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Pharacogenetic effects of dopamine transporter gene polymorphisms on response to chlorpromazine and clozapine and on extrapyramidal syndrome in schizophrenia
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
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
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.
Keywords:Antipsychotics  Association study  Chlorpromazine  Clozapine  Dopamine transporter  Extrapyramidal syndrome  Genetic polymorphism  Schizophrenia
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