Pharmacology & Pharmacy, 2011, 2, 88-93
doi:10.4236/pp.2011.22011 Published Online April 2011 (http://www.SciRP.org/journal/pp)
Genetic Polymorphisms of CYP2C9: Comparison
of Prevalence in the Lebanese Population with
Other Populations’
Yolande B. Saab1, Taimour Langaee2
1School of Pharmacy, Lebanese American University, Byblos, Lebanon; 2Center for Pharmacogenomics, College of Pharmacy, Uni-
versity of Florida, Gainesville, USA.
Received January 15th, 2011; revised February 28th, 2011; accepted March 10th, 2011.
ABSTRACT
Background: There is little knowledge about genotyping of cytochrome P450s in the Middle East, and there has not
been any report on the genotype of CYP2C9 allelic variants in Lebanese population . Aims and objectives: The purpose
of the study was to determine and compare the frequencies of the cytochrome P450 CYP2C9 variants in the Lebanese
population with the frequencies in other ethnic populations. Methods: CYP2C9 genotypes were determined in a total of
146 samples of unrelated, healthy Lebanese individua ls residing in different areas in Lebanon. Fo llowing DNA extrac-
tion from buccal cells and polymerase chain reaction, genotyping was performed by Pyrosequencing method. CYP2C9
genotypes results were compared to other populations’; i.e., Middle Easterns, Europeans, Asians, and African Ameri-
cans. Results and discussion: The frequencies of the CYP2C29*2, CYP2C9*3, and CYP2C9*4 alleles were 11.305%,
11.645%, and 1.025% respectively. No CYP2C9*5 allele variants were found among the Lebanese study sample. Vol-
unteers could be divided into three CYP2C9 genotype groups: subjects (76.71%) with no mutated alleles (CYP2C9*1*1;
homozygous extensive metabolizers, EM), 21.23% with one mutated allele (CYP 2C9*1*2, *1*3, *1*4, and *1*5; het-
erozygous intermediate metabolizers IM), and 2.06% with two mutated alleles, homozygous variants as poor metabo-
lizers, PM). The comparative analysis using genotyp e groups of different populations showed differences among Leba-
nese and other Caucasians. Conclusion: This is the first report from Lebanon on CYP2C9 variants; it highlights a
higher frequency of CYP2C9 extensive metabolizers compared to other populations including Caucasians. The results
serve as a database on CYP 2C9 polymorphisms and baseline clinica l data for dosing and avoiding adverse drug reac-
tions of drugs met a bol i s ed by CYP2C9 in Lebanese patients.
Keywords: CYP2C9, Gene Pol y m orphisms, Lebanese, Middle East
1. Introduction
The cytochrome P-450 system (CYP) is responsible for
the metabolism of several naturally occurring and syn-
thetic compounds. The CYP2C9 isoenzyme is primarily
responsible for the oxidative metabolism of several drugs,
including warfarin, phenytoin, losartan, irbesartan, tol-
butamide, glipizide, torsemide, and various nonsteroidal
anti-inflammatory drugs [1]. Multiple single nucleotide
polymorphisms within the gene for CYP2C9 have been
identified, and at least 13 of these encode CYP2C9 al-
leles [2,3]. Three alleles, CYP2C9*1, *2 and *3, are pre-
sent in most ethnic populations. The most common allele
is designated *1 and is considered the wild-type allele.
The *2 allele results from a single base substitution (430
C > T) that is located in exon 3. The *3 (1075 A > C), *4
(1076 T > C), and *5 (1080 C > G) alleles result from
base changes located in exon 7. In addition, some null
polymorphisms have been recently identified except for
CYP2C9*34 in Japanese population [3]. The *2 and *3
alleles encode a protein with reduced enzymatic activity
in vitro, and patients with these alleles have been design-
nated as “poor metabolizers” [4,5], that may experience
drug toxicity. Thus the dose of these drugs may need to
be adjusted according to CYP2C9 genotype. The geno-
type distribution among individuals varies with ethnic
background. In Caucasian populations, for example, ap-
proximately two thirds of individuals express the wild-
type genotype, *1/*1; one third express the *1/*2 or
*1/*3 genotype; and fewer than 2.5% express the *2/*2,

Genetic Polymorphisms of CYP2C9: Comparison of Prevalence in the Lebanese Population with Other Populations’89
*2/*3, or *3/*3 genotype [2]. The allele frequencies of
CYP2C9*2 and CYP2C9*3 tend to be greater in Cauca-
sians populations compared to African-American and
Asian populations; the CYP2C9*2 was not found in East
Asians including Chinese and Japanese [6].
