| 1 | Int J Psychiatry Clin Pract 2001 -1 5: 71-3 |
|---|---|
| PMID | 24937002 |
| Title | Clozapine-induced concordant agranulocytosis in monozygotic twins. |
| Abstract | Two monozygotic twin sisters were admitted to a psychiatric hospital and diagnosed as having first-episode schizophrenia. Clozapine treatment led to the complete remission of psychotic symptoms within a short time. In both twins the low leukocyte count was detected after 9 weeks of clozapine. Serological typing of the HLA system was performed and an identical pattern was detected in both twins: HLA-A: 28, 26; HLA-B: 49, 63; DR: 2 (vs 16), 12, 52; DQ:1. It is the first report of concordant manifestation of clozapine-induced agranulocytosis in monozygotic twins. Our case report of twins afflicted synchronously with schizophrenia and later with agranulocytosis after clozapine is of interest because it suggests that genetic factors may participate not only in timing of onset of schizophrenia, but also in the emergence and timing of agranulocytosis in response to clozapine treatment. ( Int J Psych Clin Pract 2001; 5:71-73). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Am. J. Med. Genet. 2002 Jan 114: 42-5 |
| PMID | 11840504 |
| Title | HLA class I distribution in Japanese patients with schizophrenia. |
| Abstract | Several Caucasian studies and one Japanese study have observed associations between human leukocyte antigen (HLA) class I specificities, including A24 (9) and A26 (10) and schizophrenia. Most of those studies were conducted in 1970s and early 1980s, when the typing technique of HLA was not adequately reliable. Also, an operational diagnostic system was not employed in many of the studies. The present study investigated frequencies of HLA-A specificities in schizophrenia patients (ICD-10 and DSM-III-R, n=98) and sex-matched healthy controls (n=392) from population in the southwestern part of Japan. HLA-B and -C specificities were studied in addition. Frequencies of subjects possessing A24 and A26 were not different between the patients and controls (54% and 24% in the patients and 62% and 24% in the controls, respectively). No significant difference was found in frequencies of other class I (A, B, and C) specificities between the patients and the controls. Thus, the present study provided no evidence for an association between the HLA class I specificities, including A24, A26, and others, and schizophrenia in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Nature 2003 Oct 425: 805-11 |
| PMID | 14574404 |
| Title | The DNA sequence and analysis of human chromosome 6. |
| Abstract | Chromosome 6 is a metacentric chromosome that constitutes about 6% of the human genome. The finished sequence comprises 166,880,988 base pairs, representing the largest chromosome sequenced so far. The entire sequence has been subjected to high-quality manual annotation, resulting in the evidence-supported identification of 1,557 genes and 633 pseudogenes. Here we report that at least 96% of the protein-coding genes have been identified, as assessed by multi-species comparative sequence analysis, and provide evidence for the presence of further, otherwise unsupported exons/genes. Among these are genes directly implicated in cancer, schizophrenia, autoimmunity and many other diseases. Chromosome 6 harbours the largest transfer RNA gene cluster in the genome; we show that this cluster co-localizes with a region of high transcriptional activity. Within the essential immune loci of the major histocompatibility complex, we find HLA-B to be the most polymorphic gene on chromosome 6 and in the human genome. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Schizophr. Res. 2005 Jul 76: 195-8 |
| PMID | 15949652 |
| Title | The association of the HLA in patients with schizophrenia, schizoaffective disorder, and in their biological relatives. |
| Abstract | To determine the association of the HLA in 50 patients with schizophrenia, schizoaffective disorder, 48 healthy controls, 41 biological relatives without psychiatric disease, and 48 biological relatives with mood disorder, the HLA genotype at the class I and class II were determined. The subjects were interviewed by structured diagnostic criteria categorized according to DSM-IV, axis I, (SCID-IV). Significant positive association was found with HLA-B.15 in patients, family with humor disorder and without mental disorder (p=0.003) and negative association of the HLA-B.35 in relatives without psychiatric disease (p=0.03). The HLA-B.15 frequency was significantly increased in a subgroup of patients with age at onset in the early 20s, lower educational achievement, occupational disability, chronically ill, more paranoid type. These findings suggest the existence of some involvement of an immunogenetic mechanism in a subgroup of schizophrenic, schizoaffective patients, and biological relatives. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Schizophr. Res. 2005 Jul 76: 195-8 |
