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The association of the HLA in patients with schizophrenia, schizoaffective disorder, and in their biological relatives
Schizophrenia Research 76 (2005) 195 – 198 www.elsevier.com/locate/schres
The association of the HLA in patients with schizophrenia, schizoaffective disorder, and in their biological relatives S.O.V. Nunesa,T, S.D. Borellib, T. Matsuoc, M.A.E. Watanabed, E.N. Itanod a
Department of Psychiatry-Londrina State University (UEL), Av Adhemar de Barros, 625, 86050190 Londrina, Brazil b Department of Clinical Analysis-Maringa´ State University (UEM), Brazil c Department of Statistics and Applied Mathematics (UEL), Brazil d Department of General Pathology (UEL), Brazil Received 1 February 2005; accepted 10 February 2005 Available online 19 March 2005
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. D 2005 Elsevier B.V. All rights reserved. Keywords: Schizophrenia; Schizoaffective disorder; HLA; Biological relatives; Immunogenetic
1. Introduction Various diseases with a noticeable autoimmune component and frequent occurrence in family show a statistically significant correlation with specific T Corresponding author. Tel.: +55 43 33390404; fax: +55 43 33238210. E-mail address: [email protected] (S.O.V. Nunes). 0920-9964/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2005.02.005
human leukocyte antigens (HLA). This correlation was also found in studies of HLA in psychiatric disorders (Gattaz and Beckmann, 1982). The possible existence of a susceptibility locus for schizophrenia on the short arm of chromosome 6 in an area close to the HLA region at the 6p21.3 band has been the subject of several investigations (Levinson et al., 1996; Lindholm et al., 1999; Schwab et al., 2002). Wright et al. (2001) published a review of the HLA association with schizophrenia. They listed positive
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S.O.V. Nunes et al. / Schizophrenia Research 76 (2005) 195–198
association with A9 or the A24 sub specificity, A28, A10, DRB1*01, and DRw6. Negative association with DQB1*0602 and DRB1*04 with schizophrenia have also been reported. In a study of transmission disequilibrium analysis of HLA class II DRB1, DQA1, DQB1 and DPB1 polymorphisms in schizophrenia using family trios, a nontransmission of the DRB1*03 allele and a preferential transmission for the DRB1*13 allele were detected (Li et al., 2001). The expression of HLA-B35 was significantly reduced in the schizophrenic populations compared to control population. The reduction of incidence of HLA-B35 in schizophrenic population could thus be related to susceptibility to some specific infections or an autoimmune component (Blackwood et al., 1996). The present study evaluated the association of HLA class II (DRB1) and class I (A, B) in schizophrenic and schizoaffective patients, biological relatives and healthy controls.
2. Methods The subjects were 50 schizophrenic and schizoaffective adults outpatients of the Psychiatric Ambulatory at Londrina State University (UEL), Parana´, Brazil. The patients were in remission, in chronic treatment with typical antipsychotic (Haloperidol) and atypical antipsychotic agents (olanzapine, clozapine, risperidone, ziprasidone), 48 first-degree relatives with mood disorders, and 41 first-degree relatives without mental disorders and 50 healthy volunteers as control. After approbation of this research by the Ethics Research Committee of UEL, patients, controls and first-degree relatives had given written informed consent, and samples of peripheral blood was drawn. Subjects younger than 18 years old and older than 55 years were excluded from all groups. All subjects were of the White race. They were required to be in good health conditions, defined as the absence of chronic diseases, which affect the immune system. The schizophrenic and schizoaffective outpatients were interviewed by structured diagnostic criteria categorized according to the fourth edition of the American Psychiatric Association’s Diagnostic and
Statistical Manual of Mental Disorders or DSM-IV, Axis I, (SCID-IV) criteria (American Psychiatric Association, 1994), translated to the Portuguese language by Del Bem et al. (2001). The schizophrenic patients diagnosed were classified as undifferentiated type (n = 1), paranoid type (n = 20) disorganized type (n = 10), residual type (n = 7), and schizoaffective disorder (n = 12). The 50 volunteers were recruited from the community, free of any serious medical illnesses, and had never taken psychotropic drugs or presented current or past psychiatric disorder as determined by their reported history during the clinical interview and by structured diagnostic criteria categorized according to DSM-IV, Axis I. Two controls were excluded from the study after blood test detected hepatitis virus C infection, a chronic illness known to affect the immune system. First-degree relative volunteers were recruited with ages ranging from 18 to 55 years. All members were 90 first-degree relatives, and were interview by the structured interview (DSM-IV, Axis I, SCID-IV). One first-degree relative was excluded from the study after blood test detected HIV infection. The 89 relatives included were 2 fathers, 2 mothers, 50 sisters, 30 brothers, 1 son, and 4 daughters. The 48 first-degree relatives had been diagnosed as Major Depressive Disorder (n = 45) and Bipolar I Disorder (n = 3). The HLA typing was performed using polymerasechain-reaction based on genotyping method. The DNA was extracted using the Puregene DNA Isolation Kit (Gentra Systems, Minneapolis, MN, USA). Final concentration of DNA was 100 ng/Al with the A269 / A280 ratio between 1.65 and 1.80. Individuals were genotyped for class I and class II alleles by Micro SSPk 384 System DNA Typing Trays (One Lambda, Canoga Park, CA, USA). The Statistical Analyses Groups were compared in demographic and clinical variables by using Chisquare test (v 2) or Exact Fisher’s test and Kruskal– Wallis test (H). The HLA associations with groups were analyzed using Chi-square test (v 2) or Fisher’s exact test. Odds ratio (OR) and 95% confidence intervals (CI 95%) were calculated for comparison between reference groups. Differences between the groups were considered to be statistically significant when p b 0.05.
