examined 9 SNPs of the IL-1 gene complex P = 0.013). When the analysis was performed separately in Japanese subjects, none of the SNPs examined in their in each gender, significant difference between patients study was in remarkable linkage disequilibrium with and controls in allele distribution of rs1143633 was rs1143633 or rs16944 (all r <0.1 basedonHapMap observed only in females (odds ratio 1.34, 95% CI 1.08 to Japanese and Han Chinese population data, release 22). 1.66, P = 0.0073). The A allele of rs16944 also showed a The inconsistent results regarding the effect of rs1143633 trend towards association with schizophrenia in female between Shirts, et al [19] and our study may be attributa- subjects (odds ratio 1.26, 95% CI 1.02 to 1.56, P = 0.032). ble to ethnic difference. Indeed, a recent meta-analysis Linkage disequilibrium (LD) coefficients (D’ and r ) has shown a significant association of the G allele of and haplotype blocks are shown in Figure 1. Results of rs16944 and the G allele carrier status of rs1143634 with the haplotype association analyses are shown in Table 4. a risk of schizophrenia in Caucasian, but not in Asian, No significant difference in haplotype distribution was populations [37]. Our samples provided sufficient power found between patients with schizophrenia and controls to detect relatively small relative risks, and therefore sug- (all P > 0.05 by permutation test). gest that rs16944 and rs1143634 have no major effect on Sasayama et al. Behavioral and Brain Functions 2011, 7:35 Page 4 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/35 Table 2 Association analysis of the 5 SNPs in males Males SNP name Allele 1/2 N Genotype Allele P-value HWE P-value 1/1 1/2 2/2 1 2 Genotype Allele (a) rs2853550 A/G Schizophrenia 300 4 74 222 82 518 0.68 0.69 0.62 (0.01) (0.25) (0.74) (0.14) (0.86) Controls 383 7 85 291 99 667 0.82 (0.02) (0.22) (0.76) (0.13) (0.87) (a) rs1143634 A/G Schizophrenia 298 0 24 274 24 572 0.81 0.82 1.00 (0.00) (0.08) (0.92) (0.04) (0.96) Controls 383 1 27 355 29 737 0.42 (0.00) (0.07) (0.93) (0.04) (0.96) rs1143633 C/T Schizophrenia 299 59 145 95 263 335 0.43 0.47 0.81 (0.20) (0.48) (0.32) (0.44) (0.56) Controls 383 77 168 138 322 444 0.059 (0.20) (0.44) (0.36) (0.42) (0.58) rs1143630 T/G Schizophrenia 295 7 81 207 95 495 0.75 0.73 1.00 (0.02) (0.27) (0.70) (0.16) (0.84) Controls 383 6 106 271 118 648 0.32 (0.02) (0.28) (0.71) (0.15) (0.85) rs16944 A/G Schizophrenia 295 66 143 86 275 315 0.92 0.67 0.64 (0.22) (0.48) (0.29) (0.47) (0.53) Controls 385 82 186 117 350 420 0.61 (0.21) (0.48) (0.30) (0.45) (0.55) (a) Calculated using Fisher’s exact test. SNP: single nucleotide polymorphism; HWE: Hardy-Weinberg Disequilibrium Numbers in parentheses represent the frequencies of genotypes and alleles. Table 3 Association analysis of the 5 SNPs in females Males SNP name Allele 1/2 N Genotype Allele P-value HWE P-value 1/1 1/2 2/2 1 2 Genotype Allele rs2853550 A/G Schizophrenia 231 5 54 172 64 398 0.18 0.096 0.78 (0.02) (0.23) (0.74) (0.14) (0.86) Controls 732 7 147 578 161 1303 0.57 (0.01) (0.20) (0.79) (0.11) (0.89) (a) rs1143634 A/G Schizophrenia 227 1 17 209 19 435 0.46 0.84 0.32 (0.00) (0.07) (0.92) (0.04) (0.96) Controls 738 1 63 674 65 1411 1.00 (0.00) (0.09) (0.91) (0.04) (0.96) rs1143633 C/T Schizophrenia 225 52 104 69 208 242 0.013 0.0073 0.29 (0.23) (0.46) (0.31) (0.46) (0.54) Controls 740 111 357 272 579 901 0.76 (0.15) (0.48) (0.37) (0.39) (0.61) rs1143630 T/G Schizophrenia 225 6 59 160 71 379 0.97 0.83 0.80 (0.03) (0.26) (0.71) (0.16) (0.84) Controls 736 18 190 528 226 1246 0.89 (0.02) (0.26) (0.72) (0.15) (0.85) rs16944 A/G Schizophrenia 226 57 110 59 224 228 0.11 0.032 0.69 (0.25) (0.49) (0.26) (0.50) (0.50) Controls 726 