Pharacogenetic effects of dopamine transporter gene polymorphisms on response to chlorpromazine and clozapine and on extrapyramidal syndrome in schizophrenia |
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Authors: | Mingqing Xu Qinghe Xing Sheng Li Yonglan Zheng Shengnan Wu Rui Gao Lan Yu Tingwei Guo Yifeng Yang Jixia Liu Aiping Zhang Xinzhi Zhao Guang He Jian Zhou Lei Wang Jiekun Xuan Jing Du Xingwang Li Guoyin Feng Zhiguang Lin Yifeng Xu David St Clair Zhicheng Lin Lin He |
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Institution: | 1. Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, PR China;2. Institute for Nutritional Sciences, Chinese Academy of Sciences, Shanghai 200031, PR China;3. School of Public Health, Harvard University, Boston, Massachusetts 02115, USA;4. Brigham and Women’s Hospital, School of Medicine, Harvard University, Boston, Massachusetts 02115, USA;5. Mailman Research Center, Massachusetts General hospital/Mclean Hospital, School of Medicine, Harvard University, Belmont, Massachusetts 02478, USA;6. Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, PR China;g Shanghai Institute of Mental Health, 600 South Wan Ping Road, Shanghai 200030, PR China;h Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen AB252ZD, UK |
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Abstract: | A number of studies have investigated the effectiveness of the dopamine transporter (SLC6A3) Gene as an antipsychotic target. However, the focus has mainly been on a 40-bp variable number of a tandem repeat (VNTR) in the 3′-region and results have been inconsistent. To fully evaluate SLC6A3 as a therapeutic antipshycotic target we investigated association of the gene with responses to chlorpromazine and clozapine and with chlorpromazine-induced extrapyramidal syndrome (EPS) in the Chinese schizophrenia population. Six polymorphisms across the whole region of this gene were analyzed, namely rs2652511 (T-844C) and rs2975226 (T-71A) in the 5′-regulatory region, rs2963238 (A1491C) in intron 1, a 30-bp VNTR in intron 8, rs27072 and the 40-bp VNTR in the 3′-region. We found that the polymorphic marker, rs2975226, showed significant association of allele and genotype frequencies with response to clozapine (allele-wise: adjusted p = 0.00404; genotype-wise: adjusted p = 0.024), and that patients with the T allele had a better response to the drug. The haplotype block constructed from the first three markers near the 5′-region showed significant association with response to clozapine (for haplotype T-T-A: p = 0.0085; for haplotype C-A-C: p = 0.0092). We did not identify any significant association of the six genetic variants or haplotypes with EPS after Bonferoni correction. Our findings suggest that the 5′-regulatory region of SLC6A3 plays an important role in response to clozapine and that its role in EPS needs to be replicated in a large-scale well designed study. |
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Keywords: | Antipsychotics Association study Chlorpromazine Clozapine Dopamine transporter Extrapyramidal syndrome Genetic polymorphism Schizophrenia |
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