S.O.V. Nunes et al. / Schizophrenia Research 76 (2005) 195–198
197
3. Results
4. Discussion
There were no group differences in age (H = 0.27, df = 3, p = 0.90), or gender (v 2 = 7.52, df = 3, p = 0.57). The group differed in educational background and marital status. Patients presented lower educational achievement (v 2 = 13.26, df = 3, p = 0.004) than controls and relatives, and most of them were unmarried (v 2 = 16.28, df = 3, p b 0.001), differently from controls and relatives. In patients, there were more significant differences regarding occupational impairment than controls and relatives (v 2 = 133.2, df = 3, p b 0.001). The illness mean duration was 15.34 years (SD F 9.90) and the median age of onset was 22.4 years (SD F 7.37). A higher percentage of patients had suicide attempt than controls, relatives without psychiatric disease with humor disorder (Fisher’s exact test = 27, df = 3, p b 0.001). The frequency of HLA-B*15 was significantly higher in patients and family with and without mental disorders than controls (Table 1). No significant differences were found for HLA-A and HLA-DRB1 (Table 1). The frequency of the HLA-B*35 was significantly reduced in family without mental disorders than in controls (Table 1).
We found significant positive association of the class I HLA-B*15 in patients, family with humor disorder and family without mental disorder ( p = 0.003) and negative association of the HLA-B*35 in relatives without psychiatric disease ( p = 0.03). The frequency of HLA B*15 was significantly increased in the patient group with lower educational achievement ( p = 0.004) than controls and relatives, and most of them were unmarried ( p b 0.001), differently from controls and relatives. In patients there were more significant differences regarding occupational impairment, and more suicide attempters than controls and relatives ( p b 0.001). The illness mean duration was 15.3 years (SD F 9.9) and the median age of onset was 22.4 years (SD = 7.4). The age at onset in the early 20s, lower educational achievement, occupational disability, chronically ill, more paranoid type was in accordance with previous studies. The frequency of HLAB27 was significantly increased in the patient group as a whole and in the subgroups of paranoid patients, chronic schizophrenics, patients with poor
Table 1 The frequency of the HLA class I and class II that show different distributions in patients, controls, family with mood disorder, and family without mental disorder HLA HLA*A24 n (%) OR (95% CI) HLA*A26 n (%) OR (95% CI) HLA*B15 n (%) OR (95% CI) HLA*B35 n (%) OR (95% CI) HLADRB*01 n (%) OR (95% CI) HLADRB*03 n (%) OR (95% CI) HLADRB*04 n (%) OR (95% CI) HLADRB*11 n (%) OR (95% CI) HLADRB*13 n (%) OR (95% CI)