144 348 234 636 816 0.50 (0.20) (0.48) (0.32) (0.44) (0.56) (a) Calculated using Fisher’s exact test. SNP: single nucleotide polymorphism; HWE: Hardy-Weinberg Disequilibrium Numbers in parentheses represent the frequencies of genotypes and alleles. Significant P-values (< 0.013) are shown in boldface. Sasayama et al. Behavioral and Brain Functions 2011, 7:35 Page 5 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/35 the opposite direction to that of the Caucasians, with schizophrenia susceptibility in female subjects. Therefore, there remains a possibility that a larger study would yield a significant difference between Japanese female schizo- phrenic patients and controls in the allele frequency of rs16944. A number of genome-wide association studies (GWAS) have searched for polymorphisms associated with schizo- phrenia [38-43]. Although no evidence of association with IL-1b gene has been reported, common risk alleles in the major histocompatibility region on chromosome 6, a. SNPs in the promoter region which is involved in the immune response, have shown b. Intronic SNPs statistically significant evidence of association [38-40]. c. Synonymous SNPs Furthermore, a genome-wide pharmacogenomic study has shown that IL-1a rs11677416, which is in weak LD Figure 1 Haplotype block structure of the IL-1b gene.Genomic with rs1143633 (r = 0.094, D’ = 0.809 based on HapMap organization and linkage disequilibrium (LD) structure of the IL-1b Japanese and Han Chinese population data, release 22), gene are shown. Exons are shown as boxes. Shades of red represent extent of LD (darker red denotes D’ = 1). Numbers in was associated with response of neurocognitive symp- squares give r values multiplied by 100. toms to antipsychotic treatment [44]. These findings, together with ours, suggest genetic influence on immune alterations in schizophrenia. schizophrenia susceptibility in Asian populations, which A shift towards the T helper type 2 (Th2) system has is consistent with the previous Asian findings [21-23]. been indicated in schizophrenia [45-47]. IL-1b stimulates However, there was a trend of association of rs16944, in Table 4 Haplotype analysis of IL-1b gene polymorphisms Males Females Block Haplotype Diagnosis Carrier Non- c2 Nominal P Permutation Carrier Non- c2 Nominal P Permutation carrier value P value carrier value P value GT Schizophrenia 336.3 265.7 0.557 0.456 0.957 251.0 213.0 6.240 0.0125 0.118 (0.559) (0.441) (0.541) (0.459) Controls 447.9 326.1 901.0 585.0 (0.579) (0.421) (0.606) (0.394) 1 GC Schizophrenia 183.1 418.9 0.216 0.642 0.995 149.0 315.0 2.298 0.130 0.691 (0.304) (0.696) (0.321) (0.679) Controls 226.4 547.6 422.5 1063.5 (0.293) (0.707) (0.284) (0.716) AC Schizophrenia 82.6 519.4 0.215 0.643 0.995 63.7 400.3 3.281 0.0701 0.461 (0.137) (0.863) (0.137) (0.863) Controls 99.6 674.4 158.5 1327.5 (0.129) (0.871) (0.107) (0.893) GG Schizophrenia 321.4 280.6 0.154 0.694 0.996 231.2 228.8 5.012 0.0252 0.207 (0.534) (0.466) (0.503) (0.497) Controls 422.6 353.4 837.4 652.6 (0.545) (0.455) (0.562) (0.438) 2 GA Schizophrenia 183.5 418.5 0.040 0.841 1.00 156.4 303.6 5.326 0.0210 0.178 (0.305) (0.695) (0.340) (0.660) Controls 232.7 543.3 422.8 1067.2 (0.300) (0.700) (0.284) (0.716) TA Schizophrenia 97.1 504.9 0.081 0.776 0.999 72.4 387.6 0.027 0.869 1.00 (0.161) (0.839) (0.157) (0.843) Controls 120.7 655.3 229.8 1260.2 (0.156) (0.844) (0.154) (0.846) Numbers in parentheses represent the frequencies of haplotypes. Permutation P values were based on 10,000 permutations. Sasayama et al. Behavioral and Brain Functions 2011, 7:35 Page 6 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/35 the production of prostaglandin E2, which is an impor- Furthermore, in vitro stimulation