To our knowledge, there is little knowledge about ge-
notyping of cytochrome P450s in the Middle East, and
there has not been any report on the genotype of CYP2C9
allelic variants in Lebanese population who are con-
sidered White Caucasians. Lebanon is a small country of
10500 km2 on the eastern shores of the Mediterranean
Sea; it has made a historical crossroads between Asia,
Africa, and Europe. Today, the population is approxi-
mately 4 million people, with a worldwide diaspora es-
timated at 16 million. Thus the purpose of the study was
to determine the CYP2C9*1, CYP2C9*2, CYP2C9*3,
CYP2C9*4, and CYP2C9*5, allele and genotype fre-
quentcies in Lebanese and compare with other populations.
The results will serve as baseline clinical data for dosing
of drugs metabolised by CYP2C9 based on Lebanese pa-
tients’ genotypes and avoiding the adverse drug reactions.
2. Materials and Methods
2.1. Subjects
A total of 146 healthy volunteers were recruited from the
Lebanese population. All subjects signed a consent form.
Included were non-obese subjects (body mass index
(BMI)  29.5 Kg/m2), with no history or clinical evi-
dence of diabetes, cardiovascular problems, hypertension,
renal insufficiency, and/or depression. All study subjects
are of Lebanese origin, and were living in Lebanon at the
time of study. The School of Pharmacy research com-
mittee approved the project.
2.2. CYP2C9*2*3*4*5 Gene Polymorphism
Genotyping
Each volunteer was asked to give a DNA sample from the
cheek using a cheek swab. DNA was isolated from cheek
swabs by a method previously described [7].
Genotype polymorphisms for the CYP2C9*2,*3,*4,
and *5 alleles was performed by means of PCR (MyCy-
cler; BioRad laboratories, Hercules, Calif) followed by
Pyrosequencing [8] by using PSQ HS 96A System (Bio-
tage AB), with use of automated PSQ HS 96A SNP soft-
ware (Biotage AB); a previously validated protocol [9].
In brief, the PCR reaction mixture used for target se-
quence amplification consisted of 13 μl of HotStarTaq
Master Mix (Qiagen), 10 pmol of each primer (Invitro-
gen) (1 μlL), and 50 - 100 ng (10 μl) of genomic DNA.
Primer sequences are as detailed in Table 1 [10]. The
PCR amplification was performed under the following
conditions: initial denaturation at 95˚C for 15 minutes, 45
cycles of denaturation at 95˚C for 30 seconds, annealing
at 55˚C for 30 seconds, and extension at 72˚C for 1 min-
ute, followed by a final extension step at 72˚C for 7 min-
utes. As for the pysrosequencing analysis, 10 μl of bioti-
- nylated PCR product was immobilized to streptavidin-
coated Sepharose beads (Amersham Biosciences, Pis-
cataway, NJ). After incubation, the beads were isolated
and treated with 70% ethanol, denaturation buffer, and
wash buffer. The beads then were released into design-
nated wells containing annealing buffer and 10 pmol of
sequencing primer, followed by a 2-minute incubation at
80˚C. Reproducibility was assessed by analyzing 42
samples in duplicate DNA.
Table 1. PCR and sequencing primers for CYP2C9*2, *3, *4, and *5.
CYP2C9
Allele Exon Nucleotide change Primers1
*2 3 430C > T PCR Primers
F: 5’-GTATTTTGGCCTGAAACCCATA-3’
R: B-5’-CACCCTTGGTTTTTCTCAACTC-3’
Sequencing primer
5’-GGGAAGAGGAGCATTGAGGC-3’
*3 7 1075A > C PCR Primers for *3,*4, and*5
*4 7 1076T > C F: B-5’-TGCACGAGGTCCAGAGAT-3’
*5 7 1080C > G R: 5’-GATACTATGAATTTGGGACTTC-3’
Sequencing primer for *3,*4, and*5
5’-GCTGGTGGGGAGAAG-3’
F
, forward; R, reverse; B, biotin labeled.