Controls (n = 48) 13 (27.1%) 1.00 (Reference) 2 (4.2%) 1.00 (Reference) – (Undefined) 19 (39.6%) 1.00 (Reference) 14 (29.2%) 1.00 (Reference) 10 (20.8%) 1.00 (Reference) 10 (20.8%) 1.00 (Reference) 9 (18.8%) 1.00 (Reference) 1 (2.1%) 1.00 (Reference)
Family without mental disorder (n = 41)
Family with mood disorder (n = 48)
Patients (n = 50)
3 (7.3%) 0.21 (0.06–0.81) 3 (7.3%) 1.82 (0.29–11.43) 11 (26.8%) 1.30 (0.50–3.40) 5 (12.2%) 0.21 (0.07–0.64) 4 (9.8%) 0.26 (0.08–0.88) 12 (29.3%) 1.57 (0.60–4.14) 9 (22.0%) 1.07 (0.39–2.95) 14 (34.1%) 2.25 (0.85–5.93) 2 (4.9%) 2.41 (0.21–27.59)
9 (18.8%) 0.62 (0.24–1.63) 1 (2.1%) 0.49 (0.04–5.58) 11 (22.9%) 1.05 (0.41–2.72) 16 (33.3%) 0.76 (0.33–1.76) 9 (18.8%) 0.56 (0.22–1.46) 7 (14.6%) 0.65 (0.22–1.88) 8 (16.7%) 0.76 (0.27–2.13) 17 (35.4%) 2.38 (0.93–6.06) 2 (4.2%) 2.04 (0.18–23.32)
7 (14.0%) 0.44 (0.16–1.22) – (Undefined) 11 (22.0%) 1.00 (Reference) 13 (26.0%) 0.54 (0.23–1.26) 8 (16.0%) 0.46 (0.17–1.23) 12 (24.0%) 1.20 (0.46–3.11) 9 (18.0%) 0.83 (0.313–2.27) 18 (36.0%) 2.44 (0.96–6.16) 6 (12.0%) 6.41 (0.74–55.39)
Analysis v 2 (df = 3)
P values
6.57
0.087
Fisher
0.193
14.23
0.003
8.97
0.030
5.85
0.119
2.96
0.398
0.53
0.913
4.58
0.205
Fisher
0.233
198
S.O.V. Nunes et al. / Schizophrenia Research 76 (2005) 195–198
prognosis, and in patients with the onset of the disease before the age of 20 years (Gattaz and Beckmann, 1982). No significant differences were found for HLA-A and HLA-DRB1. In other studies the frequency of DRB1*04 alleles was significantly lower in both the schizophrenic patients and the unrelated mothers of schizophrenic offspring than in the healthy comparison subjects. DRB1*04 gene is positively associated with rheumatoid arthritis, an autoimmune disease that exhibits a strong negative association with schizophrenia (Wright et al., 1996a). A higher frequency of autoimmune diseases has been reported in first-degree relatives of schizophrenic (Wright et al., 1996b). The findings should be interpreted in light of a number of limitations. Given the study sizes here, statistical power was limited for comparison among four groups across. The data enable us to identify demographic and clinical characteristics of outpatients, their biological relatives, a positive association of the HLA-B*15, and negative association of the HLA-B*35, but larger samples are needed to validate and refine these findings. The topics of the positive association of the class I alleles B*15 in patients and biological relatives and negative association of HLA-B*35 in relatives without mental disorder could be interpreted with the increased risk or protection of developing the disease in response to infections, and other stressors during critical stages of brain development, or to imbalances of neurotransmitter system. Both these factors could be explored in future reports. Future research could delineate if the association of HLA-B for a subtype of psychosis may be explained by a genetic linkage or by an autoimmune process.