| PMID | 15949652 |
| Title | The association of the HLA in patients with schizophrenia, schizoaffective disorder, and in their biological relatives. |
| Abstract | To determine the association of the HLA in 50 patients with schizophrenia, schizoaffective disorder, 48 healthy controls, 41 biological relatives without psychiatric disease, and 48 biological relatives with mood disorder, the HLA genotype at the class I and class II were determined. The subjects were interviewed by structured diagnostic criteria categorized according to DSM-IV, axis I, (SCID-IV). Significant positive association was found with HLA-B.15 in patients, family with humor disorder and without mental disorder (p=0.003) and negative association of the HLA-B.35 in relatives without psychiatric disease (p=0.03). The HLA-B.15 frequency was significantly increased in a subgroup of patients with age at onset in the early 20s, lower educational achievement, occupational disability, chronically ill, more paranoid type. These findings suggest the existence of some involvement of an immunogenetic mechanism in a subgroup of schizophrenic, schizoaffective patients, and biological relatives. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Am. J. Hum. Genet. 2006 Oct 79: 710-5 |
| PMID | 16960807 |
| Title | HLA-B maternal-fetal genotype matching increases risk of schizophrenia. |
| Abstract | schizophrenia and human leukocyte antigen (HLA) matching between couples or between mothers and offspring have independently been associated with prenatal/obstetric complications, including preeclampsia and low birth weight. Here, we report the results of a family-based candidate-gene study that brings together these two disparate lines of research by assessing maternal-fetal genotype matching at HLA-A, -B, and -DRB1 as a risk factor of schizophrenia. We used a conditional-likelihood modeling approach with a sample of 274 families that had at least one offspring with schizophrenia or a related spectrum disorder. A statistically significant HLA-B maternal-fetal genotype-matching effect on schizophrenia was demonstrated for female offspring (P=.01; parameter estimate 1.7 [95% confidence interval 1.22-2.49]). Because the matching effect could be associated with pregnancy complications rather than with schizophrenia per se, these findings are consistent with the neurodevelopmental hypothesis of schizophrenia and with accumulating evidence that the prenatal period is involved in the origins of this disease. Our approach demonstrates how genetic markers can be used to characterize the biology of prenatal risk factors of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Indian J Psychiatry 2008 Jul 50: 166-70 |
| PMID | 19742184 |
| Title | Analysis of the role of human leukocyte antigen class-I genes to understand the etiopathology of schizophrenia. |
| Abstract | schizophrenia is the paradigmatic illness of psychiatry. The involvement of immunological and immunopathological mechanisms in the etiopathogenesis of schizophrenia has been a matter of research, with recently increasing effort. In this study, we investigated the incidence of human leukocyte antigen (HLA) Class I antigens to understand the role of HLA genes in schizophrenia. India born schizophrenic patients in and around Siliguri who attended outpatient department (OPD) of Department of Psychiatry, North Bengal Medical College and Hospital were considered for the present study. After the longitudinal follow up, 50 patients were enrolled for the study. The same number of age, sex and ethnically matched healthy subjects were considered as control. Low resolution polymerase chain reaction-sequence specific primer method was applied for typing the HLA antigens. The phenotype frequencies were calculated by direct count. chi(2) test was done to compare the frequency of each antigen among the patients and control group and it was followed by Fisher's exact test. Relative risk was estimated by using Haldane's method. The result showed that some of the HLA antigens are associated with the schizophrenia and significant increase were observed for HLA A*03 antigen along with the significant decrease for HLA A*25, A*31 and HLA B*51. The study provides the evidence for the possible existence of susceptibility locus for schizophrenia within the HLA region. This preliminary observation may help to understand the etiological basis of this disorder and the study may further strengthen the HLA antigens as the marker for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Indian J Psychiatry 2008 Jul 50: 166-70 |
| PMID | 19742184 |
| Title | Analysis of the role of human leukocyte antigen class-I genes to understand the etiopathology of schizophrenia. |
