J. Biomedical Science and Engineering, 2011, 4, 180-186 JBiSE
doi:10.4236/jbise.2011.43025 Published Online March 2011 (http://www.SciRP.org/journal/jbise/).
Published Online March 2011 in SciRes. http://www.scirp.org/jour nal/JBiSE
Frequency of GSTT1*0 genotype as a non-conjugator
phenotype in a group of healthy Iranian people
Monireh Aghajany-Nasab1, Siamak Mirab Samiee2,4, Mojtaba Panjehpour1,5, Aliakbar Malekirad3,
Ahmad Movahedian-Attar1
1Department of Clinical Biochemistry, Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical
Sciences, Isfahan University of Medical Sciences, Isfahan, Iran;
2Food and Drug Laboratory Research Center, Ministry of Health and Medical Education, Tehran, Iran;
3Payame Noor University (P.N.U), Tehran, Iran;
4Day General Hospital Laboratory, Tehran, Iran;
5Bioinformatics Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
Email: movahedian@pharm.mui.ac.ir
Received 17 December 2010; revised 25 January 2011; accepted 29 January 2011.
Glutathione S-transferases (GSTs) are dimeric mainly
cytosolic enzymes involved in detoxification of many
exogenous and endogenous disease-causing electro-
philic substrates. GSTs also have critical role in phase
II biotransformation of a number of drugs, xenobiot-
ics and industrial chemicals and protect cellular
macromolecules. The evidences supported that hu-
man GSTT1 contributes in the deactivation of reac-
tive oxygen species which more likely to be effective
in inflammatory diseases, ageing and some non-can-
cer diseases also different types of cancers. The
GSTT1 is genetically deleted in a high percentage of
the different ethnic groups. Although this gene is
highly conserved during evolution, it is indeed sur-
prising that the GSTT1 deleted gene could be found
in high incidence of human population. Conjugator
and non-conjugator phenotypes are coincident with
this deletion (GSTT1*1 and GSTT1*0 genotype).The
consequences of this deletion could be involved in
some diseases outcome, toxicology and drug resis-
tances. In this study the Real-time PCR assay and a
set of hybridization probes was used as a one-step
and accurate method to estimate the frequency of
GSTT1*0 genotype as a non-functional phenotype in
90 healthy individuals from the province of Isfahan
in Iran. GSTT1 genotypes were identified in DNA
samples using fluorogenic Real-Time PCR (LightCy-
cler) followed by online melting curve analysis. The
incidence of GSTT1*1(wild type) and GSTT1*0(Null
type) were 74.5% and 25.5% respectively. No differ-
ences in genotypes frequencies were perceived in
samples stratified by age and gender P > 0.05. The
results were compared with other ethnic groups to
get more insight into the frequency differences of
defected carcinogens metabolizer gene due to deletion
polymorphism of GSTT1. It has been indicated the
incidence of GSTT1*0 in this group of Iran showed
significant differences with East Asian and some
European and American countries P < 0.05.The
prevalence of GSTT1 null genotype in the study group
from Isfahan province of Iran was slightly higher in
comparison with other Iranian ethnic group (Iranian
Georgian 15.7%), but this difference was not signifi-
cant (χ2 = 1.66, P = 0.197). Further experimental in-
vestigations are needed to inquiry the clinical impli-
cations of GSTT1 genetic polymorphism with con-
sider to significant variability among different eth-
Keywords: GSTT1 Genotyping, Genetic Polymorphism,
Real-Time PCR, Ethnic Differences, Iran
Glutathione S-transferase T1 detoxifies the genotoxic
compounds containing an electrophilic center and pro-
tects from DNA damage. GSTT protects cells by cata-
lyzing the conjugation of toxic and carcinogenic elec-
trophilic molecules with glutathione that are excreted
through kidney [1]. It is hypothesized that reduced GSTs
activity is associated with higher incidence of cancer that
seems a results of decreased elimination of electrophilic
carcinogens [2] Inter-individual differences in the capac-
ity of detoxifying toxins, cancer susceptibility, and drug
resistance maybe mediated in part through polymorphic
variability in the bioactivation and detoxification of oc-
cupational carcinogens, environmental pollutants [3].