References American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Press, Washington, DC. Blackwood, D.H., Muir, W.J., Stephenson, A., Wentzel, J., Ad’hiah, A., Walker, M.J., et al., 1996. Reduced expression of HLA-B35 in schizophrenia. Psychiatr. Genet. 6, 51 – 59. Del Bem, C., Vilela, J., Crippa, J., Labate, C., Zuardi, A., 2001. Confiabilidade da bEntrevista clı´nica estruturada para o D.S.M.IVQ versa˜o clı´nica traduzida para o portugueˆs. Rev. Bras. Psiquiatr. 23 (3), 156 – 159. Gattaz, W., Beckmann, H., 1982. O sistema de histocompatibilidade nas esquizofrenias. Arq. Neuro-Psiquiatr. 40 (3), 224 – 229. Levinson, D., Ekholm, B., Balciuniene, J., Johanson, G., Castensson, A., Koisti, M., et al., 1996. Additional support for schizophrenia linkage on chromosome 6 and 8: a multicenter study. Am. J. Med. Genet. 67, 580 – 594. Li, T., Underhill, J., Liu, X., Sham, P., Donaldson, P., Murray, R., et al., 2001. Transmission disequilibrium analysis of HLA class II DRB1, DQA1, DQB1 and DPB1 polymorphisms in schizophrenia using family trios from a Han Chinese population. Schizophr. Res. 49, 73 – 78. Lindholm, E., Ekholm, B., Balciuniene, J., Johansson, G., Castensson, A., Koisti, M., et al., 1999. Linkage analysis of large Swedish kindred provides further support for a susceptibility locus for schizophrenia on chromosome 6p23. Am. J. Med. Genet. 88, 369 – 377. Schwab, S., Hallmayer, J., Freimann, J., Lerer, B., Albus, M., Borrmann-Hassenbach, M., et al., 2002. Investigation of linkage and association/linkage disequilibrium of HLA-DQA1-DQB1DRB1-Alleles in 69 sib-pair-and 89 trio-families with schizophrenia. Am. J. Med. Genet. 114, 315 – 320. Wright, P., Donaldson, P., Underhill, J., Chouhuri, K., Doheety, D., Murray, R., 1996a. Genetic association of the HLA DRB1 gene locus on chromosome 6p21.3 with schizophrenia. Am. J. Psychiatry 153, 1530 – 1533. Wright, P., Sham, P.C., Gilvarry, C.M., Jones, P.B., Cannon, M., Sharma, T., et al., 1996b. Autoimmune diseases in the pedigrees of schizophrenic and controls subjects. Schizophr. Res. 20, 261 – 267. Wright, P., Nimgaonkar, V., Donaldson, P., Murray, R., 2001. Schizophrenia and HLA: a review. Schizophr. Res. 47, 1 – 12.
The association of the HLA in patients with schizophrenia, schizoaffective disorder, and in their biological relatives S.O.V. Nunesa,T, S.D. Borellib, T. Matsuoc, M.A.E. Watanabed, E.N. Itanod a
Department of Psychiatry-Londrina State University (UEL), Av Adhemar de Barros, 625, 86050190 Londrina, Brazil b Department of Clinical Analysis-Maringa´ State University (UEM), Brazil c Department of Statistics and Applied Mathematics (UEL), Brazil d Department of General Pathology (UEL), Brazil Received 1 February 2005; accepted 10 February 2005 Available online 19 March 2005
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. D 2005 Elsevier B.V. All rights reserved. Keywords: Schizophrenia; Schizoaffective disorder; HLA; Biological relatives; Immunogenetic
1. Introduction Various diseases with a noticeable autoimmune component and frequent occurrence in family show a statistically significant correlation with specific T Corresponding author. Tel.: +55 43 33390404; fax: +55 43 33238210. E-mail address: [email protected] (S.O.V. Nunes). 0920-9964/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2005.02.005
human leukocyte antigens (HLA). This correlation was also found in studies of HLA in psychiatric disorders (Gattaz and Beckmann, 1982). The possible existence of a susceptibility locus for schizophrenia on the short arm of chromosome 6 in an area close to the HLA region at the 6p21.3 band has been the subject of several investigations (Levinson et al., 1996; Lindholm et al., 1999; Schwab et al., 2002). Wright et al. (2001) published a review of the HLA association with schizophrenia. They listed positive
196
S.O.V. Nunes et al. / Schizophrenia Research 76 (2005) 195–198
association with A9 or the A24 sub specificity, A28, A10, DRB1*01, and DRw6. Negative association with DQB1*0602 and DRB1*04 with schizophrenia have also been reported. In a study of transmission disequilibrium analysis of HLA class II DRB1, DQA1, DQB1 and DPB1 polymorphisms in schizophrenia using family trios, a nontransmission of the DRB1*03 allele and a preferential transmission for the DRB1*13 allele were detected (Li et al., 2001). The expression of HLA-B35 was significantly reduced in the schizophrenic populations compared to control population. The reduction of incidence of HLA-B35 in schizophrenic population could thus be related to susceptibility to some specific infections or an autoimmune component (Blackwood et al., 1996). The present study evaluated the association of HLA class II (DRB1) and class I (A, B) in schizophrenic and schizoaffective patients, biological relatives and healthy controls.