| Abstract | schizophrenia is the paradigmatic illness of psychiatry. The involvement of immunological and immunopathological mechanisms in the etiopathogenesis of schizophrenia has been a matter of research, with recently increasing effort. In this study, we investigated the incidence of human leukocyte antigen (HLA) Class I antigens to understand the role of HLA genes in schizophrenia. India born schizophrenic patients in and around Siliguri who attended outpatient department (OPD) of Department of Psychiatry, North Bengal Medical College and Hospital were considered for the present study. After the longitudinal follow up, 50 patients were enrolled for the study. The same number of age, sex and ethnically matched healthy subjects were considered as control. Low resolution polymerase chain reaction-sequence specific primer method was applied for typing the HLA antigens. The phenotype frequencies were calculated by direct count. chi(2) test was done to compare the frequency of each antigen among the patients and control group and it was followed by Fisher's exact test. Relative risk was estimated by using Haldane's method. The result showed that some of the HLA antigens are associated with the schizophrenia and significant increase were observed for HLA A*03 antigen along with the significant decrease for HLA A*25, A*31 and HLA B*51. The study provides the evidence for the possible existence of susceptibility locus for schizophrenia within the HLA region. This preliminary observation may help to understand the etiological basis of this disorder and the study may further strengthen the HLA antigens as the marker for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Schizophr Bull 2009 Nov 35: 1163-82 |
| PMID | 18552348 |
| Title | Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii. |
| Abstract | Many genes implicated in schizophrenia can be related to glutamatergic transmission and neuroplasticity, oligodendrocyte function, and other families clearly related to neurobiology and schizophrenia phenotypes. Others appear rather to be involved in the life cycles of the pathogens implicated in the disease. For example, aspartylglucosaminidase (AGA), PLA2, SIAT8B, GALNT7, or B3GAT1 metabolize chemical ligands to which the influenza virus, herpes simplex, cytomegalovirus (CMV), rubella, or Toxoplasma gondii bind. The epidermal growth factor receptor (EGR/EGFR) is used by the CMV to gain entry to cells, and a CMV gene codes for an interleukin (IL-10) mimic that binds the host cognate receptor, IL10R. The fibroblast growth factor receptor (FGFR1) is used by herpes simplex. KPNA3 and RANBP5 control the nuclear import of the influenza virus. Disrupted in schizophrenia 1 (DISC1) controls the microtubule network that is used by viruses as a route to the nucleus, while DTNBP1, MUTED, and BLOC1S3 regulate endosomal to lysosomal routing that is also important in viral traffic. Neuregulin 1 activates ERBB receptors releasing a factor, EBP1, known to inhibit the influenza virus transcriptase. Other viral or bacterial components bind to genes or proteins encoded by CALR, FEZ1, FYN, HSPA1B, IL2, HTR2A, KPNA3, MED12, MED15, MICB, NQO2, PAX6, PIK3C3, RANBP5, or TP53, while the cerebral infectivity of the herpes simplex virus is modified by Apolipoprotein E (APOE). Genes encoding for proteins related to the innate immune response, including cytokine related (CCR5, CSF2RA, CSF2RB, IL1B, IL1RN, IL2, IL3, IL3RA, IL4, IL10, IL10RA, IL18RAP, lymphotoxin-alpha, tumor necrosis factor alpha [TNF]), human leukocyte antigen (HLA) antigens (HLA-A10, HLA-B, HLA-DRB1), and genes involved in antigen processing (angiotensin-converting enzyme and tripeptidyl peptidase 2) are all concerned with defense against invading pathogens. Human microRNAs (Hsa-mir-198 and Hsa-mir-206) are predicted to bind to influenza, rubella, or poliovirus genes. Certain genes associated with schizophrenia, including those also concerned with neurophysiology, are intimately related to the life cycles of the pathogens implicated in the disease. Several genes may affect pathogen virulence, while the pathogens in turn may affect genes and processes relevant to the neurophysiology of schizophrenia. For such genes, the strength of association in genetic studies is likely to be conditioned by the presence of the pathogen, which varies in different populations at different times, a factor that may explain the heterogeneity that plagues such studies. This scenario also suggests that drugs or vaccines designed to eliminate the pathogens that so clearly interact with schizophrenia susceptibility genes could have a dramatic effect on the incidence of the disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | J. Biomed. Biotechnol. 2010 -1 2010: 576318 |
| PMID | 20379378 |
| Title | Evidence for maternal-fetal genotype incompatibility as a risk factor for schizophrenia. |
