Distribution of allelic and genotypic frequencies of NAT2 and CYP2E1 variants in Moroccan population
Guaoua et al. BMC Genetics
Distribution of allelic and genotypic frequencies of NAT2 and CYP2E1 variants in Moroccan population
Soukaina Guaoua 0 3
Ilham Ratbi 0 3
Fatima Zahra Laarabi 2
Siham Chafai Elalaoui 0 2 3
Imane Cherkaoui Jaouad 0 2 3
Amina Barkat 1
Abdelaziz Sefiani 0 2 3
0 Centre de genomique humaine, Faculte de medecine et de pharmacie, Universite Mohammed V , Rabat , Morocco
1 Centre National de Reference en Neonatologie et en Nutrition , Rabat , Morocco
2 Departement de genetique medicale, Institut National d'Hygiene , Rabat , Morocco
3 Centre de genomique humaine, Faculte de medecine et de pharmacie, Universite Mohammed V , Rabat , Morocco
Background: Several pathogenesis and genetic factors influence predisposition to antituberculosis drug-induced hepatotoxicity (ATDH) especially for isoniazid (INH). However, the major susceptibility genes for ATDH are N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1). NAT2 gene determines the individual's acetylator status (fast, intermediate or slow) to metabolize drugs and xenobiotics, while CYP2E1 c1/c1 genotype carriers had an increased risk of ATDH. Polymorphisms of the NAT2 and CYP2E1 genes vary remarkably among the populations of different ethnic origins. The aim of this study was to determine, for the first time, the frequency of slow acetylators in Moroccan population by genotyping of NAT2 gene variants and determining the genotype c1/c1 for CYP2E1 gene, in order to predict adverse effects of Tuberculosis treatment, particularly hepatotoxicity. Results: The frequencies of specific NAT2 alleles were 53%, 25%, 2% and 4% for NAT2*5, NAT2*6, NAT2*7 and NAT2*14 respectively among 163 Moroccan studied group. Genotyping of CYP2E1 gene, by real-time polymerase chain reaction using TaqMan probes, revealed frequencies of 98.5% for c1/c1 and 1.5% for c1/c2 among 130 Moroccan studied group. Conclusion: The most prevalent genotypes of NAT2 gene in Moroccans are those which encode slow acetylation phenotype (72.39%), leading to a high risk of ATDH. Most Moroccans are homozygous for c1 allele of CYP2E1 gene which aggravates hepatotoxicity in slow acetylators. This genetic background should be taken into account in determining the minimum dose of INH needed to treat Moroccan TB patients, in order to decrease adverse effects.
Tuberculosis; CYP2E1 gene; NAT2 gene; Polymorphism; Acetylators; Adverse effects; Moroccans
Pharmacogenetics refers to genetic differences in
metabolic pathways which can affect individual responses to
drugs, both in terms of therapeutic effect as well as
adverse effects. Pharmacogenetics is generally regarded
as the study or clinical testing of genetic variation that
gives rise to differing responses to drugs. Its purpose is to
optimize the therapeutic decisions based on the genome
of the individual and the target molecule. Medicines are
developed and used together with pharmacodiagnosis
tools to achieve desired drug efficacy and safety.
Tuberculosis (TB) is an infectious disease caused by
the Mycobacterium tuberculosis. TB remains to date one
of the major public health problems in the world, with
8.6 million of incident cases, 12.0 million prevalent cases
and 1.3 million deaths in 2012 . In Morocco, 27,429
new cases of TB were reported in 2012, an incidence of
83 new cases per 100,000 inhabitants, according to the
epidemiological services of the Moroccan Ministry of
Health (Unpublished data).
The main drugs to treat TB are isoniazid (INH),
rifampicin (RMP) and pyrazinamide (PZA), ethambutol (EMB)
and/or streptomycin used in combination for 6 months or
more . Tuberculosis treatment cause adverse drug
reactions (ADRs), including hepatitis, gastrointestinal
intolerance, kidney failure, cutaneous and hematological
reactions, which can lead to therapy discontinuation or
more serious morbidity and mortality . Among
firstline anti-TB drugs, INH is the most effective but also
the one that can easily cause hepatotoxicity.
The incidence of anti-tuberculosis drug-induced
hepatotoxicity ranges from 1% to 36% [3-6]. Genetic factors
have been reported as a risk for hepatotoxicity [7-10].