2. Methods The subjects were 50 schizophrenic and schizoaffective adults outpatients of the Psychiatric Ambulatory at Londrina State University (UEL), Parana´, Brazil. The patients were in remission, in chronic treatment with typical antipsychotic (Haloperidol) and atypical antipsychotic agents (olanzapine, clozapine, risperidone, ziprasidone), 48 first-degree relatives with mood disorders, and 41 first-degree relatives without mental disorders and 50 healthy volunteers as control. After approbation of this research by the Ethics Research Committee of UEL, patients, controls and first-degree relatives had given written informed consent, and samples of peripheral blood was drawn. Subjects younger than 18 years old and older than 55 years were excluded from all groups. All subjects were of the White race. They were required to be in good health conditions, defined as the absence of chronic diseases, which affect the immune system. The schizophrenic and schizoaffective outpatients were interviewed by structured diagnostic criteria categorized according to the fourth edition of the American Psychiatric Association’s Diagnostic and
Statistical Manual of Mental Disorders or DSM-IV, Axis I, (SCID-IV) criteria (American Psychiatric Association, 1994), translated to the Portuguese language by Del Bem et al. (2001). The schizophrenic patients diagnosed were classified as undifferentiated type (n = 1), paranoid type (n = 20) disorganized type (n = 10), residual type (n = 7), and schizoaffective disorder (n = 12). The 50 volunteers were recruited from the community, free of any serious medical illnesses, and had never taken psychotropic drugs or presented current or past psychiatric disorder as determined by their reported history during the clinical interview and by structured diagnostic criteria categorized according to DSM-IV, Axis I. Two controls were excluded from the study after blood test detected hepatitis virus C infection, a chronic illness known to affect the immune system. First-degree relative volunteers were recruited with ages ranging from 18 to 55 years. All members were 90 first-degree relatives, and were interview by the structured interview (DSM-IV, Axis I, SCID-IV). One first-degree relative was excluded from the study after blood test detected HIV infection. The 89 relatives included were 2 fathers, 2 mothers, 50 sisters, 30 brothers, 1 son, and 4 daughters. The 48 first-degree relatives had been diagnosed as Major Depressive Disorder (n = 45) and Bipolar I Disorder (n = 3). The HLA typing was performed using polymerasechain-reaction based on genotyping method. The DNA was extracted using the Puregene DNA Isolation Kit (Gentra Systems, Minneapolis, MN, USA). Final concentration of DNA was 100 ng/Al with the A269 / A280 ratio between 1.65 and 1.80. Individuals were genotyped for class I and class II alleles by Micro SSPk 384 System DNA Typing Trays (One Lambda, Canoga Park, CA, USA). The Statistical Analyses Groups were compared in demographic and clinical variables by using Chisquare test (v 2) or Exact Fisher’s test and Kruskal– Wallis test (H). The HLA associations with groups were analyzed using Chi-square test (v 2) or Fisher’s exact test. Odds ratio (OR) and 95% confidence intervals (CI 95%) were calculated for comparison between reference groups. Differences between the groups were considered to be statistically significant when p b 0.05.
S.O.V. Nunes et al. / Schizophrenia Research 76 (2005) 195–198
197
3. Results
4. Discussion
There were no group differences in age (H = 0.27, df = 3, p = 0.90), or gender (v 2 = 7.52, df = 3, p = 0.57). The group differed in educational background and marital status. Patients presented lower educational achievement (v 2 = 13.26, df = 3, p = 0.004) than controls and relatives, and most of them were unmarried (v 2 = 16.28, df = 3, p b 0.001), differently from controls and relatives. In patients, there were more significant differences regarding occupational impairment than controls and relatives (v 2 = 133.2, df = 3, p b 0.001). The illness mean duration was 15.34 years (SD F 9.90) and the median age of onset was 22.4 years (SD F 7.37). A higher percentage of patients had suicide attempt than controls, relatives without psychiatric disease with humor disorder (Fisher’s exact test = 27, df = 3, p b 0.001). The frequency of HLA-B*15 was significantly higher in patients and family with and without mental disorders than controls (Table 1). No significant differences were found for HLA-A and HLA-DRB1 (Table 1). The frequency of the HLA-B*35 was significantly reduced in family without mental disorders than in controls (Table 1).