| Abstract | Prenatal/obstetric complications are implicated in schizophrenia susceptibility. Some complications may arise from maternal-fetal genotype incompatibility, a term used to describe maternal-fetal genotype combinations that produce an adverse prenatal environment. A review of maternal-fetal genotype incompatibility studies suggests that schizophrenia susceptibility is increased by maternal-fetal genotype combinations at the RHD and HLA-B loci. Maternal-fetal genotype combinations at these loci are hypothesized to have an effect on the maternal immune system during pregnancy which can affect fetal neurodevelopment and increase schizophrenia susceptibility. This article reviews maternal-fetal genotype incompatibility studies and schizophrenia and discusses the hypothesized biological role of these ''incompatibility genes". It concludes that research is needed to further elucidate the role of RHD and HLA-B maternal-fetal genotype incompatibility in schizophrenia and to identify other genes that produce an adverse prenatal environment through a maternal-fetal genotype incompatibility mechanism. Efforts to develop more sophisticated study designs and data analysis techniques for modeling maternal-fetal genotype incompatibility effects are warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | Asian J Psychiatr 2011 Dec 4: 277-83 |
| PMID | 23051162 |
| Title | Immunomodulation in schizophrenia: A study among the Indian schizophrenia patients of Siliguri, West Bengal. |
| Abstract | Authors investigated the circumstantial evidence for autoimmunity in schizophrenia patients of Siliguri by considering the immune parameters like HLA Class I genes, IL-2 and IL6 and T cell subsets. Low resolution PCR-SSP method was applied for typing the HLA genes. Serum levels of IL-2 and IL-6 were measured by ELISA method. The CD4+ and CD8+ subset count were done using flow cytometry. A significant increase in HLA A*03 gene was observed in patients along with the significant decrease of HLA-A*31 and HLA-B*51. Both IL-2 and IL-6 were found to have decreased levels in the patients. Although the mean percentage of CD4+ and CD8+ cells was higher in patients but not significantly higher than controls. These cumulative preliminary findings are suggestive of alterations in the immune system of schizophrenia patients of this region. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Psychiatry Res 2011 Sep 189: 215-9 |
| PMID | 21459456 |
| Title | Study of HLA Class I gene in Indian schizophrenic patients of Siliguri, West Bengal. |
| Abstract | The authors studied the prevalence of the human leukocyte antigen (HLA) Class I gene in 136 (85 male, 51 female) India-born schizophrenia patients residing in and around the Siliguri subdivision of West Bengal by the PCR-SSP method. The control group consisted of 150 age- and sex-matched healthy individuals from the same ethnic group as the patients. Increased frequency of HLA A*03 as well as decreased frequencies of HLA A*31 and HLA B*51, was noted. The study suggests the possible existence of a susceptibility locus for schizophrenia within the HLA region. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | Psychiatry Res 2011 Sep 189: 215-9 |
| PMID | 21459456 |
| Title | Study of HLA Class I gene in Indian schizophrenic patients of Siliguri, West Bengal. |
| Abstract | The authors studied the prevalence of the human leukocyte antigen (HLA) Class I gene in 136 (85 male, 51 female) India-born schizophrenia patients residing in and around the Siliguri subdivision of West Bengal by the PCR-SSP method. The control group consisted of 150 age- and sex-matched healthy individuals from the same ethnic group as the patients. Increased frequency of HLA A*03 as well as decreased frequencies of HLA A*31 and HLA B*51, was noted. The study suggests the possible existence of a susceptibility locus for schizophrenia within the HLA region. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | Hum. Hered. 2011 -1 72: 161-72 |
| PMID | 22004985 |
| Title | Detection of intergenerational genetic effects with application to HLA-B matching as a risk factor for schizophrenia. |
| Abstract | Association studies using unrelated individuals cannot detect intergenerational genetic effects contributing to disease. To detect these effects, we improve the extended maternal-fetal genotype (EMFG) incompatibility test to estimate any combination of maternal effects, offspring effects, and their interactions at polymorphic loci or multiple SNPs, using any size pedigrees. We explore the advantages of using extended pedigrees rather than nuclear families. We apply our methods to schizophrenia pedigrees to investigate whether the previously associated mother-daughter HLA-B matching is a genuine risk or the result of bias. Simulations demonstrate that using the EMFG test with extended pedigrees increases power and precision, while partitioning extended pedigrees into nuclear families can underestimate intergenerational effects. Application to actual data demonstrates that mother-daughter HLA-B matching remains a schizophrenia risk factor. Furthermore, ascertainment and mate selection biases cannot by themselves explain the observed HLA-B matching and schizophrenia association. Our results demonstrate the power of the EMFG test to examine intergenerational genetic effects, highlight the importance of pedigree rather than case/control or case-mother/control-mother designs, illustrate that pedigrees provide a means to examine alternative, non-causal mechanisms, and they strongly support the hypothesis that HLA-B matching is causally involved in the etiology of schizophrenia in females. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | Brain Behav. Immun. 2013 Aug 32: 51-62 |