These factors were attributed to genetic variability in
arylamine N-acetyltransferase2 (NAT2) gene, a cytosolic
phase II conjugation enzyme primarily responsible for
the deactivation of INH [7-11]. INH is metabolized to
acetylisoniazid via hepatic NAT2 . On the other
hand, acetylisoniazid is hydrolyzed to acetylhydrazine,
which is oxidized by cytochrome P450 2E1 (CYP2E1) to
form some hepatotoxic intermediates [13,14]. Disposal
of acetylhydrazine also depends on further acetylation by
NAT2 to form a non-toxic metabolite, diacetylhydrazine
NAT2 gene on 8p22 is a key human enzyme in drug
detoxification and elimination. Variants in NAT2 gene
affect the activity of anti-tuberculosis drugs and result in
three different phenotypes: rapid (RA), intermediate (IA)
and slow acetylators (SA). Most SNPs reported to date
are found within the 873 bp intronless coding region of
NAT2 gene. Among the seven most common SNPs, four
result in amino acid changes leading to a significant
decrease in acetylation capacity and are associated to slow
acetylator phenotype rs1801280 (c.341 T > C; NAT2*5),
rs1799930 (c.590G > A; NAT2*6), rs1799931 (c.857 G > A;
NAT2*7), and rs1801279 (c.191G > A; NAT2*14) [17,18].
The three others rs1041983 (c.282C > T; NAT2*13A),
rs1799929 (c.481C > T; NAT2*11A), rs1208 (c.803A > G;
NAT2*12A) are synonymous SNPs or do not alter the
phenotype [17,18]. They have been identified as fast alleles
NAT2*4 is considered as the reference allele in the
case of absence of all the known SNPs, and is designated
as a fast allele [19,20]. A heterozygous compound
genotype (NAT2*4/*14 or NAT2*4/*5 or NAT2*4/*6 or
NAT2*4/*7) is considered as intermediate acetylator.
The pharmacogenetic interest of these data lies in
adjusting the dose of isoniazid based on genotype and
phenotype found in the patient in order to prevent
In humans, the CYP2E1 enzyme is encoded by the
CYP2E1 gene on 10q24.3qter . Various
polymorphisms have been identified in the CYP2E1 gene, of
which the CYP2E1 RsaI/PstI polymorphism (rs2031920;
-1053 C > T (Rsa 1 c1 > c2)) in its 50-flanking region
may affect the activity or inductibility of the enzyme
Polymorphisms of the NAT2 and CYP2E1 genes vary
remarkably among the populations of different ethnic
origins. Acetylators phenotypes in Moroccan population
were previously reported to have a higher frequency of
phenotypic slow acetylators .
The aim of this study was to determine the
distribution of allelic and genotypic frequencies of NAT2 and
CYP2E1 variants in Moroccan controls in order to
estimate the prevalence of slow acetylators among Moroccans,
who are facing the risk to develop hepatotoxicity after TB
In this study we identified twelve different genotypes for
NAT2 gene. The most of them encode for the slow
acetylator phenotype. Genotypes of the four variants of
NAT2 gene and their corresponding phenotypic profiles
are presented in Table 1. With regard to phenotype, the
results show that 72.39% [95% CI 65.39-79.39] of the
studied group were SA, 21.48% [95% CI 15.04-27.91]
were IA and 6.13% [95% CI 2.38-9.88] were RA. For the
four variants NAT2*5, NAT2*6, NAT2*7 and NAT2*14 of
NAT2 gene, the allelic frequencies in the studied group
were 53% [95% CI 47-58], 25% [95% CI 20-29], 2% [95%
CI 1-3] and 4% [95% CI 2-6], respectively (Table 2).
NAT2 alleles frequencies of Moroccans compared with
other populations are shown in Table 2.
The allelic and genotypic distribution of the rs2031920
variant of CYP2E1 in the studied group is reported in
Table 3. The c2/c2 genotype was not found in the
studied group. It seems that the majority of Moroccans are
carriers of c1/c1 genotype with a frequency of 98.5%
[95% CI 96-100]. CYP2E1 genotypic frequencies of
Moroccans compared with different populations of the world
are shown in Table 4.
