Characterization of the glutathioneS-transferaseGSTT1deletion: discrimination of all genotypes by polymerase chain reaction indicates a trimodular genotype–phenotype correlation
作者:
Raimund Sprenger,
Robert Schlagenhaufer,
Reinhold Kerb,
Claudia Bruhn,
Jürgen Brockmöller,
Ivar Roots,
Ulrich Brinkmann,
期刊:
Pharmacogenetics
(OVID Available online 2000)
卷期:
Volume 10,
issue 6
页码: 557-565
ISSN:0960-314X
年代: 2000
出版商: OVID
关键词: cancer;pharmacogenetics;ultraviolet-sensitivity;recombination;polymorphism
数据来源: OVID
摘要:
GlutathioneS-transferase theta enzyme activity involved in the metabolism of toxic compounds is absent in approximately 20% of Caucasians due to a homozygous deletion ofGSTT1(*0/0). Because the exact manner of theGSTT1deletion was unknown, current genotyping ofGSTT1was limited to detect the presence versus complete absence of the gene by aGSTT1-specific polymerase chain reaction (PCR). Thus, heterozygous (*A/0) and homozygous (*A/A) samples could not be discriminated. We have characterized the boundaries of the deletion of the human glutathioneS-transferase theta (GSTT1) gene: PCR mapping and sequencing revealed a 54251 bp fragment includingGSTT1to be deleted from chromosome 22, most likely by a homologous recombination event between two highly homologous sequence stretches that flankGSTT1. Based on the knowledge of theGSTT1*0region, a PCR assay was devised for unambiguous discrimination of homozygously deleted (*0/0), heterozygously (*A/0) and homozygouslyGSTT1carrying (*A/A) individuals. Genotyping of 180 samples of a Caucasian population revealed that the deletion consists of one defined allele, whose distribution in the population fits the Hardy–Weinberg equilibrium with observed 20%*0/0, 46%*A/0and 34%*A/Aindividuals. The number ofGSTT1*Aalleles detected by this procedure correlated highly significant with the enzyme activity in erythrocytes. Genotype–phenotype comparisons demonstrated a codominant type of inheritance by a gene–dose effect: samples with two active alleles expressed a statistically significant higher enzymatic activity compared to those with one null allele (P< 0.0001, ANOVA).
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