1. Introduction

Pharmacogenomics is an important tool in personalized medicine. There is wide variability in the response of individuals to standard doses of drug therapy which can lead to therapeutic failures or adverse drug reactions ^[1]. Polymorphism in drug-metabolizing enzymes is of great importance for inter-individual differences in drug therapy ^[2]. P-glycoprotein (P-gp) is a 170-kD plasma glycoprotein that was discovered in multidrug-resistance cancer cells ^[3]. P-gp is expressed in the liver, kidney, pancreas, small intestine and colon, adrenal gland, brain and testes ^{[4, 5, 6, 7]}. P-gp is encoded by multidrug resistance gene (MDR1/ABCB1). Because of its crucial role in pharmacokinetics, it is one of the most widely studied ATP-binding membrane transporters ^[8]. P-gp functions as an ATP-dependent drug efflux pump with broad substrate specificity, protecting the cell by transporting toxic metabolites out of it ^[9].

The MDR1 gene is located on chromosome 7q21.12 and consists of 28 exons and can encode a protein of 1280 amino acids ^[10]. It is highly polymorphic and over 50 single nucleotide polymorphisms (SNPs) have been reported for MDR1 gene, of which more than 20 are known to be silent ^{[8, 11]}. SNPs may change the protective role of P-gp and thus influence disease risk ^[12]. One of the most popular MDR1 polymorphism, C3435T SNP (rs1045642), is a silent mutation and locates in exon 26. It affects the expression and function of P-gp ^[13]. C3435T SNP is associated with altered P-gp expression and substrate drug pharmacokinetics ^[12], and also with increased risk of some diseases (renal tumor, Crohn’s disease, ulcerative colitis, Parkinson’s disease, HIV infection) ^[14]. The intestinal P-gp expression is much higher in individuals with the 3435CC genotype than those with the 3435TT genotype ^{[13, 15]}.

The frequencies of the MDR-1 alleles have been studied in many ethnic groups, and demonstrated interethnic variation in their distribution. The frequency of the homozygous CC genotype was highest among Africans and lowest in the South-west Asians ^[16]. Heterozygous individuals displayed an intermediate phenotype ^[17]. However, limited information is available for Jordanian and Sudanese populations regarding the distribution of C3435T polymorphism. The present study investigated the frequencies of the MDR-1 (C3435T) gene polymorphism in 116 Jordanians and 131 Sudanese individuals, providing a basis for future clinical studies concerning variability in the bioavailability to drugs known to be substrates for MDR-1.

2. Materials and Methods

In this study 247 unrelated healthy Jordanian and Sudanese volunteers of both sexes were investigated (without a history of chronic diseases like cancer, hepatitis, HIV and neural diseases and none of the participants were receiving continuous medical treatment (substrates for P-gp)). The Jordanian sample studied were collected randomly from 116 unrelated healthy subjects (age ranges from 18 to 65 years old) of which 44 were males and 72 were females from the city of Amman and the Sudanese sample, included 131 unrelated healthy subjects, were recruited randomly from the city of Khartoum (age ranges from 20 to 60 years old) of which 53 were males and 78 were females under institutionally approved internal review board protocols, with informed consent. Genomic DNA was prepared from whole blood by standard methods ^[18].

DNA samples were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method ^[19]. A 231-bp fragment was amplified with the following primers: MDR-1 Forward primer 5'- ACTCTTGTTTTCAGCTGCTTG-3' and MDR-1 Reverse primer 5'-AGAGACTTACATTAGGCAGTGACTC-3'. PCR amplification consisted of an initial denaturation step at 94°C for 4 min followed by 32 cycles of denaturation at 94°C for 30 s, annealing at 56°C for 30 s, and extension at 72°C for 30 s. The final extension step was performed at 72°C for 10 min. The PCR products were digested with the restriction enzyme Bfu CI at 37°C overnight. The digested products were separated on a 3% agarose gel. The wild-type C allele contains a Bfu CI restriction site. Digestion of the 231-bp fragment yielded two fragments of 163 and 68 bp. All subjects were genotyped twice for all the tested mutations, which makes the possibility of genotyping error less likely.

Statistical analysis was performed using SPSS statistical package for Windows (version 19). Allele and genotype frequencies were calculated by direct counting. The Hardy-Weinberg equilibrium was assessed by an exact test ^[20] provided by the Arlequin program (version 3.0) ^[21]. Differences in allele frequencies between Jordanians and Sudanese, and other ethnic groups were measured using Chi square test and Fisher’s exact test. A P-value <0.05 was considered statistically significant.