Table 1 Observed frequency of NAT2 genotypes encoding
fast (RA), intermediate (IA) and slow (SA) acetylation
phenotypes among Moroccan population studied
Southern Korean 
Southern Brazil 
South Africa 
Moroccans (This study)
Table 2 NAT2 alleles frequencies among Moroccan population and other ethnic groups
This results show that slow acetylators are the most
frequent in our Moroccan population, and the NAT2*5
allele is the most represented. Comparing the allele
frequencies of the four NAT2 variants reported in Table 2,
the distribution pattern of NAT2*14 in Tunisian and
NAT2*6, NAT2*7 in Caucasians populations did not
vary significantly from our population (p > 0.05). On the
other side, the allelic distribution in our population is
different from other populations as Tunisians for the
three alleles NAT2*5, NAT2*6 and NAT2*7 and from
Caucasians for two alleles NAT2*5 and NAT2*14, this
difference is statistically significant (p < 0.05) [26,32].
This difference with Tunisian neighbors could be
explained by the origins of the Moroccan and Tunisian
populations. Since about 8000 years ago native Berbers
have been the major population group in all the North
African regions, but through the centuries, Berbers have
mixed differently with many other ethnic groups,
Phoenicians, Carthaginians, Romans, Vandals, Byzantines,
and Arabs whereas Ottoman rule reached Tunisia only
[41,42]. Other explanation of the difference between our
population and Tunisians could be a selection bias, and
the limited size of their group controls.
Table 3 Allele and genotype frequencies of rs2031920
polymorphism in Moroccan controls
Studies have shown variation in the distribution of
NAT2 alleles among different populations, where four
major groups could be distinguished according to the
frequency of NAT2*5 and NAT2*6 alleles and according
to the presence of NAT2*7 and NAT2*14 alleles. NAT2*5
allele is the most common among Caucasian, Egyptian
and Omanian populations as in our population [26,29,31],
while Asians such as South Korean and Japanese
populations, have less NAT2*5 and more NAT2*7 [26,27,33].
NAT2*6 variant is at the second position in our
population similarly to Caucasians . NAT2*14 allele, at the
third position in our population, is rare in Caucasians
and absent in Omanian and Southern Korea
Junichi Azuma et al. 2012 , proposed in their
recent study about NAT2 genotypes and impact on doses
of INH to increase the recommended dose of 5 mg/kg
by the World Health Organization (WHO) to 7.5 mg/kg
in rapid acetylators, maintain it in intermediate
acetylators, and reduce it to 2.5 mg/kg in slow acetylators. As
Moroccans are mainly slow acetylators, we propose
according to our results to reduce the dose of INH in
TB patients carrying slow acetylators genotypes, in order
to prevent hepatotoxicity and to decrease the cost of
managing adverse events.
For the polymorphism rs2031920 of the CYP2E1 gene,
our studied group consisted of 130 controls, originated
from different regions of Morocco. From our results, it
appears that there is a high frequency of c1/c1 genotype
in Moroccan population (Table 3), which aggravates
hepatotoxicity in slow acetylators patients under TB
treatment. In Table 4, we compared our results with
Table 4 Genotypic frequencies of rs2031920 polymorphism of CYP2E1 gene in different populations of the world
those of other reported populations. The frequencies of
c1/c1, c1/c2 and c2/c2 genotypes in Moroccans were
close to those found in Caucasians [35,37,38].
In conclusion, this preliminary study shows that more
than 70% of Moroccan subjects are carriers of NAT2*5,
NAT2*6, NAT2*7 and NAT2*14 genotypes compatible
with a slow acetylators status, and therefore, they are
sensitive to lower doses of TB treatment. We should
take into account this high prevalence of slow
acetylators in order to decrease adverse effects, especially
knowing that a vast majority of Moroccans are also
homozygous for the c1 allele of CYP2E1 gene, which
Blood samples were collected from umbilical cords of
163 unrelated newborns. They originated from different
regions of Morocco and the Moroccan origin of their
parents and grandparents was confirmed. Informed
consent for DNA analysis was obtained from the parents.
Ethics approval was obtained from the local committee
of National institute of Hygiene in Rabat for this study.
