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Genetic polymorphism of cytochrome p450 (2C19) enzyme in Iranian Turkman ethnic group.

Introduction

There are at least four isoforms of human CYP2C subfamily in mankind. The main forms are principally 2C8, 2C9, 2C18 and 2C19. Their related genes are located on chromosome 10. (1,2) It has been shown that drug metabolism is directly related to genetic polymorphism and gene mutations manipulate the enzyme activities responsible for the drugs metabolism. Such enzyme activity modulation can present itself in three scenario of high, low and zero activities. (3-5) From drug related genetic pattern, the human gene are sub-grouped into few phenotypes of poor (or slow) metabolizers (PM), intermediate metabolizers (IM), extensive (or rapid) metabolizers (EM), and ultrarapid metabolizers (UM). (6) There are various reports of drugs which adversely affect human metabolism, resulting either from drug toxicity or long-lasting therapeutic effect of some drugs even consumption at therapeutic dosage in poor or slow metabolizer phenotypes. The ultra rapid metabolizer phenotype probably does not demonstrate the related therapeutic effect and this may be the reason why some drugs do not produce any therapeutic effect even in genetically susceptible subjects. This manifestation of specific phenotypes is related to the pharmocogeneticity of particular polymorphism of poor or slow, extensive or rapid and ultra-rapid metabolizer. It has been shown that about 3% of Caucasians express the poor metabolizer phenotypes S-mephenytoin, however literature review in this regards shows slight differences. (7,8) Other studies indicated that East Asian subjects express the poor metabolizer phenotypes at higher frequency. Some researchers have indicated that 18-23% of Japanese, (9,10) 15-17% of Chinese (11,12) and 12-16% Koreans express the poor metabolizer phenotype. (13,14) The same index for Black African was reported to be 4-7%.15 Reports suggest that the poor metabolizer phenotype is an autosomal recessive trait which is inherited. (8) Same reports have considered CYP2C19*2 and CYP2C19*3 to be the dominant poor metabolizer phenotype for malfunction of CYP2C19 alleles. (16,17) Among East Asians, CYP2C19*2 is the major allele and it dominates about 75% of the defective alleles. (16) These allele defections for Caucasians account for 93% of population. (18) CYP2C19*3 is the phenotype which comprises approximately 25% of the defective gene among East Asians which was initially found in a Japanese poor metabolizer population. (17) But it was discovered that the above mentioned phenotype is significantly rare among non-East Asian sub-population. (19) The incidence of the poor metabolizer phenotype in European whites, (7) and the residents of Vanuatu Island as well as Melanesia subjects, (20) at a rate of 3-5% and 70%, respectively. The incidence of CYP2C19*2 and CYP2C19*3 alleles among north Indian subjects was reported to be as 29.7% and 0.00%, respectively. (21) In an other study, the frequency of CYP2C19*2 and CYP2C19*3 alleles among South Indian of Tamil, Telgu, Kannada, and Malayalam backgrounds were reported to be 35% and 1%, respectively. (22) The narrow therapeutic index of some drugs in particular are important safety in determining the drug metabolic capacity indications of some individual by applying the necessary phenotype and genotype standards to provide a safe guard for susceptible subjects. The aim of this study was to assess the distribution of CYP2C19 allele and genotypic variants among the Turkman ethnic group in comparison with other populations.

Methods

The study group included 140 unrelated healthy subjects of Turkman origin (people who speak Turkman as a native language and population inbreeding people) who were referred to the Health Center in Gonbadkavoos (located in North Eastern Iran, South East of the Caspian Sea). This present study, set to establish the prevalence of CYP2C19 variants in a sample of Turkman ethnic group and compare the collected data with other populations. Ethical approval was obtained from the ethics committee of Golestan University of Medical Sciences and informed consent was obtained from all participants.

Five milliliters of venous blood was sampled from each subject and collected into EDTA tubes. Extraction of DNA from peripheral white blood cells was done by salting out method. (23) DNA extract was dissolved in sterilized distilled water and samples were kept in -20[degrees]C until analysis by polymerase chain reaction (PCR).