3. Results

Genotyping of C3435T SNP of MDR1 gene was assessed by PCR-RFLP in 116 Jordanians and 131 Sudanese subjects. The genotype and allele frequencies obtained for Jordanian and Sudanese individuals are summarized in Table 1. The genotype frequencies of the C3435T SNP in Jordanian subjects were: CC 20.7%, CT 51.7% and TT 27.6%. C and T allele frequencies were 0.466 and 0.534, respectively.

Table 1. Genotype, allele frequencies, and heterozygosities of the MDR1 gene C3435T polymorphism in Jordanian and Sudanese subjects

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In 131 Sudanese subjects, 52.7% were homozygous for CC genotype, 42.0% were heterozygous for CT genotype and 5.3% were homozygous for TT genotype.

Figure 1. Electrophoresis patterns for MDR1 genotypes by PCR-RFLP based assay. M is a 100 bp DNA marker. Samples 1, 4, 7 and 8 are homozygous CC genotype (Has Bfu CI restriction site). Samples 5 and 6 are homozygous TT genotype (Lack Bfu CI restriction site). Sample 2 and 3 are heterozygous CT genotype.

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In Jordanians, the frequencies of the 3435C wild-allele and the 3435T variant were found to be 0.466 and 0.534, respectively. In Sudanese, the frequencies of the 3435C wild-allele and the 3435T variant were found to be 0.737 and 0.263, respectively. Figure 1 shows the electrophoresis patterns for the MDR1 C3435T genotypes analyzed by PCR-RFLP.

The results (Table 1) were in good accordance with the expected genotype distributions of the tested genes, calculated by the Hardy–Weinberg law (p > 0.05, Chi squared goodness of fit). The frequencies of the tested alleles in Jordanian and Sudanese subjects, compared with data reported for other ethnic groups are given in Table 2.

Table 2. Genotype and allele frequencies of MDR-1 gene C3435T polymorphism in various ethnic groups

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4. Discussion

The medicine will move from being largely reactive to being predictive, personalized, preventive and participatory. Personalized medicine will focus on the integrated diagnosis, treatment and prevention of disease in individual patients. This will tailor drug therapy at a dosage that is most appropriate for an individual patient, with the potential benefits of increasing the efficacy and safety of medications ^[22].

P-gp, encoded by MDR1gene, is an ATP-dependent efflux pump which can drive intracellular toxins and drug metabolites of the cell. Single-nucleotide polymorphisms in MDR1 gene are associated with variation in the P-gp expression. Lower expression of P-gp would reduce the protection for cells and may contribute to disease susceptibility ^[23]. Although P-gp expression is highly variable between individuals, the molecular basis for this variation was not clear until recently, with the description of functional (C3435T) SNP in exon 26 of the MDR-1 gene ^[13]. The silent mutation C3435T is the most commonly reported polymorphism linked to different responses of patients to various MDR1 substrates. The frequency of this mutation is not uniformly distributed among diverse population, but ethnic and geographical differences were observed ^[24].

The present study investigated the frequency of the C3435T SNP in MDR1 gene among unrelated Jordanian and Sudanese subjects, and compared the results with data reported for other ethnic groups (Table 2). The results obtained in Jordanians showed genotype frequencies of 20.7%, 51.7%, and 27.6% for CC, CT and TT genotypes, respectively, while that obtained in Sudanese showed genotype frequencies of 52.7%, 42.0%, and 5.3% for CC, CT and TT genotypes, respectively.

The frequencies of the wild C-allele (0.466) and the wild-genotype CC (20.7%) in Jordanians subjects were different significantly from that reported in Sudanese (0.737 and 52.7%). This could be due to higher frequency of the C-allele found in Sudanese population.

Our results give the evidence that the frequencies of MDR1 alleles, and genotypes determined in Jordanians, are very similar to the respective frequencies observed in Bahrainis and Saudi Arabians which may be attributed to their common Arab origin. Interestingly, the frequency of the wild C-allele in Jordanian subjects did not differ from that reported in Asian populations, apart from Japanese, including Iranian, Turkish, Indians, and Chinese and in European populations including British, Spanish, Germans, and French.

However, the frequency of 3435T variant in Jordanians subjects, most often associated with a decreased P-gp activity, is significantly higher compared to populations of African origin (Kenyan, Ghanaian, Moroccan and Egyptians). Significant differences in C3435T genotype distribution were seen between Jordanians and Ashkenazi Jews. The Jordanian samples in our study did not show any statistically significant difference from a previous study done by Khabour ^[25] on a smaller number of Jordanians (100 subjects).

As regards the Sudanese, the frequency of the wild CC genotype and C-allele were similar to that present in Africans (Moroccan, Kenyan) which may be attributed to their common origin.