Genomic DNA was extracted from three mL of blood
using the salting-out method . The quality and
quantity of the DNA were controlled by A260/A280 using a
Nanodrop spectrophotometer (2000/2000c Nanodrop;
Fisher Scientific, Wilmington, DE, USA) and aliquots
(50-100 L) of packed blood cells were stored at 4C
until analyses. One hundred nanograms of extracted
DNA was amplified in a final volume of 20 L. Real time
PCR mixture contained 10 L of Master Mix (2X,
TaqMan Genotyping Master Mix, Applied Biosystems),
0.5 L of a specific probe (40 X, TaqMan, Applied
Biosystems). The amplification protocol involves three
steps, PCR which includes activation of Taq polymerase
heating at 95C for 10 minutes, followed by 40 cycles of
amplification of 75 seconds each cycle (DNA
denaturation for 15 seconds at 92C, Hybridization for 1 minute
at 60C) and ends with Post-PCR Read at 60C for
We genotyped 163 DNA samples for the four SNPs
with strongest impact on the acetylation profile: rs1801280
(c.341 T > C; NAT2*5), rs1799930 (c.590G > A; NAT2*6),
rs1799931 (c.857 G > A; NAT2*7), and rs1801279
(c.191G > A; NAT2*14) polymorphisms of NAT2 gene
and 130 DNA samples for the rs2031920 polymorphism
of CYP2E1 gene.
Genotyping of SNPs of both genes was performed with
an allele-specific probe of SNP using allele-specific
realtime polymerase chain reaction (StepOne Real-Time PCR
System; Applied Biosystems7500, Foster City, CA, USA)
using TaqMan (Applied Biosystems, Warrington, UK)
probes. This method combines PCR and mutation
detection in a single step. A hybridization probe is cleaved by
the 5 nuclease activity of Taq DNA polymerase only if the
specific sequence is successfully amplified. Two TaqMan
probes are used, one for each allele. TaqMan probes
consist of a 1822 bp oligonucleotide probe which is labeled
with a reporter fluorophore at the 5 end and a quencher
fluorophore at the 3 end. Allelic discrimination was
obtained by the post-PCR read of fluorescence intensity.
For the CYP2E1 polymorphisme the primers
sequences were from assays-by-designs SM of the
manufacturers (Applied Biosystems). Alleles of rs2031920 were
assessed using primers rs2031920_F: TGACTTTTA
and rs2031920_R: GTTTTTCATTCTGTCTTCTAACT
GGCAATAT and the Taqman probes rs2031920_V: VIC
AGGTTGCAATTTTGTACTTT and rs2031920_F: FAM
GTTGCAATTTTATACTTT (SNP position highlighted).
For the four polymorphisms of NAT2 gene, the primers
sequences were from Drug metabolism genotyping assay
of the manufacturers (Applied Biosystems) which
reference is (p / n 4362038).
Genotype frequencies in our population were
calculated in accordance with the Hardy-Weinberg
equilibrium. Intervals confidence 95% were calculated for
phenotypic genotypic and allelic frequencies.
Statistical analysis was performed using the SPSS
(Statistical Package for the Social Sciences) version 17.0 for
windows. The chi-square test was used to determine
whether there is a significant difference between the
expected frequencies and the observed frequencies relative
to NAT2 gene distribution in the studied group versus
other populations. Statistical significance was assumed at
the p < 0.05.
ATDH: Antituberculosis drug-induced hepatotoxicity; INH: Isoniazid; NAT2:
N-acetyltransferase 2; CYP2E1: Cytochrome P450 2E1; TB: Tuberculosis;
INH: Isoniazid; RMP: Rifampicin; PZA: Pyrazinamide; EMB: Ethambutol;
ADRs: Adverse drug reactions; RA: Rapid acetylator; IA: Intermediate
acetylator; SA: Slow acetylator; WHO: World Health Organization;
SPSS: Statistical package for the social sciences; n: Sample size.
The authors declare that they have no competing interests.
SG molecular study, redaction of the manuscript, statistic study. IR analysis
of data, redaction of the manuscript. FZL contribution to molecular study.
SCEA preparation of the controls data. CJI contribution to statistic study.
AB recruitment of controls. AS conception of the study, analysis of data.
All authors read and approved the final manuscript.
The authors would like to thank all the staff of the Medical Genetics Department
of the National Institute of Health for their support.
The authors would like to thank also Dr Jauad El Kharraz for his careful
reading of the paper.
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