Several studies have found GSTs consistency in cancer
susceptibility genes [4-6] and few studies report the rela-
M. Aahajany-Nasab et al. / J. Biomedical Science and Engineering 4 (2011) 180-186
Copyright © 2011 SciRes. JBiSE
tion of toxicity of chemotherapeutic agents with GSTs
inactive genotype [7]. Other studies have shown that
GST theta null genotypes individuals are more suscepti-
ble to the mutagenic effects of some GSTT1 substrates
The human theta subfamily of GSTs consists of two
different genes, GSTT1 and GSTT2, both of them lo-
cated on chromosome 22q11.2, consisting of 5 exons.
GSTT1 has a functional allele GSTT1*1 and a null allele,
GSTT1*0. GSTT1*0 is formed by homologous recom-
bination which result in 54 kb deletion comprising the
complete GSTT1 gene so it has an impaired ability to
metabolically eliminate carcinogenic compounds. It has
been reported that GSTT1*1 presents conjugator pheno-
type while GSTT1*0 has non-conjugator phenotypes [9].
The gene and associated proteins were found in a defi-
nite percentage of the human population with different
The GSTT1*0 genotype has been found to elevate
baseline level of sister chromatid exchange (SCE) fre-
quently after exposure to 1, 3-butadiene and haloalkanes.
It has been found SCE, in turn, has strong positive cor-
relation with cancer risk [10].
Polymorphism interaction analysis (PIA) indicated
that GSTT1 is a polymorphism predicting cancer [9].
Among known substrates metabolized by GST theta,
dichloromethane (DCM) is one of the most thoroughly
studied [11]. Erythrocytes from some subjects (“conju-
gators”) catalyze the conjugation of DCM with GSH,
whereas the remaining individuals (“non-conjugators”)
do not. Formaldehyde obtained from metabolism of
DCM covalently binds to cellular macromolecules like
single-stranded DNA, serum albumin, or the N-terminal
valine of hemoglobin and form molecular adducts [12].
Formaldehyde-adducted RNAs were found in DCM-
exposed isolated hepatocytes GSTT1*1 (positive) hu-
man but not in hepatocytes from GSTT1*0(negative)
donors [13].
1,3-Butadiene, ethylene, drinking water after chlori-
nation, and metabolites of aflatoxin are other substrates
for GSTT1 and genetic polymorphism in metabolism of
these compounds modifies the risk of encephalopathy in
human [14,15].
Styrene as carcinogen that is used worldwide in the
production of different polymers is also metabolized by
GSTT1 enzymatic activity causing DNA and hemoglo-
bin adducts [16]. In vivo studies are required to differen-
tiate the genotype of GSTT1 positive and null forms to
determine the enzymatic activity of GSTT1 whether it
acts as conjugator(GSTT1*1)or nonconjugator enzyme
In the present work, we analyzed the frequency of
GSTT1*0 as an inactive gene product in a group of Ira-
nian from Isfahan province using Real-time PCR. To get
more insight into the frequency differences of defected
carcinogens metaboliser gene due to deletion polymor-
phism of GSTT1 in this study group, results have com-
pared with other ethnic groups.
The participants in this study were from Isfahan prov-
ince, center of Iran. Ninety healthy volunteers of both
sex (41 male and 49 female) .The mean age (SD; Min-
Max) of the individuals was 51.8 years (51.8; 22-76).
After signing the informed consent, the structured ques-
tionnaire, establishing demographic information and
history of cancer in their first–degree relatives, was
completed in an interview for each individual to docu-
ment his or her personal and health history.
The study was approved and conducted by Institu-
tional Review Board of Isfahan Pharmaceutical Sciences
Research Center, Isfahan University of Medical Sciences,
Genomic DNA was collected from blood of each sub-
ject. DNA was extracted from lymphocytes using a Pure-
gene DNA purification kit (Gentra Puregen, Germany).
For genotyping, the thermocycler LightCycler (Roche,
Mannheim, Germany) was used and hybridization probes
were applied in combination with a LightCycler Fast
start DNA Master Plus hybprobes kit (Roche, Mannheim,
Germany). The PCR primers and probes were synthe-
sized by TIB MOLBIOL (Berlin, Germany) according to
Ko et al. method [17].
After optimization of the primers and probes concen-
tration and temperature profiling, the final PCR condi-
tions were optimized as follows: 0.2 μM of each hybridi-
zation probe, 1μM of each primer, 2 μL of the LightCy-
cler Fast Start DNA Master Plus Hybridization Mix, and
10-50 ng of genomic DNA in a final volume of 10 μL.
The primers and probes sequence are shown in Table 1.
The temperature profiling of PCR was started with 10
min Pre-incubation time at 95˚C, Initial denaturation for
Table 1. Real-time PCR primers, Hybridization probes.