Genotyping of CYP2C19 alleles (CYP2C19*1, CYP2C19*2, and CYP2C19*3 alleles) was carried out by Polymerase Chain Reaction (PCR)-Restriction Fragment Length Polymorphism (RFLP) technique. (24) PCR was done in 25 microliter mixture containing PCR buffer 10 mM Tris-HCl, pH 9, 1.5 mM Mg[Cl.sub.2] (Fermentase, Burlington; Canada), 50 mM KCl (Fermentase, Burlington; Canada), 10 mM deoxyribonucleotide triphosphate (dNTP) mix, 5 U/[micro]l Taq polymerase (Fermentase, Burlington; Canada), 5 pM of each primer (Bioneer; Korea), 500 ng DNA (Genomic; Korea) and sterile distillated water. PCR was carried out in a genetix CG palm-thermocycler (New Delhi; India). PCR products (10[micro]l) were digested with restriction enzymes (Fermentase; Burlington; Canada), (SmaI for CYP2C19*2 and BamHI for CYP2C19*3) at 30[degrees]C and 37[degrees]C for 16 hrs for compelte digestion, respectively. Primers amplification was done as described by De Morais et al. (17) The DNA fragments were electrophoresed (Apelex, France) on a 2% (for CYP2C19*3) and 3% (for CYP2C19*3) agarose gel and stained with Ethidium bromide. Bands were detected by a short wavelength UV transluminator, photographed using a Polaroid Gel Camera with Polaroid black and white film. The CYP2C19*2 mutation was detected using sense primer 5'-AATTACAACCAGAGCTTGGC-3' and antisense primer 5'-TATCACTTTCCATAAAAGCAAG-3. The detection of CYP2C19*3 was carried out using sense primer 5'-AAATTGTTTCCAATCATTTAGCT-3' and antisense primer 5'-ACTTCAGGGCTTGGTCAATA-3. The PCR amplification conditions for CYP2C9*2 and CYP2C9*3 were as follow: Initial denaturation, Number of cycle(s), Denaturation, Extention and Final extention step, which were 94[degrees]C, 300 sec.; 37; 94[degrees]C, 60 sec.; 72[degrees]C, 30 sec. and 72[degrees]C, 300 sec., respectively. The annealing temperature and time for CYP2C9*2 and CYP2C9*3 were 55[degrees]C, 30 sec. and 52[degrees]C, 45 sec., respectively. The Products of PCR before and after restriction enzyme digestion for CYP2C9*2 and CYP2C9*3 genotypes are summarized in Fig. 1 and 2, respectively.

Statistical analysis was done to evaluate allele frequencies of CYP2C19 in Turkman subjects alongside other ethnic groups. The 95% confidence intervals (95% CI) for frequency of the variant alleles of each gene were determined. The observed genotype frequencies of CYP2C19 were observe and compared with expected frequencies according to the Hardy-Weinberg law. Differences in allele frequencies and PM genotype frequencies between the Turkman ethnic group and other populations from various area swere measured by Fisher exact test. Data was analysed using SPSS version 16.0. and statistical significance was considered at p<0.05.

Results

The data revealed mean ages of the participants to be 29.73 [+ or -] 9.11 years old. Allele and genotype frequencies of CYP2C19 gene among the Turkman ethnic group are shown in Tables 1 and 2. The allele frequency of CYP2C19*1 (Wild type), CYP2C19*2 and CYP2C19*3 were 56.43% (95% CI: 48.15-64.36), 23.57% (95% CI: 17.31-31.25) and 20% (95% CI: 14.22-27.36), respectively. CYP2C19*1 was the most frequently (56.43%) determined allele in Turkman ethnic groups. The observed frequencies of CYP2C19 genotypes in Turkman ethnic group were found to be in the Hardy-Weinberg equilibrium (Table 2). The results showed that 39.7% of subjects expressed the CYP2C19*1/*1 genotype (95% CI: 30.25-46.11). While 59 (42.1%), 13 (9.3%), 13 (9.3%) and 2 (1.4%) subjects expressed the CYP2C19*1/*2 (95% CI: 34.2850.42), CYP2C19*1/*3 (95% CI: 5.51-15.24), CYP2C19*2/*2 (95% CI: 5.51-15.24) and CYP2C19*3/*3 (95% CI: 0.3-5) genotypes, respectively. There was no expression CYP2C19*2/*3 (0%) genotype. Out of the alleles, CYP2C19*1/*2 (42.1%) was the most frequently observed mutant allele. Table 3 shows the prevalence of the predicted phenotypes of CYP2C19, which were as follow: 10.7% of subjects were PM carrying the CYP2C19*2/*2 and CYP2C19*3/*3 genotypes (95% CI: 5.5-15). Fifty one percent of subjects were IM carrying the CYP2C19*1/*2, CYP2C19*2/*3 and CYP2C19*1/*3 genotypes (95% CI: 43-60). Which 37.86% were found to be EM expressing the CYP2C19*1/*1 genotype (95% CI: 29.72-45.99). IM genotype frequency was high (51%) in the Turkman ethnic group.

