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The CCR5 32-bp deletion allele is rare in a Chinese population
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Schizophrenia Research 101 (2008) 341 – 343 www.elsevier.com/locate/schres
Letter to the Editors The CCR5 32-bp deletion allele is rare in a Chinese population Dear Editors, Infection and immunity have been hypothesized to play a role in the pathogenesis of schizophrenia (Muller, 2004). Recently, a case–control whole-genome association (WGA) study in schizophrenia found a novel genetic marker (RS4129248) near a cytokine receptor gene, interleukin-3 receptor alpha (IL3RA) and near the colony stimulating factor receptor 2 alpha (CSF2RA) gene in the pseudoautosomal region. Using an independent sequencing sample to confirm this association, intronic haplotype blocks within IL3RA also were significantly associated with schizophrenia (Lencz et al., 2007), suggesting involvement of immune-mediated mechanism in this disorder. Chemokines, together with adhesion molecules and proteases, are essential for the directional migration of leukocytes during normal and inflammatory processes. It has been proven that chemokines are involved in diseases such as autoimmune diseases and bacterial or viral infection (Badolato and Oppenheim, 1996). The chemokine receptor 5 (CCR5) binds a number of chemokines. A common nonfunctional allele of the CCR5 gene characterized by deletion of a 32-bp segment in the open reading frame has been associated with susceptibility to a variety of other immune-related diseases, including diseases of presumed autoimmune etiology (Thio et al., 2007). Very recently, Rasmussen et al have provided the first important evidence that the CCR5 could act as a genetic risk factor for late-onset schizophrenia among Danish population (Rasmussen et al., 2006), which supports an “inflammatory-infective” hypothesis of schizophrenia. It was thought important to replicate the work with a different ethnic population to rule out a false-positive result from ethnic differences in the frequency distribution of the DNA marker or from the population structure. The present work was therefore undertaken to examine the association between the CCR5 receptor gene and clinical profiles of schizophrenia in a Chinese population. 0920-9964/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2008.01.015
Two hundred and fifty unrelated schizophrenic individuals (200 men and 50 women) were recruited from Beijing HuiLongGuan Psychiatric hospital in this study. Their ages ranged from 25 to 70 years with a median of 44 years. The patients had a mean duration of illness of 25 ± 11 years, a mean duration of hospitalization of 10± 8 and an average duration of antipsychotic treatment of 22 ± 7 years. Information on their age at appearance of first symptoms, age at first admission to a psychiatric hospital department was obtained from medical records. The age at appearance of first symptoms was used as a measure of the age at onset of schizophrenia. The age at appearance of first symptoms of most of the patients ranged from 16 to 30 years, which was strongly correlated with age at first admission (p b 0.001). Among female patients, age at first admission ranged from 11 to 56 years with a median of 26.7 years. Among male patients, the median age at first admission was significantly lower (23.8 years, range = 12– 54) (p b 0.05). Twenty male patients and 8 female patients represented cases of early onset or very early onset schizophrenia, having been admitted to psychiatric hospital departments before reaching 18 years of age. Late-onset schizophrenia was defined as a disease entity with onset after 40 years of age, with 5 males and 4 females. The detailed clinical pictures, medical histories and family history regarding mental illness were taken. The psychopathology was assessed on the day of the blood sampling using the Positive and Negative Symptom Scale (PANSS). Also included in the study were 332 unrelated healthy subjects (74 women, 258 men). Their ages ranged from 25 to 68 years with a median of 42 years. All subjects in this study were Han Chinese and came from the area of Beijing or nearby, Northern China. No significant difference was noted in both gender and age between the patient and normal control groups. All the subjects gave informed consent to participate in the genetic research, which was approved by the Institutional Review Board (IRB), Beijing HuiLonGuan Psychiatric hospital. The blood samples were drawn from the ante-cubital vein in the morning. Genomic DNA used for the polymerase chain reaction (PCR) was extracted from the whole blood sample. Genotyping of the CCR5 32-nucleotide
342
Letter to the Editors
Table 1 Genotype distribution and allele counts among normal controls and patients with schizophrenia genotype for the CCR5 32-bp deletion polymorphism Genotype distribution