Reagents Per sample
Forward Primer
Reverse Primer
FC probe
5´-CCgTgggTgCTggCTgCCAAgT-FC-3´ 0.2 µM
LCR640 probe
5´-LCR640TCgAAggCCgACCCAAgCTggC-PH-3´ 0.2 µM
LightCycler Fast Start DNA Master Plus Hybridization
Mix 2 µL
Genomic DNA 50 ng
M. Aghajany-Nasab et al. / J. Biomedical Science and Engineering 4 (2011) 180-186
Copyright © 2011 SciRes. JBiSE
nealing at 50˚C and followed 20 Sec. by extension at
72˚C. Differentiation of GSTT1 genotype was performed
10 Sec. at 95˚C. Then 45 cycles amplification were per-
formed with single acquisition followed by 15 Sec. an-
-by determination of melting curves after PCR. Melting
curves were obtained an annealing period of 40˚C and a
final temperature of 85˚C with a temperature gradient
0.2/Sec followed by cooling cycle 40˚C for 30 Sec.
Hybridization probes (Hybprobes) consisted of two
different short labeled oligonucleotides that bind to an
internal sequence of the amplified fragment. The donor
dye probe has a fluorescein label at the 3´-end and the
acceptor dye probe has a LightCycler Red label (Light-
Cycler Red 640) at its 5´-end.During the annealing phase,
the probes are hybridized to the amplified DNA frag-
ment, thereby bringing the two fluorescence dyes into
close proximity.
Fluorescein is excited by the light source of the Light
Cycler system, which causes to emit green fluorescence
light. The emitted energy excites LightCycler red fluo-
rescence resonance energy transfer (FRET).The red
fluorescence is measured at the end of each annealing
step, when the fluorescence intensity is greatest [18].
Intra-assay (the amount of the error seen with the
same assay in each run) and inter-assay (the error between
separate assays) were performed.
Statistical significance of differences between age,
gender and GSTT1 genotypes was calculated by the
chi-squared or Fisher exact tests. The chi-squared test
was performed to investigate differences between the
frequencies of the null genotypes in the specified ar-
eas .The probability P < 0.05 was considered statistically
significant. All the P-values were two-tailed. Analyses
were performed using the statistical package SPSS for
windows, version 12 (SAS Institute, NC, USA)
Sufficient quantities of DNA were obtained from all
specimens. A total of 90 individuals were genotyped for
GSTT1 by use of Real-time PCR. Table 2 shows the
percentage of GSTT1 variants by age and gender.
The frequency of GSTT1*1 was 77.4% in the indi-
viduals older than 60 years and 72.8% in the younger
ones (age less than 60 years). GSTT1*0 was 27.1% in
the group of below 60 years versus 22.6% in subjects
above 60 years. No differences in genotype frequency
were perceived in samples stratified by age (p-value =
0.8). In Table 2 also frequency by gender is shown. To-
tally 73.5% of females showed GSTT1*1 genotype and
26.5% null genotype. The frequency of GSTT1 null
genotype in male group was 24.4% and GSTT1*1was
75.6%. No significant difference between gender was
seen with GSTT1 genotype (p-value = 1).
Table 2. Frequency of GSTT1 genotypes by age and gender.
Features Number (%)GSTT1*1 GSTT1*0
N (%) N (%)
60 59 (65.5%) 43/59 (72.8%) 16/59 (27.2%)
> 60 31 (34.4%) 24/31 (77.4%) 7/31 (22.6%)
p-value 0.8
Female 49 (54.4) 36/49 (73.5%) 13/49 (26.5%)
Male 41 (45.6) 31/41 (75.6) 10/41 (24.4%)
p-value 1
The differences of GSTT1*0 genotype frequency
were marginally significant in comparision with some
East Asian countries (China χ2 = 19.16, df = 1, P < 0.05,
Shanghai χ2 = 14.22, df = 1, P < 0.05, Korea χ2 = 18.40,
df = 1, P < 0.05, Japan χ2 = 18.53, df = 1, P < 0.05).
The result of our study are shown significant differ-
ences with Caucasian χ2 = 5.23, P < 0.05 and Mexi-
can-Americans χ2 = 5.6.84, P < 0.05).