of lymphocytes with tant cofactor for the induction of T-helper lymphocyte phytohemagglutinin has shown that females produce activity towards Th2 direction. Significant increase in cir- more Th2 cytokines than males [58]. Thus, future studies culating mRNA expression levels of IL-1b has been investigating associations of immune-related genes with observed in schizophrenic patients [9]. The changes in schizophrenia should take into consideration the possible mRNA levels may reflect the genetic variation in IL-1b gender differences. There are some limitations to this study. The ethnicity gene. The findings on biological roles of IL-1b poly- of the participants was based on self-reports and was morphisms, however, have not been consistent across not confirmed by genetic analyses. Our positive results studies. A/A genotype of rs16944 has been associated with higher gastric mucosa IL-1b levels in H. pylori posi- might be derived from sample bias due to population tive population [48]. On the other hand, subjects with stratification, although the Japanese are a relatively G/G genotype showed an increased release of IL-1b from homogeneous population. Furthermore, structured inter- mononuclear cells after stimulation with lipopolysacchar- view such as SCID (Structured Clinical Interview for ide [49]. Recent studies suggest that the functional role of DSM) was not used for diagnosis in this study. Finally, rs16944 may depend on the IL-1b promoter region hap- the function of the IL-1b gene SNPs are unclear. Future lotypes including rs16944 and rs1143627 [50-53]. studies are necessary to elucidate the function and its Although the findings are inconsistent, these previous relationship with the pathogenesis of schizophrenia. studies suggest that rs16944 could affect the expression levels of IL-1b. On the other hand, the influence of Conclusions rs1143633 on IL-1b expression levels has not been pre- Our results suggest that rs1143633 of IL-1b gene is viously reported. associated with schizophrenia susceptibility in a Japanese Intriguingly, rs1143633 and rs16944 have also been population and that the influence of IL-1b gene varia- associated with cortisol response to dexamethasone in tions on susceptibility to schizophrenia may be greater healthy subjects [30]. Alleles associated with increased in females than in males. We obtained no significant cortisol response to dexamethasone were shown to be evidence for a well-studied polymorphism rs16944 being associated with schizophrenia in the present study. associated with schizophrenia, which is consistent with Higher rates of non-suppression to dexamethasone com- previous studies in Asian populations. However, a trend pared to healthy subjects have been reported in schizo- of higher A allele frequency of rs16944 in female phrenia [54] and schizotypy [55]. On the other hand, patients with schizophrenia leaves open a possibility that Ismail et al [56] reported that less than 2% of their schi- a larger study may yield a significant difference. The zophrenic patients were non-suppressors. Although the results of the present study provide further support for findings are inconsistent, these studies indicate that the role of IL-1b in the etiology of schizophrenia. Future schizophrenia may be associated with alteration in studies are warranted to replicate the present findings hypothalamic- pituitary- adrenal (HPA) axis. Taken and to reveal the functional role of IL-1b gene in patho- together, our findings suggest that IL-1b gene poly- physiology of schizophrenia. morphisms may play a role in the HPA axis alteration in schizophrenic patients. Acknowledgements Our results showed significant association of rs1143633 This study was supported by