Allele counts
Homozygous for deletion allele Heterozygotes Homozygous for wild type allele Deletion allele Wild type allele Normal controls (n = 332) 0 (0%) Schizophrenia (n = 250) 0
3 (0.9%) 0
deletion polymorphism was accomplished by enzymatic amplification of genomic DNA and agarose gel electrophoresis of amplified fragments (Martinson et al., 1997). The frequencies of genotypes of CCR5 32-bp deletion in our study population are shown in Table 1. Among the 250 patients with schizophrenia studied, no one carried the mutant allele. Only 3 normal controls carried the heterozygotes, and the homozygotes for the mutation was not detected at all in this study population. Because of this distribution, the original case–control analysis was not pursued. A previous report has suggested the presence of ethnic differences in the CCR5 32-bp deletion (Martinson et al., 1997). The mutant allele frequency was found to be about 10% in population of Europeans descent, about 2–5% in population from Saudi Arabia as far east as India and Pakistan, and less than 0.01 in Eastern Asians (Martinson et al., 1997). Our results support this previous report upon the frequency of the mutant allele in Asians. The reason for the rarity of mutant allele is unclear. In fact, we observed much more homogeneous distributions of a particular allele in the gene polymorphisms of several cytokines such as interleukin-10, and tumor necrosis factoralpha in our population than those of polymorphisms reported in Caucassian population (unpublished our data). Considering the very low frequencies of the CCR5 mutant allele in Japanese and Chinese population, it probably reflects the genetic characteristic of Eastern Asians. However, it is worthy of noting that our study sample has low number of late-onset of schizophrenia, namely, 5 males and 4 females. Theoretically, examination of a sample with a larger number of this type of schizophrenia might have revealed an over-representation of the 32-bp deletion allele in this type of schizophrenia (Rasmussen et al., 2006), which deserves further investigation. In summary, we found that the CCR5 32-bp allele frequency is extremely rare in the Chinese. The 32-bp deletion allele in chemokine receptor CCR5 is unlikely to contribute significantly to susceptibility to or the onset of schizophrenia in Chinese population. Acknowledgment This study was funded by the Stanley Medical Institute Foundation (03T-459, 05T-726) (XYZ), the National
329 (99.1%) 250
3 (0.45%) 0
661 (99.55%) 500
Basic Research Program of China (973 Program; 2007BC512307) (DFZ), and the Department of Veterans Affairs, VISN 1, Mental Illness Research, Education and Clinical Center (MIRECC) and National Institute on Drug Abuse K05-DA0454 and P50-DA18827 (TRK).
References Badolato, R., Oppenheim, J.J., 1996. Role of cytokines, acutephase proteins, and chemokines in the progression of rheumatoid arthritis. Semin. Arthritis Rheum. 26, 526–538. Lencz, T., Morgan, T.V., Athanasiou, M., Dain, B., Reed, C.R., Kane, J.M., Kucherlapati, R., Malhotra, A.K., 2007. Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia. Mol. Psychiatry 12, 572–580. Martinson, J.J., Chapman, N.H., Rees, D.C., Liu, Y.T., Clegg, J.B., 1997. Global distribution of the CCR5 gene 32-basepair deletion. Nat. Genet. 16, 100–103. Muller, N., 2004. Immunological and infections aspects of schizophrenia. Eur. Arch. Psychiatry Clin. Neurosci. 254, 1–3. Rasmussen, H.B., Timm, S., Wang, A.G., Soeby, K., Lublin, H., Fenger, M., Hemmingsen, R., Werge, T., 2006. Association between the CCR5 32-bp deletion allele and late onset of schizophrenia. Am. J. Psychiatry 163, 507–511. Thio, C.L., Astemborski, J., Bashirova, A., Mosbruger, T., Greer, S., Witt, M.D., Goedert, J.J., Hilgartner, M., Majeske, A., O'Brien, S.J., Thomas, D.L., Carrington, M., 2007. Genetic protection against hepatitis B virus conferred by CCR5Delta32: evidence that CCR5 contributes to viral persistence. J. Virol. 81, 441–445.
Fan Wang1 Mei Hong Xiu1 Lian Yuan Cao Xiang Yang Zhang* Center for Biological Psychiatry, Beijing HuiLongGuan Hospital, Beijing100096, PR China E-mail: address [email protected] (X.Y. Zhang). ⁎ Corresponding author. Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, VA Medical Center, Research Building 109, Room 130, 2002 Holcombe Boulevard, Houston, Texas, 77030, USA. Tel.: +1 713 791 1414x5824; fax: +1 713 794 7938. 1 Fan Wang and Mei Hong [email protected]. contributed to this work equally.
Letter to the Editors
Dong Feng Zhou Institute of Mental Health, Peking University, Beijing, 100083, PR China E-mail address: [email protected]. Corresponding author. Institute of Mental Health, Peking University, 51 HuaYuanBei Road, HaiDian District, Beijing 100083, PR China.