We found significant positive association of the class I HLA-B*15 in patients, family with humor disorder and family without mental disorder ( p = 0.003) and negative association of the HLA-B*35 in relatives without psychiatric disease ( p = 0.03). The frequency of HLA B*15 was significantly increased in the patient group with lower educational achievement ( p = 0.004) than controls and relatives, and most of them were unmarried ( p b 0.001), differently from controls and relatives. In patients there were more significant differences regarding occupational impairment, and more suicide attempters than controls and relatives ( p b 0.001). The illness mean duration was 15.3 years (SD F 9.9) and the median age of onset was 22.4 years (SD = 7.4). The age at onset in the early 20s, lower educational achievement, occupational disability, chronically ill, more paranoid type was in accordance with previous studies. The frequency of HLAB27 was significantly increased in the patient group as a whole and in the subgroups of paranoid patients, chronic schizophrenics, patients with poor
Table 1 The frequency of the HLA class I and class II that show different distributions in patients, controls, family with mood disorder, and family without mental disorder HLA HLA*A24 n (%) OR (95% CI) HLA*A26 n (%) OR (95% CI) HLA*B15 n (%) OR (95% CI) HLA*B35 n (%) OR (95% CI) HLADRB*01 n (%) OR (95% CI) HLADRB*03 n (%) OR (95% CI) HLADRB*04 n (%) OR (95% CI) HLADRB*11 n (%) OR (95% CI) HLADRB*13 n (%) OR (95% CI)
Controls (n = 48) 13 (27.1%) 1.00 (Reference) 2 (4.2%) 1.00 (Reference) – (Undefined) 19 (39.6%) 1.00 (Reference) 14 (29.2%) 1.00 (Reference) 10 (20.8%) 1.00 (Reference) 10 (20.8%) 1.00 (Reference) 9 (18.8%) 1.00 (Reference) 1 (2.1%) 1.00 (Reference)
Family without mental disorder (n = 41)
Family with mood disorder (n = 48)
Patients (n = 50)
3 (7.3%) 0.21 (0.06–0.81) 3 (7.3%) 1.82 (0.29–11.43) 11 (26.8%) 1.30 (0.50–3.40) 5 (12.2%) 0.21 (0.07–0.64) 4 (9.8%) 0.26 (0.08–0.88) 12 (29.3%) 1.57 (0.60–4.14) 9 (22.0%) 1.07 (0.39–2.95) 14 (34.1%) 2.25 (0.85–5.93) 2 (4.9%) 2.41 (0.21–27.59)
9 (18.8%) 0.62 (0.24–1.63) 1 (2.1%) 0.49 (0.04–5.58) 11 (22.9%) 1.05 (0.41–2.72) 16 (33.3%) 0.76 (0.33–1.76) 9 (18.8%) 0.56 (0.22–1.46) 7 (14.6%) 0.65 (0.22–1.88) 8 (16.7%) 0.76 (0.27–2.13) 17 (35.4%) 2.38 (0.93–6.06) 2 (4.2%) 2.04 (0.18–23.32)
7 (14.0%) 0.44 (0.16–1.22) – (Undefined) 11 (22.0%) 1.00 (Reference) 13 (26.0%) 0.54 (0.23–1.26) 8 (16.0%) 0.46 (0.17–1.23) 12 (24.0%) 1.20 (0.46–3.11) 9 (18.0%) 0.83 (0.313–2.27) 18 (36.0%) 2.44 (0.96–6.16) 6 (12.0%) 6.41 (0.74–55.39)
Analysis v 2 (df = 3)
P values
6.57
0.087
Fisher
0.193
14.23
0.003
8.97
0.030
5.85
0.119
2.96
0.398
0.53
0.913
4.58
0.205
Fisher
0.233
198
S.O.V. Nunes et al. / Schizophrenia Research 76 (2005) 195–198
prognosis, and in patients with the onset of the disease before the age of 20 years (Gattaz and Beckmann, 1982). No significant differences were found for HLA-A and HLA-DRB1. In other studies the frequency of DRB1*04 alleles was significantly lower in both the schizophrenic patients and the unrelated mothers of schizophrenic offspring than in the healthy comparison subjects. DRB1*04 gene is positively associated with rheumatoid arthritis, an autoimmune disease that exhibits a strong negative association with schizophrenia (Wright et al., 1996a). A higher frequency of autoimmune diseases has been reported in first-degree relatives of schizophrenic (Wright et al., 1996b). The findings should be interpreted in light of a number of limitations. Given the study sizes here, statistical power was limited for comparison among four groups across. The data enable us to identify demographic and clinical characteristics of outpatients, their biological relatives, a positive association of the HLA-B*15, and negative association of the HLA-B*35, but larger samples are needed to validate and refine these findings. The topics of the positive association of the class I alleles B*15 in patients and biological relatives and negative association of HLA-B*35 in relatives without mental disorder could be interpreted with the increased risk or protection of developing the disease in response to infections, and other stressors during critical stages of brain development, or to imbalances of neurotransmitter system. Both these factors could be explored in future reports. Future research could delineate if the association of HLA-B for a subtype of psychosis may be explained by a genetic linkage or by an autoimmune process.
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