title: Pharacogenetic effects of dopamine transporter gene polymorphisms on response to chlorpromazine and clozapine and on extrapyramidal syndrome in schizophrenia.
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.
authors.affiliation: Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders Ministry of Education, Shanghai Jiao Tong University, Shanghai 200030, PR China.
authors.forename: Mingqing
authors.initials: M
authors.lastname: Xu
authors.forename: Qinghe
authors.initials: Q
authors.lastname: Xing
authors.forename: Sheng
authors.initials: S
authors.lastname: Li
authors.forename: Yonglan
authors.initials: Y
authors.lastname: Zheng
authors.forename: Shengnan
authors.initials: S
authors.lastname: Wu
authors.forename: Rui
authors.initials: R
authors.lastname: Gao
authors.forename: Lan
authors.initials: L
authors.lastname: Yu
authors.forename: Tingwei
authors.initials: T
authors.lastname: Guo
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Yang
authors.forename: Jixia
authors.initials: J
authors.lastname: Liu
authors.forename: Aiping
authors.initials: A
authors.lastname: Zhang
authors.forename: Xinzhi
authors.initials: X
authors.lastname: Zhao
authors.forename: Guang
authors.initials: G
authors.lastname: He
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Jiekun
authors.initials: J
authors.lastname: Xuan
authors.forename: Jing
authors.initials: J
authors.lastname: Du
authors.forename: Xingwang
authors.initials: X
authors.lastname: Li
authors.forename: Guoyin
authors.initials: G
authors.lastname: Feng
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Lin
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Xu
authors.forename: David
authors.initials: D
authors.lastname: St Clair
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Lin
authors.forename: Lin
authors.initials: L
authors.lastname: He
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000627:therapeutic use; D001480:Basal Ganglia Diseases / Q000139:chemically induced / Q000235:genetics*; D002746:Chlorpromazine / Q000009:adverse effects / Q000627:therapeutic use*; D003024:Clozapine / Q000627:therapeutic use*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D003024:Clozapine; D002746:Chlorpromazine