Health and Labor Sciences Research Grants with schizophrenia in only females. Although our male (Comprehensive Research on Disability, Health, and Welfare), Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science sample was not large enough to detect a small relative (JSPS), Core Research of Evolutional Science & Technology (CREST), Japan risk, our data suggest that susceptibility to schizophrenia Science and Technology Agency (JST), the Strategic Research Program for is more influenced by the IL-1b gene variation in females. Brain Sciences by the Ministry of Education, Culture, Sports, Science and Technology of Japan (Understanding of molecular and environmental bases To our knowledge, no previous studies have examined for brain health), and Intramural Research Grant for Neurological and the gender differences in the association between IL-1b Psychiatric Disorders of NCNP (H.K.). gene polymorphisms and schizophrenia. However, gen- Author details der differences have been reported in the association Department of Mental Disorder Research, National Institute of Neuroscience, between schizophrenia and RELA gene [27] encoding the National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8502, major component of NF-B, which is activated by IL-1b. Japan. Department of Psychiatry, Shinshu University School of Medicine, Matsumoto, 390-8621, Japan. Core Research of Evolutional Science & Taken together with our results, the influence of IL-1b Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, on susceptibility to schizophrenia may differ between 102-0075, Japan. Department of Medical Genetics, Majors of Medical genders. Indeed, gender differences in immunity have Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, 305-8577, Japan. Yokohama Shinryo Clinic, Yokohama, been reported in previous studies [36]. IL-1 release from 221-0835, Japan. National Center of Neurology and Psychiatry, Kodaira, mononucleated cells has been shown to be menstrual Tokyo, 187-8502, Japan. phase dependent in females and lower in males [57]. Sasayama et al. Behavioral and Brain Functions 2011, 7:35 Page 7 of 8 http://www.behavioralandbrainfunctions.com/content/7/1/35 18. Zanardini R, Bocchio-Chiavetto L, Scassellati C, Bonvicini C, Tura GB, Rossi G, Authors’ contributions Perez J, Gennarelli M: Association between IL-1beta -511C/T and IL-1RA DS and HK designed the study and DS wrote the draft of the manuscript. (86bp)n repeats polymorphisms and schizophrenia. J Psychiatr Res 2003, DS, HH, TT, KH, MO, MT, and HK made the diagnosis according to DSM-IV 37:457-462. criteria. DS, HH, TT, KH, MO, and HK screened the healthy participants using 19. Shirts BH, Wood J, Yolken RH, Nimgaonkar VL: Association study of IL10, the Mini International Neuropsychiatric Interview (M.I.N.I.). DS and YI IL1beta, and IL1RN and schizophrenia using tag SNPs from a performed the genotyping. HK supervised the data analysis and writing of comprehensive database: suggestive association with rs16944 at the paper. TH and NA also supervised the writing of the paper and gave IL1beta. Schizophr Res 2006, 88:235-244. critical comments on the manuscript. All authors contributed to and have 20. Betcheva ET, Mushiroda T, Takahashi A, Kubo M, Karachanak SK, approved the final manuscript. Zaharieva IT, Vazharova RV, Dimova II, Milanova VK, Tolev T, et al: Case- control association study of 59 candidate genes reveals the DRD2 SNP Competing interests The authors declare that they have no competing interests. rs6277 (C957T) as the only susceptibility factor for schizophrenia in the Bulgarian population. J Hum Genet 2009, 54:98-107. Received: 27 April 2011 Accepted: 16 August 2011 21. 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