| PMID | 23395714 |
| Title | Expression of immune genes on chromosome 6p21.3-22.1 in schizophrenia. |
| Abstract | schizophrenia is a common mental illness with a large genetic component. Three genome-wide association studies have implicated the major histocompatibility complex gene region on chromosome 6p21.3-22.1 in schizophrenia. In addition, nicotine, which is commonly abused in schizophrenia, affects the expression of central nervous system immune genes. Messenger RNA levels for genes in the 6p21.3-22.1 region were measured in human postmortem hippocampus of 89 subjects. The effects of schizophrenia diagnosis, smoking and systemic inflammatory illness were compared. Cell-specific expression patterns for the class I major histocompatibility complex gene HLA-A were explored utilizing in situ hybridization. Expression of five genes was altered in schizophrenic subjects. Messenger RNA levels for the class I major histocompatibility complex antigen HLA-B were increased in schizophrenic nonsmokers, while levels for smokers were indistinguishable from those of controls. ?2 microglobulin, HLA-A and Notch4 were all expressed in a pattern where inflammatory illness was associated with increased expression in controls but not in subjects with schizophrenia. schizophrenia was also associated with increased expression of Butyrophilin 2A2. HLA-A was expressed in glutamatergic and GABAergic neurons in the dentate gyrus, hilus, and the stratum pyramidale of the CA1-CA4 regions of the hippocampus, but not in astrocytes. In conclusion, the expression of genes from the major histocompatibility complex region of chromosome 6 with likely roles in synaptic development is altered in schizophrenia. There were also significant interactions between schizophrenia diagnosis and both inflammatory illness and smoking. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Brain Behav. Immun. 2013 Aug 32: 51-62 |
| PMID | 23395714 |
| Title | Expression of immune genes on chromosome 6p21.3-22.1 in schizophrenia. |
| Abstract | schizophrenia is a common mental illness with a large genetic component. Three genome-wide association studies have implicated the major histocompatibility complex gene region on chromosome 6p21.3-22.1 in schizophrenia. In addition, nicotine, which is commonly abused in schizophrenia, affects the expression of central nervous system immune genes. Messenger RNA levels for genes in the 6p21.3-22.1 region were measured in human postmortem hippocampus of 89 subjects. The effects of schizophrenia diagnosis, smoking and systemic inflammatory illness were compared. Cell-specific expression patterns for the class I major histocompatibility complex gene HLA-A were explored utilizing in situ hybridization. Expression of five genes was altered in schizophrenic subjects. Messenger RNA levels for the class I major histocompatibility complex antigen HLA-B were increased in schizophrenic nonsmokers, while levels for smokers were indistinguishable from those of controls. ?2 microglobulin, HLA-A and Notch4 were all expressed in a pattern where inflammatory illness was associated with increased expression in controls but not in subjects with schizophrenia. schizophrenia was also associated with increased expression of Butyrophilin 2A2. HLA-A was expressed in glutamatergic and GABAergic neurons in the dentate gyrus, hilus, and the stratum pyramidale of the CA1-CA4 regions of the hippocampus, but not in astrocytes. In conclusion, the expression of genes from the major histocompatibility complex region of chromosome 6 with likely roles in synaptic development is altered in schizophrenia. There were also significant interactions between schizophrenia diagnosis and both inflammatory illness and smoking. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | Schizophr. Res. 2013 Jan 143: 11-7 |
| PMID | 23177929 |
| Title | Non-random mating, parent-of-origin, and maternal-fetal incompatibility effects in schizophrenia. |