Since the occurrence of the GSTT1 polymorphism
seems to be strongly dependent on ethnic origin, we in-
vestigated the frequency of the GSTT1 genotypes in our
study group for comparing with the other groups as well
as with other countries population. In our study the
prevalence of GSTT1*0 was 25.5% .This result was
slightly higher than Turkish, Mexican-Americans and
Caucasians but lower than Chinese, Korean and Japa-
nese (Table 3). The reported frequency for other Iranian
groups also presented significant differences between
Iranian populations [19]. Iran is a big country with an
estimated 70.5 million people that they are ethnically
diverse. At least 8 different ethnic groups live in Iran.
Our study group selected from Persian Muslims who
living in Isfahan province. Isfahan is third largest city in
Iran with more than 1.500.000 populations. It should be
considered that many people have immigrated from
other cities with different ethnicity to Isfahan specially
from the Iranian-Iraqi border province (Khuzestan) in
southwest of Iran since Iran-Iraq war (1981-1989). They
had different ethnicity “Iranian Arab” and this people
have still stayed there. It means the study group could be
heterogeneous thus may be different from other Persian
population in Iran. It should be noted despite of different
frequencies in present study from other Iranian ethnic
groups which was reported by Rafiee in 2010 [19] there
M. Aahajany-Nasab et al. / J. Biomedical Science and Engineering 4 (2011) 180-186
Copyright © 2011 SciRes. JBiSE
were no statistically significant differences (Iranian Geor-
gian, χ2 = 1.66, df = 1, p = 0.197 and Iranian Persian, χ2
= 3.34, df = 1, p = 0.068).
According to result of worldwide studies in different
ethnic groups (Table 3) it is completely obvious that
there is a wide range differences between populations.
The frequency of the null genotype is highest among
Chinese (64.4%) followed by Koreans and Japanese [20].
GSTT1*0 is much more frequent (64%-54%) in this area
populations [21] comparing with the others. Germans
[17] and Caucasians [22] and New England [23] have
shown less frequency (12-18%) and the prevalence was
low among Mexican-American [24]. However, some
gradient and intra ethnic differences are reported as well,
such as Shanghai [21], Turkey [21], Korea [25-27] and
Iran [19]. The chi-squared and p-values have been
shown in Table 3. GSTT1*0 genotype showed a distri-
bution profile regarding to geographical area. It is more
likely the pattern of deletion polymorphism of GSTT1
shows a geographical distribution from East Asian coun-
tries to middle Asia followed by European countries to
According to our result in comparison with other stud-
ies, Iranians showed the middle frequency for this null
genotype. As it has shown in Table 3 our study group
significantly (P < 0.05) differs from East Asian countries
and Caucasians, Mexican Americans and Turkish.
Following the identification of the deletion in GSTT1
gene deletion underlying the impaired capacity for de-
toxification of environmental pollutant and carcinogens,
it was reported that a wide range differences present in
different population.
The prospect of screening in the gene level for pre-
vention, prediction or early diagnosis of some diseases
especially cancer is becoming real. A vast number of
studies are focused on this aim, to investigate whether
genetic variation between populations contributes to dif-
ferent capacity for detoxifying carcinogens and conse-
quently susceptibility to cancers as well as relapse [28,29].
Moving toward individualized drug treatment as a
new and very interesting approach attracts so many at-
tention to defining the polymorphic genes coding for
drug metabolizing enzyme and prediction of anticancer
drug [30-32].
Table 3. Frequency GSTT1 genotypes in the present study, in comparison to those in other studies in worldwide populations.
Group Population Reference Number %GSTT1*0%GSTT1*1Chi square df = 1 P value
East Asian
1 Chinese 36 45 64.4 35.6 19.16 P < 0.05
2 Shanghai 14 219 49 51 14.22 P < 0.05
3 Koreans1 28 177 53.1 46.9 18.40 P < 0.05
4 Koreans2 30 1037 54.3 45.7 27.39 P < 0.05
5 Koreans3 29 273 55.1 44.9 23.43 P < 0.05
6 Japanese 26 150 54 46 18.53 P < 0.05
European and
7 Caucasians 31 213 14.7 85.3 5.22 P < 0.05
8 Germans 17 90 17 83 2.13 P = 0.144
9 New England 32 185 15.7 84.3 3.85 P = 0.05
10 Mexican-Americans 27 73 10 90 6.84 P < 0.05
11 Brazilians 34,35 594 23.1 76.9 0.31 P = 0.57
Middle East Asian
12 Turkish 33 128 7 93 14.48 P < 0.05
13 IraniansGeorgian 25 34 15.7 84.3 1.66 P = 0.197
14 Iranians Persian 25 249 35.5 64.5 3.34 P = 0.068
15 Iranians Shiraz 25 121 24.8 75.2 0.016 P = 0.90
16 Iranians Present study90 25.5 74.5
M. Aghajany-Nasab et al. / J. Biomedical Science and Engineering 4 (2011) 180-186
Copyright © 2011 SciRes. JBiSE
GSTT1*0 genotype is one of the well known poly-
morphism of this enzyme which represent a defect phe-
notype to metabolize and biotransformation process. The
relationship between GSTs genes polymorphism and
diseases has been investigated in so many publications
since 1990. Regarding to the role of GSTs in detoxifica-
tion of carcinogens the common question was: Is there
any association between different polymorphism in
GSTs gene polymorphism and risk of specific cancers?