Genetic Polymorphisms of CYP2C9: Comparison of Prevalence in the Lebanese Population with Other Populations’ 90
2.3. Statistical Analysis
Sample size was determined a priori by use of statistical
power analysis with SAS software (SAS Institute, Cary,
NC). Calculations revealed that a minimum of 120 sam-
ples is required for the genotype representation in the
Lebanese population [11]. Statistical analyses were per-
formed using the SigmaStat 3.5. The study samples al-
leles and genotype frequencies were estimated by gene
counting method. The agreement with Hardy-Weinberg
equilibrium of the observed genotypic distribution for the
CYP2C9 gene was tested by chi-square tests. A P value
of  0.05 was considered statistically significant. Popula-
tion comparisons were also performed by Chi-square test
of population differentiation.
3. Results
3.1. Subjects Demographic Characteristics
A total of 146 Lebanese subjects were included in the
study, which aimed to determine the CYP2C9*1,*2, *3,*4,
and *5 gene polymorphism prevalence in the Lebanese
population. The study samples consisted of 51.9% and
48.1% males and females, respectively. The mean age
was 20. 63 years (range: 18 - 69 years) and the average
BMI was 21.04 Kg/m2 (range: 17.15 - 27.48 Kg/m2).
3.2. CYP2C9*1,*2,*3,*4, and *5 Gene
Polymorphism Genotype Distribution in
Lebanese and Hardy- Weinberg
Equilibrium
The detailed distribution of the CYP2C9*2,*3,*4, and *5
genotypes in the Lebanese population is depicted in Ta-
ble 2. The frequencies of the CYP2C29*2, CYP2C9*3,
and CYP2C9*4 alleles were 11.31%, 9.59%, and 1.025%
respectively. No CYP2C9*5 allele variants were found
among the Lebanese study sample.
Volunteers could be divided into three CYP2C9 geno-
types groups: subjects (76.71%) with no variant alleles
(CYP2C9*1*1; homozygous extensive metabolizers, EM),
21.23% with one variant allele (CYP2C9*1*2, *1*3,
*1*4, and *1*5; heterozygous intermediate metabolizers
IM), and 2.06% with two mutated alleles (such as CYP2C9
*2*2, *2*3, *3*3, *2*4, and other homozygous variants/
poor metabolisers, PM).
CYP2C9 allele and genotype frequencies did not devi-
ate from Hardy-Weinberg equilibrium (P = 0.743, Fisher
exact test).
Comparisons of population differentiation: CYP2C9
genotype frequencies in different populations as com-
pared to those of Lebanese.
Table 2. Proportion of CYP2C9 amino acid variants, allele frequencies and phenotype in a Lebanese population of 146 sub-
jects.
CYP2C9 Polymorphism Amino acid change n % Phenotype
*2 (430C > T) Arg/Arg144 113 77.39
Arg/Cys144 33 22.61
Cys/Cys144 0 0
*3 (1075A > C) Ile/Ile359 115 78.77
Ile/Leu359 28 19.17
Leu/Leu359 3 2.06
*4 (1076T > C) Ile/Ile359 143 97.95
Ile/Thr359 3 2.05
Thr/Thr359 0 0
*5 (1080C > G) Asp/Asp360 146 100
Asp/Glu360 0 0
Glu/Glu360 0 0
2*3*4*5 *1*1 (wild) 112 76.71 Extensive
Heterozygous variants 31 21.23 Intermediate
Homozygous variants 3 2.06 Poor

Genetic Polymorphisms of CYP2C9: Comparison of Prevalence in the Lebanese Population with Other Populations’91
The comparative analysis using genotype groups of
different populations showed differences among Leba-
nese and other Caucasians (Table 3).
