Pharacogenetic effects of dopamine transporter gene polymorphisms on response to chlorpromazine and clozapine and on extrapyramidal syndrome in schizophrenia

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 LinYifeng Xu, David M. St Clair, Zhicheng Lin, Lin He

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1026-1032
Number of pages7
JournalProgress in Neuro -Psychopharmacology & Biological Psychiatry
Volume34
Issue number6
Early online date24 May 2010
DOIs
Publication statusPublished - 16 Aug 2010

Keywords

  • adult
  • antipsychotic agents
  • basal ganglia diseases
  • chlorpromazine
  • clozapine
  • dopamine plasma membrane transport proteins
  • female
  • gene frequency
  • genetic association studies
  • genetic predisposition to disease
  • genotype
  • haplotypes
  • humans
  • male
  • middle aged
  • pharmacogenetics
  • polymerase chain reaction
  • polymorphism, single nucleotide
  • schizophrenia
  • treatment outcome

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