Discussion

The Turkman ethnic group is a unique population in Iran, due to their population inbreeding, these people were considered to be particularly important in investigating the allele frequencies and genotype distributions of some variants of a pharmacogenetic interest. This is the first study based on the CYP2C19 genotype distribution in this ethnic group. There have been many reports on the genetic polymorphisms of CYP2C. Some studies have reported that the hydroxylation metabolism of S-mephenytoin showed genetic polymorphism. (53,54) It was also determined that this enzyme catalyzes the metabolism of some drugs such as S-mephenytoin, methylphenobarbital, omeprazole, phenytoin, imipramine, proguanil, propranolol and diazepam. (55) It has also reported that CYP2C shows a possible clinical role in determining interindividual and interethnic differences in drug effectiveness.

Change in CYP expression can affect drug response and activity. The ethnic differences in the frequency of CYP2C19 mutant alleles continues to be a significant study topic. (56) In this current study, we assessed the distribution of CYP2C19 variants in the Turkman ethnic group and compared the data with those from other populations. The CYP2C19*2 variant was the most allele among Turkman ethnic groups. The frequency of this variant was 23.57% in the present study. Its frequency was lower than the figures reported from Chinese (45.5%), (27) Japanese (27.4%), (28) Thai (29%), (30) Karen (28%), (30) Malaysians (28%), (31) Filipino (29%), (32) Vanuatu and other Pacific islands (63.3%), 51 as well as Australian Aborigines (35.5%). (52) The frequency of CYP2C19*2 has been reported to range from 20.9% to 45.5%, 12%-15%, 35.5%-63.3%, 9.1%-15.9%, 13%-19.1%, 7.8%, 14%-18.8%, 10.9%-19% and 13%-14% in East Asian, (27-32) West Asian, (32-34) Oceanian, (51, 52) European, (33, 38, 39) North American and Canadian, (32, 40) South American (Bolivian), (41) Scandinavian, (42-44) African (38, 45-50) and Iranian, (25, 26) respectively. The frequency of the CYP2C19*3 allele (20%) was high among the Turkman ethnic group when compared with some East and West Asians, (27, 31-34) Oceanian, (51, 52) European, (33, 38, 39) North American and Canadian, (32, 40) South American (Bolivian), (41) Scandinavian, (42-44) African (38, 45-50) and Iranian (25, 26) populations, respectively. All combinations of alleles are shown in Tables 4 and 5. These results appear to suggest that CYP2C19*2 and CYP2C19*3 mutations are distinctive in different ethnic groups. Some studies have shown that the CYP2C19*2 and CYP2C19*3 mutant alleles are collaborated with reduced enzyme activity. Clinical studies have shown that patients with CYP2C19*2 allele showed lower levels of the metabolite's activities. This causes a decrease in platelet inhibition activity and higher rates of cardiac occurrences. (57) According to various studies, the functional loss of CYP2C19 allelic variants is not in favor of cardiovascular systems following clopidogrel therapeutical regiment. (58-60)

In a separate study, it was shown that CYP2C19 allelic variants functional loss did not have any adverse effect on the safety and efficacy of clopidogrel among patients with acute coronary diseases. (61) Comparison of the Turkman ethnic group with other ethnic populations indicates differences and resemblances in the distribution of CYP2C19 allele and PM genotype. The differences may be associated with racial origin, geographical distribution and environmental factors, etc. Differences in the frequency of CYP2C19 polymorphism in different populations have epidemiologic importance. The frequency of CYP2C19*2 is reported to be around 10% worldwide. Studies have shown that the frequency of CYP2C19*2 generally increases sequentially from Western Asia, Iran to India and Melanesian (with higher than 75% rate). On the other hand, CYP2C19*3 frequency exhibits the same direction. The increase begins in Eastern Asia with the highest prevalency in Melanesia with 33%, but it has been obeserved that its frequency in other part of the world is very low (lower and/or equal to 1%). The frequency of CYP2C19 variant can be as high as 90% in other regions of the world. (62)

CYP2C19 polymorphism is related to metabolism of some important drugs. (55, 56) CYP 2C19 phenotypes are reported to affect clinical benefit of several drugs, such as proton pump inhibitors, clopitogrel, sertraline, escitalopram, moclobemide and voriconazol. (63) Gastric acid-related abnormalities can be treated with the drug inhibitors and the proton pump inhibitors are sequentially metabolized by CYP2C19 in the liver. CYP2C19 from different genetic backgrounds metabolize the above mentioned drug differently and studies have shown that Japanese and Caucasians poor metabolizers respond properly to the drug with therapeutic dosage, but extensive metabolizers have been shown to have no effect on the above drug at therapeutic dosage. (64-66) In a recent clinical trial study, the advantage of CYP2C19 genotype sub-population in having a good response to the proton pump inhibitor in therapeutic dosage was confirmed. (67) The finding from another study indicated that Asian populations represent slower metabolism of diazepam than Caucasians. This may depend on the high frequency of the mutant CYP2C19*2 and CYP2C19*3 alleles in Asian populations. (56) Toxic doses of diazepam may arise as the result of slower metabolism in PMs. Thus, extra care must be taken with the dosage of diazepam in Asian populations. Subjects with the variants CYP2C19*2 or CYP2C19*3 can denomstrate abnormality in metabolism for drugs such as diazepam, with adverse drug reactions.

The present study showed that PM genotype frequency was highly (10.7%) expressed among the Turkman ethnic group when compared with West Asian, (32-34) Europeans, (33,35-39) North and South Americans, (32,40,41) as well as Scandinavians, (42-44) and Africans. (45-49) While PM genotype frequency in the Turkman ethnic group was lower than some East Asian (27-32) and Oceanian (51,52) populations. Moreover, our study showed that the frequency of poor metabolizers in the Turkman ethnic group (10.7%) is relatively close to Thai (9.2%) and Burmese (11%) populations. (30)

Conclusion

This study confirms the ethnic differences in the CYP2C19 allele and genotype frequencies. Our results also showed that the determined allelic variants of CYP2C19 (CYP2C19*2 and CYP2C19*3 mutations) in the Turkman ethnic group are comparable to other populations. Overall, the determination of CYP2C19 variants in different ethnic groups can be very useful for clinicians to determine the optimal dosage and efficacy of drugs metabolized by this polymorphic enzyme.

DOI 10.5001/omj.2013.69

Received: 26 Feb 2013/Accepted: 28 May 2013

Acknowledgements

The authors would like to thank the personnel at the Metabolic Disorders Research Center, the Research Deputy of Golestan University of Medical Sciences for their cooperation and financial support.

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Robabeh Ghiyas Tabari, Abdoljalal Marjani ([mail]), Ogholdondy Agh Ataby, Azad Reza Mansourian and Nader Mansour Samai

Department of Biochemistry and Biophysics, Metabolic Disorders Research Center, Gorgan Faculty of Medicine, Golestan_University of Medical Sciences, Gorgan, Golestan province, Iran.

E-mail: abdoljalal@yahoo.com

Table 1: Allele frequencies of CYP2C19 gene among Turkman
ethnic groups (n = 140).

Variant allele   n    Frequency (%)     95% CI

CYP2C19*1        79       56.43       48.15-64.36
CYP2C19*2        33       23.57       17.31-31.25
CYP2C19*3        28        20         14.22-27.36

Table 2: Genotype frequencies of CYP2C19 gene among
Turkman ethnic groups (n = 140).

Genotype       n        Observed           Expected
                       frequency %      frequency % by
                                        Hardy-Weinberg
                                             law

CYP2C19*1/*1   53   37.9(30.25-46.11)       40.41
CYP2C19*1/*2   59   42.1(34.28-50.42)        38.6
CYP2C19*1/*3   13    9.3(5.51-15.24)         7.72
CYP2C19*2/*2   13    9.3(5.51-15.24)         9.22
CYP2C19*2/*3   --         0(-)               3.69
CYP2C19*3/*3   2       1.4(0.3-5)            0.37

Table 3: Prevalence of CYP2C19 predicted phenotypes in
Turkman ethnic groups (n = 140) [[chi square] test,
p > 0.05].

Genotype            predicted   Frequency     95% CI
                    phenotype      (%)

CYP2C19*1/*1           EM         37.86     29.72-45.99

CYP2C19*1/*2,          IM          51          43-60

CYP2C19*1/*3 and
CYP2C19*2/*3

CYP2C19*2/*2 and       PM         10.7        5.5-15
CYP2C19*3/*3

EM: Extensive metabolizers, IM: Intermediate metabolizers,
PM: poor metabolizers.

Table 4: Comparison of allele frequencies of CYP2C19 of the Turkman
ethnic group with different populations.

Population study      Sample   Allele frequency % (p-value versus
                       size          Turkman ethnic group)

                                 1           2              3

Iran

Turkman                140     56.43       23.57            20
Iranian(Tehran)        200      86       14 (0.04)      0 (<0.001)
  (25)
Iranian                150     86.73    13 (0.001)      1 (<0.001)
  (Southern) (26)
East Asia

Chinese (27)           121      50     45.5 (<0.001)   4.5 (0.005)
Japanese (28)          217     61.8      27.4 (NS)     10.8 (0.013)
Koreans (29)           103     67.5      20.9 (NS)      11.7 (NS)
Thai (30)              774      68        29 (NS)       3 (<0.001)
Burmese (30)           127      66        30 (NS)       4 (<0.001)
Karen (30)             131      71        28 (NS)       1 (<0.001)
Malaysians (31)        142      66        28 (NS)       6 (<0.001)
Filipino (32)           52      54      39 (0.040)      8 (0.042)

West Asia

Turkish (33)           404      87      12 (0.001)     0.4 (<0.001)
Jewish Israel (34)     140      84        15 (NS)       1 (<0.001)
Saudi Arabia (32)       97      85        15 (NS)       0 (<0.001)

Europe

Russians (35)          290      88     11.4 (0.001)    0.3 (<0.001)
Italians (36)          360     88.9    11.1 (0.001)     0 (<0.001)
Croatians (37)         200      85      15 (0.045)      0 (<0.001)
Belgian (38)           121      90      9.1 (0.001)     0 (<0.001)
Germans (33)           328      84     15.9 (0.047)    0.2 (<0.001)
Portuguese (39)        153      87      13 (0.001)      0 (<0.001)

North America and Canada

Canadian Native        115     80.9      19.1 (NS)      0 (<0.001)
  Indian (40)
Americans (32)         105      87      13 (0.044)      0 (<0.001)

South America

Bolivian (41)          778     92.1     7.8 (0.001)    0.1 (<0.001)

Scandinavia

Faroese (42)           310     81.8      18.8 (NS)      0 (<0.001)
Swedish (43)            83      85        14 (NS)      0.1 (<0.001)
Danish (44)            239      84        16 (NS)       0 (<0.001)

Africa

African                517      81        19 (NS)       0 (<0.001)
  Americans (45)
Egyptians (46)         247     88.8    10.9 (0.001)    0.2 (<0.001)
Ethiopians (47)        114      85        14 (NS)       3 (<0.001)
Tansanians (48)        251      81        18 (NS)       1 (<0.001)
Zimbabweans (49)        84      87        13 (NS)       0 (<0.001)
Venda (50)              76     78.3      21.7 (NS)      0 (<0.001)
Beninese (38)          111      87      13 (0.027)      0 (<0.001)

Oceania

Vanuatu and other      5538    22.3    63.3 (0.001)     14.4 (NS)
  Pacific islands
  (51)
Australian             227     50.1    35.5 (0.015)     14.3 (NS)
  aborigines (52)

Differences in the allele frequencies were determined by Fisher exact
test. NS: No significant differences.

Table 5: Comparison of CYP2C19 genotype and poor metabolizer
frequency between Turkman ethnic group and other populations.

Study groups          Sample   Genotype frequency % (p-value versus
                       size            Turkman ethnic group)

                               *1/*1   *1/*2   *1/*3   *2/*2   *2/*3

Iran

Turkman                140     37.9    42.1     9.3     9.3      0

East Asia

Chinese (27)           121      --      --      --      --      --
Japanese (28)          217      --      --      --      --      --
Koreans (29)           103      --      --      --      --      --
Thai (30)              774     44.5    42.6     3.7     6.7     2.1
Burmese (30)           127     44.1    39.4     5.5     9.4     1.6
Karen (30)             131     51.1    39.7     0.8     7.6     0.8
Malaysians (31)        142      42      40       6       6      6.3
Filipino (32)          104      --      --      --      --      --

West Asia

Turkish (33)           404      76     22.3    0.74     0.9      0
Jewish Israel (34)     140     70.7    26.4     1.4      2       0
Saudi Arabia (32)       97      --      --      --      --      --

Oceania

Vanuatu and other     5,538     --      --      --      --      --
  Pacific islands
  (51)
Australian             227      --      --      --      --      --
  aborigines (52)

Europe

Russians (35)          290     78.7     19      0.3     1.7     0.3
Italians (36)          360     79.4    18.9      0      1.7      0
Croatians (37)         200      73      24       0       3       0
Belgian (38)           121     83.5     15       0      1.6      0
Germans (33)           328      --      --      --      --      --
Portuguese (39)        153      --      --      --      --      --

North America and Canada

Canadian Native        115      --      --      --      --      --
  (40) Indian (32)
Americans              105      --      --      --      --      --

South America

Bolinian (41)          778     85.3    13.5     0.1      1       0
Faroese (42)           310     66.2    31.2      0      3.2      0
Swedish (43)            83      71      27       1       1       0
Danish (44)            239     71.5    24.7      0      3.8      0

Africa

Africans               517      66      30       0       3      0.1
  Americans (45)
Egiptians (46)         247     78.6    20.2     0.4     0.8      0
Ethiopians (47)        114      75      19       1       3       3
Tanzanians (48)        251      66      30       1       3       0
Zimbabweans (49)        84      77      19       0       4       0
Venda (50)              76     61.8    32.9      0      5.3      0
Beninese (38)          111      74     26.1      0       0       0

Study groups            Genotype frequency    PM genotype
                        % (p-value versus         (%)
                          Turkman ethnic
                              group)

                              *3/*3

Iran

Turkman                        1.4                10

East Asia

Chinese (27)                    --            24 (0.002)
Japanese (28)                   --             15.2 (NS)
Koreans (29)                    --             11.7 (NS)
Thai (30)                      0.4             9.2 (NS)
Burmese (30)                    0               11 (NS)
Karen (30)                      0              8.4 (NS)
Malaysians (31)                 1              12.7 (NS)
Filipino (32)                   --              25 (NS)

West Asia

Turkish (33)                    0             1 (<0.001)
Jewish Israel (34)              0             2.8 (0.015)
Saudi Arabia (32)               --             2 (0.017)

Oceania

Vanuatu and other               --            61 (<0.001)
  Pacific islands
  (51)
Australian                      --           25.6 (<0.001)
  aborigines (52)

Europe

Russians (35)                   0             2 (<0.001)
Italians (36)                   0            1.7 (<0.001)
Croatians (37)                  0             3 (<0.001)
Belgian (38)                    0             1.6 (0.005)
Germans (33)                    --            4.3 (0.017)
Portuguese (39)                 --              1 (NS)

North America and Canada

Canadian Native                 --              7 (NS)
  (40) Indian (32)
Americans                       --             2 (0.011)

South America

Bolinian (41)                   0              1 (0.001)
Faroese (42)                    0             3.2 (0.003)
Swedish (43)                    0             1.2 (0.011)
Danish (44)                     0             3.8 (0.014)

Africa

Africans                        0             3.7 (0.002)
  Americans (45)
Egiptians (46)                  0             0.8 (0.001)
Ethiopians (47)                 0              5.3 (NS)
Tanzanians (48)                 0             3.2 (0.005)
Zimbabweans (49)                0              3.6 (NS)
Venda (50)                      0               7 (NS)
Beninese (38)                   0             0 (<0.001)

Differences in the allele frequencies were determined by Fisher exact
test. NS: No significant differences.
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Title Annotation:Original Articles
Author:Tabari, Robabeh Ghiyas; Marjani, Abdoljalal; Ataby, Ogholdondy Agh; Mansourian, Azad Reza; Samai, Na
Publication:Oman Medical Journal
Article Type:Report
Geographic Code:7IRAN
Date:Jul 1, 2013
Words:5903
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