4. Discussion
CYP2C9 polymorphisms give rise to inter-individual and
interethnic variability in the metabolism and disposition
of several therapeutic agents. CYP2C9 polymorphisms
may cause differences in the clinical response to these
drugs. CYP2C9 various forms include CYP2C9*1 (wild
type) and two well-characterized SNPs, an arginine-to-
cysteine change at codon 144 (Arg144Cys, CYP2C9*2),
and isoleucine-to-leucine change at codon 359 (Ile359-
Leu, CYP2C9*3). CYP2C9*4 (an isoleucine-to- threonine
change at codon 359 and CYP2C9*5 (an aspartic acid-to-
glutamic acid change at codon 360) as well as other
polymorphisms have been also reported in different po-
pulations. Patients who have variant alleles of CYP2C9
require, for example, reduced maintenance doses of war-
farin compared to those having wild type-alleles [12].
The *2/*2 homozygous variant leads to a reduction of
approximately 12% of CYP2C9 activity and the *3/*3
homozygous variant has < 5% of wild type CYP2C9 ac-
tivity [13]. The *2 and *3 alleles, have been associated
with an increased risk of warfarin over anticoagulation
and bleeding events [14]. Alternate genotypes composed
of 1 or more low-activity alleles also may account for the
difficult-to control anticoagulation status in some pa-
tients [15]. The accumulated evidence suggests that the
CYP2C9 genotype has been used to develop warfarin-
dosing algorithms to avoid the morbidity associated with
over anticoagulation [10].
Table 3. CYP 2C9 genotype frequencies in different populations as compared to those of Lebanese.
CYP 2C9 allele frequencies in different populations
Ref Genotype % No of Subjects Chi Square P values
*wt/wt wt/mut* mut/mut*
Chinese [16] 98 2 0 265 0.001
Italians [17] 53 39 8 465 0.001
Japanese [12] 95 4 1 828 0.001
Sweden [18] 66 31 3 1496 0.003
Hungarian [19] 62 33.4 4.6 535 0.004
Turkish [20] 62 35 3 499 0.004
African Americans [21] 88 10 2 268 0.007
Iranian [22] 55 38 7 58 0.007
Bolivian [23] 84.6 15 0.4 778 0.01
British [24] 56 36 8 297 0.01
French [25] 63 30 6 126 0.03
Canadian [26] 59 38 3 51 0.04
Lebanese Current study 77 21 2 146 1
Omani [27] 80 19 1 189 0.6
Dutch [28] 70 28 2 60 0.546
European Americans [21] 70 27 3 292 0.3
Malays [16] 81 15 4 151 0.2
Russians [29] 68 29 3 298 0.172
Belgian [30] 67 29 4 121 0.157
Ethiopians [31] 87 12 1 150 0.085
Egyptians [32] 66 31 3 247 0.081
*
wt: wild type, mut: mutant. Statistical Significance P ≤ 0.05.

Genetic Polymorphisms of CYP2C9: Comparison of Prevalence in the Lebanese Population with Other Populations’ 92
Earlier studies have indicated differences in CYP2C9
enzyme activity may exist not only between the major
races but also among different Caucasians populations.
Consequently, further studies on different Caucasian eth-
nic groups are needed to provide relevant genotypic data
for each population. To our knowledge, this is the first
study that reports different CYP2C9*2,*3,*4, and *5 ge-
notypes in the Lebanese population (White Caucasians).
Frequencies of CYP2C9 genotype polymorphisms re-
sulted very high, showing a higher frequency of CYP
2C9 homozygous extensive metabolisers (*1/*1) com-
pared to other Caucasians i.e., Southern Europe (Table
3). Additionally, CYP2C9*5 allele frequency was not
found among the Lebanese study sample.
The ability to determine a patient’s genotype helps fu-
ture pharmacogenomic investigations and the transition
of pharmacogenomics into mainstream clinical practice.
This feature is necessary for situations in which ran-
domization, or the start of drug therapy, is dependent on
genotype determinations.
In conclusion, CYP2C9 gene polymorphisms classi-
fied individuals mainly into extensive and intermediate
metabolisers. This first report from Lebanon highlights a
higher frequency of CYP2C9 extensive metabolisers
compared to Europeans and North American Caucasians;
a unique feature that serves a baseline clinical data for
dosing of drugs metabolised by CYP 2C9 based on
Lebanese patients’ genotypes.
5. Acknowledgements
The study was supported by research grants of the Leba-
nese American University, Lebanon, and the Center for
Pharmacogenomics at the University of Florida, Gaines-
ville, USA.
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