Pharacogenetic effects of dopamine transporter gene polymorphisms on response to chlorpromazine and clozapine and on extrapyramidal syndrome in schizophrenia.
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.
Xu
Mingqing
M
Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders Ministry of Education, Shanghai Jiao Tong University, Shanghai 200030, PR China.
Xing
Qinghe
Q
Li
Sheng
S
Zheng
Yonglan
Y
Wu
Shengnan
S
Gao
Rui
R
Yu
Lan
L
Guo
Tingwei
T
Yang
Yifeng
Y
Liu
Jixia
J
Zhang
Aiping
A
Zhao
Xinzhi
X
He
Guang
G
Zhou
Jian
J
Wang
Lei
L
Xuan
Jiekun
J
Du
Jing
J
Li
Xingwang
X
Feng
Guoyin
G
Lin
Zhiguang
Z
Xu
Yifeng
Y
St Clair
David
D
Lin
Zhicheng
Z
He
Lin
L
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
D014150:Antipsychotic Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D003024:Clozapine; D002746:Chlorpromazine