| Abstract | Although the association of common genetic variation in the extended MHC region with schizophrenia is the most significant yet discovered, the MHC region is one of the more complex regions of the human genome, with unusually high gene density and long-range linkage disequilibrium. The statistical test on which the MHC association is based is a relatively simple, additive model which uses logistic regression of SNP genotypes to predict case-control status. However, it is plausible that more complex models underlie this association. Using a well-characterized sample of trios, we evaluated more complex models by looking for evidence for: (a) non-random mating for HLA alleles, schizophrenia risk profiles, and ancestry; (b) parent-of-origin effects for HLA alleles; and (c) maternal-fetal genotype incompatibility in the HLA. We found no evidence for non-random mating in the parents of individuals with schizophrenia in terms of MHC genotypes or schizophrenia risk profile scores. However, there was evidence of non-random mating that appeared mostly to be driven by ancestry. We did not detect over-transmission of HLA alleles to affected offspring via the general TDT test (without regard to parent of origin) or preferential transmission via paternal or maternal inheritance. We evaluated the hypothesis that maternal-fetal HLA incompatibility may increase risk for schizophrenia using eight classical HLA loci. The most significant alleles were in HLA-B, HLA-C, HLA-DQB1, and HLA-DRB1 but none was significant after accounting for multiple comparisons. We did not find evidence to support more complex models of gene action, but statistical power may have been limiting. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | Biol. Psychiatry 2016 Feb -1: -1 |
| PMID | 26876947 |
| Title | Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a Japanese Population. |
| Abstract | Clozapine-induced agranulocytosis (CIA)/clozapine-induced granulocytopenia (CIG) (CIAG) is a life-threatening event for schizophrenic subjects treated with clozapine. To examine the genetic factor for CIAG, a genome-wide pharmacogenomic analysis was conducted using 50 subjects with CIAG and 2905 control subjects. We identified a significant association in the human leukocyte antigen (HLA) region (rs1800625, p = 3.46 × 10(-9), odds ratio [OR] = 3.8); therefore, subsequent HLA typing was performed. We detected a significant association of HLA-B*59:01 with CIAG (p = 3.81 × 10(-8), OR = 10.7) and confirmed this association by comparing with an independent clozapine-tolerant control group (n = 380, p = 2.97 × 10(-5), OR = 6.3). As we observed that the OR of CIA (OR: 9.3~15.8) was approximately double that in CIG (OR: 4.4~7.4), we hypothesized that the CIG subjects were a mixed population of those who potentially would develop CIA and those who would not develop CIA (non-CIA). This hypothesis allowed the proportion of the CIG who were non-CIA to be calculated, enabling us to estimate the positive predictive value of the nonrisk allele on non-CIA in CIG subjects. Assuming this model, we estimated that 1) ~50% of CIG subjects would be non-CIA; and 2) ~60% of the CIG subjects without the risk allele would be non-CIA and therefore not expected to develop CIA. Our results suggest that HLA-B*59:01 is a risk factor for CIAG in the Japanese population. Furthermore, if our model is true, the results suggest that rechallenging certain CIG subjects with clozapine may not be always contraindicated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | Biol. Psychiatry 2016 Feb -1: -1 |
| PMID | 26876947 |
| Title | Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a Japanese Population. |
| Abstract | Clozapine-induced agranulocytosis (CIA)/clozapine-induced granulocytopenia (CIG) (CIAG) is a life-threatening event for schizophrenic subjects treated with clozapine. To examine the genetic factor for CIAG, a genome-wide pharmacogenomic analysis was conducted using 50 subjects with CIAG and 2905 control subjects. We identified a significant association in the human leukocyte antigen (HLA) region (rs1800625, p = 3.46 × 10(-9), odds ratio [OR] = 3.8); therefore, subsequent HLA typing was performed. We detected a significant association of HLA-B*59:01 with CIAG (p = 3.81 × 10(-8), OR = 10.7) and confirmed this association by comparing with an independent clozapine-tolerant control group (n = 380, p = 2.97 × 10(-5), OR = 6.3). As we observed that the OR of CIA (OR: 9.3~15.8) was approximately double that in CIG (OR: 4.4~7.4), we hypothesized that the CIG subjects were a mixed population of those who potentially would develop CIA and those who would not develop CIA (non-CIA). This hypothesis allowed the proportion of the CIG who were non-CIA to be calculated, enabling us to estimate the positive predictive value of the nonrisk allele on non-CIA in CIG subjects. Assuming this model, we estimated that 1) ~50% of CIG subjects would be non-CIA; and 2) ~60% of the CIG subjects without the risk allele would be non-CIA and therefore not expected to develop CIA. Our results suggest that HLA-B*59:01 is a risk factor for CIAG in the Japanese population. Furthermore, if our model is true, the results suggest that rechallenging certain CIG subjects with clozapine may not be always contraindicated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |