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Brain-derived neurotrophic factor polymorphisms and smoking in schizophrenia
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Schizophrenia Research 97 (2007) 299 – 301 www.elsevier.com/locate/schres
Letter to the Editors Brain-derived neurotrophic factor polymorphisms and smoking in schizophrenia Dear Editors, Schizophrenia is associated worldwide with a higher rate of smoking than that observed among the general population or those with other severe mental illnesses (LLerena et al., 2003). Preclinical studies show that nicotine activates dopaminergic neurons in the mesolimbic reward pathway enhancing dopamine (DA) release (Pontieri et al., 1996), which is associated with the pleasurable effects of the drug. Studies show that brain-derived neurotrophic factor (BDNF) and DA systems interact within a number of neurobiological processes (Guillin et al., 2001). BDNF's influence on DA responsiveness might be an important determinant in the etiopathology and/or treatment of several conditions implicating DA such as drug abuse and psychiatric disorders (Guillin et al., 2001, 2007). Preclinical data show that acute administration decreases whereas chronic nicotine, but not cocaine or morphine, increases BDNF mRNA levels in the hippocampus (Kenny et al., 2000). Interestingly, genome-wide
linkage scans indicate that the region of chromosome 11p13 where the BDNF gene is located likely harbors susceptibility genes for nicotine dependence specifically (Li et al., 2003). Moreover, Beuten et al. (2005) provide evidence of an association between allelic variants of BDNF and nicotine dependence in male European– American smokers (Beuten et al., 2005). More recent reports also showed an association between smoking behavior and BDNF-Val66Met polymorphism (Lang et al., 2007). Taken together, these findings suggest that BDNF may play an important role in the etiology of nicotine dependence. One hundred forty-nine male inpatients meeting the diagnostic criteria of DSM-IV for schizophrenia were recruited. They were of the chronic type, with duration of illness for at least 5 years. All patients had been receiving a stable dose of oral antipsychotics for at least 12 months and were Han Chinese. All subjects gave written informed consent approved by the institutional Review Board, the Institute of Mental Health, Peking University. In addition, a self-made questionnaire was administered to each patient assessing cigarette smoking behavior. The number of cigarettes per day was determined in those subjects that smoked. Past smokers
Table 1 Demographic characteristics between smoker and non-smoker groups
Age (years) Education (years) Duration of illness (years) Age of onset (years) Hospitalization numbers Body mass index (kg/m2) BDNF-Val66Met AA GA GG BDNF-C270T CC CT
Smokers
Non-smokers
(n = 101)
(n = 48)
t
p
50.0 ± 7.7 9.3 ± 2.3 26.1 ± 7.6 24.3 ± 6.3 4.0 ± 2.2 23.9 ± 3.8
55.6 ± 7.7 10.2 ± 2.7 32.2 ± 10.1 23.8 ± 5.0 4.1 ± 2.1 24.4 ± 3.6
3.76 2.90 2.89 0.47 0.011 0.58
0.000 0.004 0.007 0.64 0.99 0.57
20 (21.8%) 51 (50.5%) 30 (29.7%)
16 (33.3%) 20 (41.7%) 12 (25.0%)
χ2 = 3.25
0.197
94 (93.1%) 7 (6.9%)
46 (95.8%) 2 (4.2%)
χ2 = 1.24
0.27
0920-9964/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2007.08.012
300
Letter to the Editors
were excluded from the present study. Groups included 101 patients identified as ‘smokers’, and 48 ‘nonsmokers’. The demographic data are shown in Table 1. BDNF-Val66Met polymorphisms were determined using the methods by Neves-Pereira et al. (2002) whereas the C270T polymorphism was genotyped using the method originally described by Kunugi et al. (2001). All genotype frequencies were in Hardy Weinberg Equilibrium in the patients (BDNF196: χ2 = 0.688, p = 0.56; BDNF270: χ2 = 0.96, p = 0.23). Allele frequencies and genotype distributions in smokers and nonsmokers are shown in Table 1. Compared to non-smokers, smokers were older, had less education and longer illness history (all p b 0.01). For the BDNF-Val66Met polymorphisms, individuals with Val/Met and Val/Val genotype demonstrated 2.54 and 1.47 times increased risk of smoking compared to those with Met/Met genotype after adjusting for age, education, and duration of illness, respectively (95% CI for Val/Met: 0.98–6.57, p = 0.055; 95% CI for Val/Val: 0.85–2.52, p = 0.17). Individuals with Val alleles (Val/ Val + Val/Met genotype) demonstrated a 1.54 times increased risk of smoking compared to those with Met/Met genotype, with a trend towards significance (95% CI: 1.0–2.37, p = 0.051). For the BDNF-C270T polymorphism, smokers with T allele showed a 1.71 times increased risk of smoking compared to those without T alleles (95%: 0.51–5.76, p = 0.37). But this was not statistically significant (p N 0.05). The present study supports that genetic differences in BDNF exist between schizophrenia patients who smoke and those who do not. Our data show that men with Val allele in the BDNF gene have an increased risk for smoking in the Han Chinese population with schizophrenia. The results suggest that the Val66Met polymorphism in the BDNF gene increases smoking risk in patients with schizophrenia. However, due to the limited sample size in both the smoker and non-smoker groups and the low statistical power, our results need to be replicated in a large group of patients from different ethnic populations. In addition, the absence of healthy control groups is a major limitation of the study. Acknowledgments This study was funded by the Stanley Medical Institute Foundation (03T-459, 05T-726) (XYZ), the National Basic Research Program of China (973 Program; 2007BC512307), the Department of Veterans Affairs, VISN 16, Mental Illness Research, Education and Clinical Center (MIRECC) and the National Institute on Drug Abuse K05-DA0454 and P50-DA18827 (TRK).
References Beuten, J., Ma, J.Z., Payne, T.J., Dupont, R.T., Quezada, P., Huang, W., Crews, K.M., Li, M.D., 2005. Significant association of BDNF haplotypes in European–American male smokers but not in European–American female or African–American smokers. Am. J. Med. Genet., B Neuropsychiatr. Genet. 139, 73–80. Guillin, O., Diaz, J., Carroll, P., Griffon, N., Schwartz, J.C., Sokoloff, P., 2001. BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. Nature 411, 86–89. Guillin, O., Demily, C., Thibaut, F., 2007. Brain-derived neurotrophic factor in schizophrenia and its relation with dopamine. Int. Rev. Neurobiol. 78, 377–395. Kenny, P.J., File, S.E., Rattray, M., 2000. Acute nicotine decreases, and chronic nicotine increases the expression of brain-derived neurotrophic factor mRNA in rat hippocampus. Brain Res. Mol. Brain Res. 85, 234–238. Kunugi, H., Ueki, A., Otsuka, M., Isse, K., Hirasawa, H., Kato, N., Nabika, T., Kobayashi, S., Nanko, S., 2001. A novel polymorphism of the brain-derived neurotrophic factor (BDNF) gene associated with late-onset Alzheimer's disease. Mol. Psychiatry 6, 83–86. Lang, U.E., Sander, T., Lohoff, F.W., Hellweg, R., Bajbouj, M., Winterer, G., Gallinat, J., 2007. Association of the met66 allele of brain-derived neurotrophic factor (BDNF) with smoking. Psychopharmacology 190, 433–439. Li, M.D., Ma, J.Z., Cheng, R., Dupont, R.T., Williams, N.J., Crews, K.M., Payne, T.J., Elston, R.C., 2003. A genome-wide scan to identify loci for smoking rate in the Framingham Heart Study population. BMC Genet. 4 (Suppl 1), S103. LLerena, A., de la Rubia, A., Penas-Lledo, E.M., Diaz, F.J., de Leon, J., 2003. Schizophrenia and tobacco smoking in a Spanish psychiatric hospital. Schizophr. Res. 60, 313–317. Neves-Pereira, M., Mundo, E., Muglia, P., King, N., Macciardi, F., Kennedy, J.L., 2002. The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a familybased association study. Am. J. Hum. Genet. 71, 651–655. Pontieri, F.E., Tanda, G., Orzi, F., Di Chiara, G., 1996. Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382, 255–257.
Zhi Ren Wang Dong Feng Zhou Institute of Mental Health, Peking University, Beijing, 100083, PR China E-mail address: [email protected] (D.F. Zhou). Lian Yuan Cao Yun Long Tan Xiang Yang Zhang Center for Biological Psychiatry, Beijing HuiLongGuan Hospital, Beijing 100096, PR China Tel.: +1 7137911414x5824; fax: +1 713 794 7938. E-mail address: [email protected] (X.Y. Zhang).
Letter to the Editors
Jun Li College of Pharmacology, Anhui Medical University, Hefei, Anhui Province 230032, PR China Lin Lu National Institute on Drug Dependence, Peking University, Beijing 100083, PR China
301
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 22 May 2007
Schizophrenia Research 97 (2007) 299 – 301 www.elsevier.com/locate/schres
Letter to the Editors Brain-derived neurotrophic factor polymorphisms and smoking in schizophrenia Dear Editors, Schizophrenia is associated worldwide with a higher rate of smoking than that observed among the general population or those with other severe mental illnesses (LLerena et al., 2003). Preclinical studies show that nicotine activates dopaminergic neurons in the mesolimbic reward pathway enhancing dopamine (DA) release (Pontieri et al., 1996), which is associated with the pleasurable effects of the drug. Studies show that brain-derived neurotrophic factor (BDNF) and DA systems interact within a number of neurobiological processes (Guillin et al., 2001). BDNF's influence on DA responsiveness might be an important determinant in the etiopathology and/or treatment of several conditions implicating DA such as drug abuse and psychiatric disorders (Guillin et al., 2001, 2007). Preclinical data show that acute administration decreases whereas chronic nicotine, but not cocaine or morphine, increases BDNF mRNA levels in the hippocampus (Kenny et al., 2000). Interestingly, genome-wide
linkage scans indicate that the region of chromosome 11p13 where the BDNF gene is located likely harbors susceptibility genes for nicotine dependence specifically (Li et al., 2003). Moreover, Beuten et al. (2005) provide evidence of an association between allelic variants of BDNF and nicotine dependence in male European– American smokers (Beuten et al., 2005). More recent reports also showed an association between smoking behavior and BDNF-Val66Met polymorphism (Lang et al., 2007). Taken together, these findings suggest that BDNF may play an important role in the etiology of nicotine dependence. One hundred forty-nine male inpatients meeting the diagnostic criteria of DSM-IV for schizophrenia were recruited. They were of the chronic type, with duration of illness for at least 5 years. All patients had been receiving a stable dose of oral antipsychotics for at least 12 months and were Han Chinese. All subjects gave written informed consent approved by the institutional Review Board, the Institute of Mental Health, Peking University. In addition, a self-made questionnaire was administered to each patient assessing cigarette smoking behavior. The number of cigarettes per day was determined in those subjects that smoked. Past smokers
Table 1 Demographic characteristics between smoker and non-smoker groups
Age (years) Education (years) Duration of illness (years) Age of onset (years) Hospitalization numbers Body mass index (kg/m2) BDNF-Val66Met AA GA GG BDNF-C270T CC CT
Smokers
Non-smokers
(n = 101)
(n = 48)
t
p
50.0 ± 7.7 9.3 ± 2.3 26.1 ± 7.6 24.3 ± 6.3 4.0 ± 2.2 23.9 ± 3.8
55.6 ± 7.7 10.2 ± 2.7 32.2 ± 10.1 23.8 ± 5.0 4.1 ± 2.1 24.4 ± 3.6
3.76 2.90 2.89 0.47 0.011 0.58
0.000 0.004 0.007 0.64 0.99 0.57
20 (21.8%) 51 (50.5%) 30 (29.7%)
16 (33.3%) 20 (41.7%) 12 (25.0%)
χ2 = 3.25
0.197
94 (93.1%) 7 (6.9%)
46 (95.8%) 2 (4.2%)
χ2 = 1.24
0.27
0920-9964/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2007.08.012
300
Letter to the Editors
were excluded from the present study. Groups included 101 patients identified as ‘smokers’, and 48 ‘nonsmokers’. The demographic data are shown in Table 1. BDNF-Val66Met polymorphisms were determined using the methods by Neves-Pereira et al. (2002) whereas the C270T polymorphism was genotyped using the method originally described by Kunugi et al. (2001). All genotype frequencies were in Hardy Weinberg Equilibrium in the patients (BDNF196: χ2 = 0.688, p = 0.56; BDNF270: χ2 = 0.96, p = 0.23). Allele frequencies and genotype distributions in smokers and nonsmokers are shown in Table 1. Compared to non-smokers, smokers were older, had less education and longer illness history (all p b 0.01). For the BDNF-Val66Met polymorphisms, individuals with Val/Met and Val/Val genotype demonstrated 2.54 and 1.47 times increased risk of smoking compared to those with Met/Met genotype after adjusting for age, education, and duration of illness, respectively (95% CI for Val/Met: 0.98–6.57, p = 0.055; 95% CI for Val/Val: 0.85–2.52, p = 0.17). Individuals with Val alleles (Val/ Val + Val/Met genotype) demonstrated a 1.54 times increased risk of smoking compared to those with Met/Met genotype, with a trend towards significance (95% CI: 1.0–2.37, p = 0.051). For the BDNF-C270T polymorphism, smokers with T allele showed a 1.71 times increased risk of smoking compared to those without T alleles (95%: 0.51–5.76, p = 0.37). But this was not statistically significant (p N 0.05). The present study supports that genetic differences in BDNF exist between schizophrenia patients who smoke and those who do not. Our data show that men with Val allele in the BDNF gene have an increased risk for smoking in the Han Chinese population with schizophrenia. The results suggest that the Val66Met polymorphism in the BDNF gene increases smoking risk in patients with schizophrenia. However, due to the limited sample size in both the smoker and non-smoker groups and the low statistical power, our results need to be replicated in a large group of patients from different ethnic populations. In addition, the absence of healthy control groups is a major limitation of the study. Acknowledgments This study was funded by the Stanley Medical Institute Foundation (03T-459, 05T-726) (XYZ), the National Basic Research Program of China (973 Program; 2007BC512307), the Department of Veterans Affairs, VISN 16, Mental Illness Research, Education and Clinical Center (MIRECC) and the National Institute on Drug Abuse K05-DA0454 and P50-DA18827 (TRK).
References Beuten, J., Ma, J.Z., Payne, T.J., Dupont, R.T., Quezada, P., Huang, W., Crews, K.M., Li, M.D., 2005. Significant association of BDNF haplotypes in European–American male smokers but not in European–American female or African–American smokers. Am. J. Med. Genet., B Neuropsychiatr. Genet. 139, 73–80. Guillin, O., Diaz, J., Carroll, P., Griffon, N., Schwartz, J.C., Sokoloff, P., 2001. BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. Nature 411, 86–89. Guillin, O., Demily, C., Thibaut, F., 2007. Brain-derived neurotrophic factor in schizophrenia and its relation with dopamine. Int. Rev. Neurobiol. 78, 377–395. Kenny, P.J., File, S.E., Rattray, M., 2000. Acute nicotine decreases, and chronic nicotine increases the expression of brain-derived neurotrophic factor mRNA in rat hippocampus. Brain Res. Mol. Brain Res. 85, 234–238. Kunugi, H., Ueki, A., Otsuka, M., Isse, K., Hirasawa, H., Kato, N., Nabika, T., Kobayashi, S., Nanko, S., 2001. A novel polymorphism of the brain-derived neurotrophic factor (BDNF) gene associated with late-onset Alzheimer's disease. Mol. Psychiatry 6, 83–86. Lang, U.E., Sander, T., Lohoff, F.W., Hellweg, R., Bajbouj, M., Winterer, G., Gallinat, J., 2007. Association of the met66 allele of brain-derived neurotrophic factor (BDNF) with smoking. Psychopharmacology 190, 433–439. Li, M.D., Ma, J.Z., Cheng, R., Dupont, R.T., Williams, N.J., Crews, K.M., Payne, T.J., Elston, R.C., 2003. A genome-wide scan to identify loci for smoking rate in the Framingham Heart Study population. BMC Genet. 4 (Suppl 1), S103. LLerena, A., de la Rubia, A., Penas-Lledo, E.M., Diaz, F.J., de Leon, J., 2003. Schizophrenia and tobacco smoking in a Spanish psychiatric hospital. Schizophr. Res. 60, 313–317. Neves-Pereira, M., Mundo, E., Muglia, P., King, N., Macciardi, F., Kennedy, J.L., 2002. The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a familybased association study. Am. J. Hum. Genet. 71, 651–655. Pontieri, F.E., Tanda, G., Orzi, F., Di Chiara, G., 1996. Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382, 255–257.
Zhi Ren Wang Dong Feng Zhou Institute of Mental Health, Peking University, Beijing, 100083, PR China E-mail address: [email protected] (D.F. Zhou). Lian Yuan Cao Yun Long Tan Xiang Yang Zhang Center for Biological Psychiatry, Beijing HuiLongGuan Hospital, Beijing 100096, PR China Tel.: +1 7137911414x5824; fax: +1 713 794 7938. E-mail address: [email protected] (X.Y. Zhang).
Letter to the Editors
Jun Li College of Pharmacology, Anhui Medical University, Hefei, Anhui Province 230032, PR China Lin Lu National Institute on Drug Dependence, Peking University, Beijing 100083, PR China
301
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 22 May 2007