A PubMed search using the “GSTT1 cancer risk” re-
trieved 767 references, “GSTT1 null genotype cancer
risk” retrieved 478 Articles (January 2011). Some of the
HuGE review articles and Meta analysis specified in
GST gene polymorphism and cancer risk.
Raimondi and colleagues (2006) performed a Meta
and pooled analysis of GSTT1 and lung cancer they
failed to show association between GSTT1 null geno-
type and lung cancer in Caucasians but in Asian the as-
sociation has been showed [33]. Liao et al (2010)
achieved that there was a small increased risk of colo-
rectal cancer for individuals with GSTT1 null, especially
for Caucasians populations and Asian populations [34].
In 2010 Wan and colleague demonstrated that GSTT1
null genotype is associated with an increased risk of co-
lorectal cancer, specifically, among Caucasians [35]. The
GSTT1 null genotype was found to be associated with
increased risks of tumors of the stomach [36,37], bladder
[38,39]. The results of Ha YS et al study at 2010 sug-
gested that the GSTT1 genotype could be a useful prog-
nostic marker for recurrence and progression in non-
muscle-invasive bladder cancer [40].
Hence GSTT1*0, is a potential genetic risk marker for
different diseases it seems necessary to use a rapid and
accurate technique for analyzing the GSTT1 genotypes.
The Real-time PCR that we used in this study which is
followed by fluorescence monitoring of dissociation
hybridization probes from DNA amplicon, provide a
sensitive, quick, safe and one step method for using in
clinical screening.
More of the studies for genotyping the GSTT1 gene
used conventional PCR and gel electrophoresis based
documentation methods but in this study the LightCycler
system was used. Unlike conventional PCR, in which
cycling takes several hours, PCR analysis conducted
with the LightCycler took around 1 hour. In contrast to
previous assays that used in majority of studies which
depended on the analysis of Ethidium bromide-stained
gels (with consideration of toxicity), no additional time
consuming procedure (e.g., casting agarose gel, staining,
or southern blotting analyses) were required to analyze
the PCR product by use of LightCycler. In this study the
amplified products were identified by the online melting
peak analysis, allowing more reliable distinction be-
tween genotypes. Direct, uncomplicated analysis of the
results also reduced the number of handling steps, thus
minimizing the risk of sample contamination.
Although we used a set of HybProbe that is relatively
expensive but rapid and one-step method provide a
time-effective also cost-effective method for genotyping
a large number of samples without any handling of
Ethidium bromide as a toxic material. It possible to ana-
lyze and document several samples simultaneously in
each runs of LightCycler around one hour.
The frequency of GSTT1*0 in the group of Iran is
different from some Asian countries. In base of wide
spectrum of frequency differences for GSTT1 genotypes
that have been already documented, it seems to be nec-
essary to use a rapid and reliable method for GSTT1
genotyping in each single toxicology, epidemiology and
clinical case-control studies. This study can be expanded
by: increasing the sample size, investigation of modifiers
like age and gender, designing the case-control studies
and similar studies in other functional genes mutation.
Special thanks to management of Day General Hospital Laboratory
and its Molecular Diagnosis Department, especially Dr. Farzaneh Ra-
himi and Mr. Ramin Naghizadeh for their invaluable support. Authors
are also thankful of Professor Mohammad Abdollahi from Faculty of
Pharmacy in Tehran University of Medical Sciences for editing the
manuscript. We also thank TIB MOLBIOL, Berlin, for the construction
of the primers and LightCycler Hybridization Probes and technical
suggestions. This work was supported by the Research Council of the
Isfahan University of Medical Sciences, Isfahan, Iran.
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