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 journalArticle

28 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

Fingerprint

Dopamine Plasma Membrane Transport Proteins
Clozapine
Chlorpromazine
Minisatellite Repeats
Haplotypes
Schizophrenia
Nucleic Acid Regulatory Sequences
Introns
Genes
Alleles
Genotype
Gene Frequency
Antipsychotic Agents
Pharmaceutical Preparations
Population
Therapeutics

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

Cite this

Pharacogenetic effects of dopamine transporter gene polymorphisms on response to chlorpromazine and clozapine and on extrapyramidal syndrome in schizophrenia. / Xu, Mingqing; Xing, Qinghe; Li, Sheng; Zheng, Yonglan; Wu, Shengnan; Gao, Rui; Yu, Lan; Guo, Tingwei; Yang, Yifeng; Liu, Jixia; Zhang, Aiping; Zhao, Xinzhi; He, Guang; Zhou, Jian; Wang, Lei; Xuan, Jiekun; Du, Jing; Li, Xingwang; Feng, Guoyin; Lin, Zhiguang; Xu, Yifeng; St Clair, David M.; Lin, Zhicheng; He, Lin.

In: Progress in Neuro -Psychopharmacology & Biological Psychiatry, Vol. 34, No. 6, 16.08.2010, p. 1026-1032.

Research output: Contribution to journalArticle

Xu, M, Xing, Q, Li, S, Zheng, Y, Wu, S, Gao, R, Yu, L, Guo, T, Yang, Y, Liu, J, Zhang, A, Zhao, X, He, G, Zhou, J, Wang, L, Xuan, J, Du, J, Li, X, Feng, G, Lin, Z, Xu, Y, St Clair, DM, Lin, Z & He, L 2010, 'Pharacogenetic effects of dopamine transporter gene polymorphisms on response to chlorpromazine and clozapine and on extrapyramidal syndrome in schizophrenia', Progress in Neuro -Psychopharmacology & Biological Psychiatry, vol. 34, no. 6, pp. 1026-1032. https://doi.org/10.1016/j.pnpbp.2010.05.017
Xu, Mingqing ; Xing, Qinghe ; Li, Sheng ; Zheng, Yonglan ; Wu, Shengnan ; Gao, Rui ; Yu, Lan ; Guo, Tingwei ; Yang, Yifeng ; Liu, Jixia ; Zhang, Aiping ; Zhao, Xinzhi ; He, Guang ; Zhou, Jian ; Wang, Lei ; Xuan, Jiekun ; Du, Jing ; Li, Xingwang ; Feng, Guoyin ; Lin, Zhiguang ; Xu, Yifeng ; St Clair, David M. ; Lin, Zhicheng ; He, Lin. / Pharacogenetic effects of dopamine transporter gene polymorphisms on response to chlorpromazine and clozapine and on extrapyramidal syndrome in schizophrenia. In: Progress in Neuro -Psychopharmacology & Biological Psychiatry. 2010 ; Vol. 34, No. 6. pp. 1026-1032.
@article{6f342788db8a4912881c6c0cd27c0a0a,
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.",
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",
author = "Mingqing Xu and Qinghe Xing and Sheng Li and Yonglan Zheng and Shengnan Wu and Rui Gao and Lan Yu and Tingwei Guo and Yifeng Yang and Jixia Liu and Aiping Zhang and Xinzhi Zhao and Guang He and Jian Zhou and Lei Wang and Jiekun Xuan and Jing Du and Xingwang Li and Guoyin Feng and Zhiguang Lin and Yifeng Xu and {St Clair}, {David M.} and Zhicheng Lin and Lin He",
note = "Copyright (c) 2010. Published by Elsevier Inc.",
year = "2010",
month = "8",
day = "16",
doi = "10.1016/j.pnpbp.2010.05.017",
language = "English",
volume = "34",
pages = "1026--1032",
journal = "Progress in Neuro -Psychopharmacology & Biological Psychiatry",
issn = "0278-5846",
publisher = "Elsevier Inc.",
number = "6",

}

TY - JOUR

T1 - Pharacogenetic effects of dopamine transporter gene polymorphisms on response to chlorpromazine and clozapine and on extrapyramidal syndrome in schizophrenia

AU - Xu, Mingqing

AU - Xing, Qinghe

AU - Li, Sheng

AU - Zheng, Yonglan

AU - Wu, Shengnan

AU - Gao, Rui

AU - Yu, Lan

AU - Guo, Tingwei

AU - Yang, Yifeng

AU - Liu, Jixia

AU - Zhang, Aiping

AU - Zhao, Xinzhi

AU - He, Guang

AU - Zhou, Jian

AU - Wang, Lei

AU - Xuan, Jiekun

AU - Du, Jing

AU - Li, Xingwang

AU - Feng, Guoyin

AU - Lin, Zhiguang

AU - Xu, Yifeng

AU - St Clair, David M.

AU - Lin, Zhicheng

AU - He, Lin

N1 - Copyright (c) 2010. Published by Elsevier Inc.

PY - 2010/8/16

Y1 - 2010/8/16

N2 - 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.

AB - 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.

KW - adult

KW - antipsychotic agents

KW - basal ganglia diseases

KW - chlorpromazine

KW - clozapine

KW - dopamine plasma membrane transport proteins

KW - female

KW - gene frequency

KW - genetic association studies

KW - genetic predisposition to disease

KW - genotype

KW - haplotypes

KW - humans

KW - male

KW - middle aged

KW - pharmacogenetics

KW - polymerase chain reaction

KW - polymorphism, single nucleotide

KW - schizophrenia

KW - treatment outcome

U2 - 10.1016/j.pnpbp.2010.05.017

DO - 10.1016/j.pnpbp.2010.05.017

M3 - Article

C2 - 20580759

VL - 34

SP - 1026

EP - 1032

JO - Progress in Neuro -Psychopharmacology & Biological Psychiatry

JF - Progress in Neuro -Psychopharmacology & Biological Psychiatry

SN - 0278-5846

IS - 6

ER -