343
Gui Ying Wu Therese A. Kosten Thomas R. Kosten Xiang Yang Zhang Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas, 77030, USA 9 November 2007
Schizophrenia Research 101 (2008) 341 – 343 www.elsevier.com/locate/schres
Letter to the Editors The CCR5 32-bp deletion allele is rare in a Chinese population Dear Editors, Infection and immunity have been hypothesized to play a role in the pathogenesis of schizophrenia (Muller, 2004). Recently, a case–control whole-genome association (WGA) study in schizophrenia found a novel genetic marker (RS4129248) near a cytokine receptor gene, interleukin-3 receptor alpha (IL3RA) and near the colony stimulating factor receptor 2 alpha (CSF2RA) gene in the pseudoautosomal region. Using an independent sequencing sample to confirm this association, intronic haplotype blocks within IL3RA also were significantly associated with schizophrenia (Lencz et al., 2007), suggesting involvement of immune-mediated mechanism in this disorder. Chemokines, together with adhesion molecules and proteases, are essential for the directional migration of leukocytes during normal and inflammatory processes. It has been proven that chemokines are involved in diseases such as autoimmune diseases and bacterial or viral infection (Badolato and Oppenheim, 1996). The chemokine receptor 5 (CCR5) binds a number of chemokines. A common nonfunctional allele of the CCR5 gene characterized by deletion of a 32-bp segment in the open reading frame has been associated with susceptibility to a variety of other immune-related diseases, including diseases of presumed autoimmune etiology (Thio et al., 2007). Very recently, Rasmussen et al have provided the first important evidence that the CCR5 could act as a genetic risk factor for late-onset schizophrenia among Danish population (Rasmussen et al., 2006), which supports an “inflammatory-infective” hypothesis of schizophrenia. It was thought important to replicate the work with a different ethnic population to rule out a false-positive result from ethnic differences in the frequency distribution of the DNA marker or from the population structure. The present work was therefore undertaken to examine the association between the CCR5 receptor gene and clinical profiles of schizophrenia in a Chinese population. 0920-9964/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2008.01.015
Two hundred and fifty unrelated schizophrenic individuals (200 men and 50 women) were recruited from Beijing HuiLongGuan Psychiatric hospital in this study. Their ages ranged from 25 to 70 years with a median of 44 years. The patients had a mean duration of illness of 25 ± 11 years, a mean duration of hospitalization of 10± 8 and an average duration of antipsychotic treatment of 22 ± 7 years. Information on their age at appearance of first symptoms, age at first admission to a psychiatric hospital department was obtained from medical records. The age at appearance of first symptoms was used as a measure of the age at onset of schizophrenia. The age at appearance of first symptoms of most of the patients ranged from 16 to 30 years, which was strongly correlated with age at first admission (p b 0.001). Among female patients, age at first admission ranged from 11 to 56 years with a median of 26.7 years. Among male patients, the median age at first admission was significantly lower (23.8 years, range = 12– 54) (p b 0.05). Twenty male patients and 8 female patients represented cases of early onset or very early onset schizophrenia, having been admitted to psychiatric hospital departments before reaching 18 years of age. Late-onset schizophrenia was defined as a disease entity with onset after 40 years of age, with 5 males and 4 females. The detailed clinical pictures, medical histories and family history regarding mental illness were taken. The psychopathology was assessed on the day of the blood sampling using the Positive and Negative Symptom Scale (PANSS). Also included in the study were 332 unrelated healthy subjects (74 women, 258 men). Their ages ranged from 25 to 68 years with a median of 42 years. All subjects in this study were Han Chinese and came from the area of Beijing or nearby, Northern China. No significant difference was noted in both gender and age between the patient and normal control groups. All the subjects gave informed consent to participate in the genetic research, which was approved by the Institutional Review Board (IRB), Beijing HuiLonGuan Psychiatric hospital. The blood samples were drawn from the ante-cubital vein in the morning. Genomic DNA used for the polymerase chain reaction (PCR) was extracted from the whole blood sample. Genotyping of the CCR5 32-nucleotide
342
Letter to the Editors
Table 1 Genotype distribution and allele counts among normal controls and patients with schizophrenia genotype for the CCR5 32-bp deletion polymorphism Genotype distribution
Allele counts
Homozygous for deletion allele Heterozygotes Homozygous for wild type allele Deletion allele Wild type allele Normal controls (n = 332) 0 (0%) Schizophrenia (n = 250) 0
3 (0.9%) 0
deletion polymorphism was accomplished by enzymatic amplification of genomic DNA and agarose gel electrophoresis of amplified fragments (Martinson et al., 1997). The frequencies of genotypes of CCR5 32-bp deletion in our study population are shown in Table 1. Among the 250 patients with schizophrenia studied, no one carried the mutant allele. Only 3 normal controls carried the heterozygotes, and the homozygotes for the mutation was not detected at all in this study population. Because of this distribution, the original case–control analysis was not pursued. A previous report has suggested the presence of ethnic differences in the CCR5 32-bp deletion (Martinson et al., 1997). The mutant allele frequency was found to be about 10% in population of Europeans descent, about 2–5% in population from Saudi Arabia as far east as India and Pakistan, and less than 0.01 in Eastern Asians (Martinson et al., 1997). Our results support this previous report upon the frequency of the mutant allele in Asians. The reason for the rarity of mutant allele is unclear. In fact, we observed much more homogeneous distributions of a particular allele in the gene polymorphisms of several cytokines such as interleukin-10, and tumor necrosis factoralpha in our population than those of polymorphisms reported in Caucassian population (unpublished our data). Considering the very low frequencies of the CCR5 mutant allele in Japanese and Chinese population, it probably reflects the genetic characteristic of Eastern Asians. However, it is worthy of noting that our study sample has low number of late-onset of schizophrenia, namely, 5 males and 4 females. Theoretically, examination of a sample with a larger number of this type of schizophrenia might have revealed an over-representation of the 32-bp deletion allele in this type of schizophrenia (Rasmussen et al., 2006), which deserves further investigation. In summary, we found that the CCR5 32-bp allele frequency is extremely rare in the Chinese. The 32-bp deletion allele in chemokine receptor CCR5 is unlikely to contribute significantly to susceptibility to or the onset of schizophrenia in Chinese population. Acknowledgment This study was funded by the Stanley Medical Institute Foundation (03T-459, 05T-726) (XYZ), the National
329 (99.1%) 250
3 (0.45%) 0
661 (99.55%) 500
Basic Research Program of China (973 Program; 2007BC512307) (DFZ), and the Department of Veterans Affairs, VISN 1, Mental Illness Research, Education and Clinical Center (MIRECC) and National Institute on Drug Abuse K05-DA0454 and P50-DA18827 (TRK).
References Badolato, R., Oppenheim, J.J., 1996. Role of cytokines, acutephase proteins, and chemokines in the progression of rheumatoid arthritis. Semin. Arthritis Rheum. 26, 526–538. Lencz, T., Morgan, T.V., Athanasiou, M., Dain, B., Reed, C.R., Kane, J.M., Kucherlapati, R., Malhotra, A.K., 2007. Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia. Mol. Psychiatry 12, 572–580. Martinson, J.J., Chapman, N.H., Rees, D.C., Liu, Y.T., Clegg, J.B., 1997. Global distribution of the CCR5 gene 32-basepair deletion. Nat. Genet. 16, 100–103. Muller, N., 2004. Immunological and infections aspects of schizophrenia. Eur. Arch. Psychiatry Clin. Neurosci. 254, 1–3. Rasmussen, H.B., Timm, S., Wang, A.G., Soeby, K., Lublin, H., Fenger, M., Hemmingsen, R., Werge, T., 2006. Association between the CCR5 32-bp deletion allele and late onset of schizophrenia. Am. J. Psychiatry 163, 507–511. Thio, C.L., Astemborski, J., Bashirova, A., Mosbruger, T., Greer, S., Witt, M.D., Goedert, J.J., Hilgartner, M., Majeske, A., O'Brien, S.J., Thomas, D.L., Carrington, M., 2007. Genetic protection against hepatitis B virus conferred by CCR5Delta32: evidence that CCR5 contributes to viral persistence. J. Virol. 81, 441–445.
Fan Wang1 Mei Hong Xiu1 Lian Yuan Cao Xiang Yang Zhang* Center for Biological Psychiatry, Beijing HuiLongGuan Hospital, Beijing100096, PR China E-mail: address [email protected] (X.Y. Zhang). ⁎ Corresponding author. Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, VA Medical Center, Research Building 109, Room 130, 2002 Holcombe Boulevard, Houston, Texas, 77030, USA. Tel.: +1 713 791 1414x5824; fax: +1 713 794 7938. 1 Fan Wang and Mei Hong [email protected]. contributed to this work equally.
Letter to the Editors
Dong Feng Zhou Institute of Mental Health, Peking University, Beijing, 100083, PR China E-mail address: [email protected]. Corresponding author. Institute of Mental Health, Peking University, 51 HuaYuanBei Road, HaiDian District, Beijing 100083, PR China.
343
Gui Ying Wu Therese A. Kosten Thomas R. Kosten Xiang Yang Zhang Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas, 77030, USA 9 November 2007