Interestingly, the frequency of the wild C-allele in Sudanese subjects did not differ from that reported Ashkenazi Jews. The Sudanese samples in our study was similar to a previous study done by Ameyaw ^[16] on a smaller number of Sudanese (51 subjects).

However, the frequencies of the wild C-allele (0.737) and the wild-genotype CC (52.7%) in Sudanese subjects were higher and significantly different from that reported in Asian populations (Bahraini, Saudi Arabians, Iranian, Turkish, Indians, Chinese and Japanese) and in European populations (British, Spanish, German and French).

There was a significant relationship of the silent C3435T SNP with intestinal P-gp expression levels. Individuals who were homozygous for the 3435T variant had significantly decreased intestinal P-gp expression ^[13]. About 27.6% of Jordanian and 5.3% of Sudanese subjects were homozygous for the 3435T variant and 51.7% of Jordanians and 42% of Sudanese had at least one T allele, with lower P-gp level in small intestine. As P-gp has an important role in the bioavailability of a wide variety of drugs, including anticancer, antihypertensive, antiarrythmics, antiviral, glucocorticoids, antibiotics, immunosuppressants, antidepressants, neuroleptics, opioids and many others ^{[26, 27]}. So, these drugs must be used cautiously in those subjects.

MDR1 gene encodes P-gp which functions as a physiologic intestinal barrier against drug absorption including clopidogrel and digoxin. Clopidogrel, an antiplatelet drug, reduces the cardiovascular complications in patients with coronary artery disease. The response to clopidogrel varies greatly among patients. Simon ^[28] reported that acute myocardial infarction patients on clopidogrel carrying 3435T variant of MDR1 presented more than five times the rate of adverse events of patients with wild-type genotype. Also, Shalia ^[29] observed that the prevalence of 3435T variant of MDR1 was associated with decrease clopidogrel response in patients with acute myocardial infarction. In their meta-analysis, Su ^[30] showed that the MDR1 3435T variant carrier was related to the risk of major adverse cardiovascular events in patients on clopidogrel and TT homozygotes decreased the outcome of bleeding compared with CC homozygotes. Since digoxin is not subject to metabolic transformation, it has been used as a model for substrate for the study of phenotype-genotype relationships of MDR1 polymorphism. Several studies investigated the functional significance of C3435T SNP on the disposition of digoxin revealed conflicting results ^{[31, 32]}. In their meta-analysis in Caucasian and Japanese subjects Chowbay ^[31] indicted that the MDR1 C3435T SNP does not affect the pharmacokinetics of digoxin while Aarnoudse ^[32] found an association between 3435T variant of MDR1 gene with increased digoxin serum concentration.

The substrate specificity of P-gp is altered by synonymous and silent SNPs. It has been suggested that silent SNPs may affect protein translation rates hence influencing protein folding and activity. Therefore, silent SNPs that do not change the coding sequence of the protein may contribute to altered pharmacokinetics of substrate drugs and development of certain disease conditions ^[33]. Recently, it has been reported that a silent C3435T SNP may change mRNA stability, thus it can be considered as a determinant of MDR1 expression ^[34]. Several studies have demonstrated linkage disequilibrium between C3435T polymorphism in exon 26 and other SNPs of MDR1 gene, especially G2677T in exon 21, suggesting that the functional effects may be rather haplotype dependent ^[35].

The Europeans and Asians had lower frequencies of the C-allele compared to that of Africans. The high frequency of the C-allele in Africans implies overexpression of P-gp. As overexpression of P-gp has been associated with altered drug absorption, therapy resistant malignancies, this SNP may provide a useful approach to individualize therapy and it may have important therapeutic and prognostic implications for use of P-gp dependent drugs in Sudanese.

The association of MDR1 allele frequencies with certain drugs and diseases constitute a topic of intense research ^{[36, 37]}. Kim ^[38] showed lack of association between C3435T SNP and multidrug resistant epilepsy. Also, Mihaljevic-Peles ^[39] showed no association with therapeutic response to paroxetine in patients with major depressive disorder, while evidence is accumulating in favor of an association between MDR1 gene polymorphism and altered risk of different diseases ^{[14, 33]}. Association studies between 3435T allele and other SNPs of MDR1 gene and various diseases and drug responses in Jordanian and Sudanese populations are needed.

5. Conclusion

Jordan is located in Southwest Asia and its population is predominantly Arab ^[40] while Sudan is located in northeastern Africa and its people show considerable ethnic, cultural and linguistic diversity ^[41]. Thus, according to the distribution of the C3435T SNP, the Jordanian population is more closely related to Caucasian and Asian populations while the Sudanese is more closely related to Africans. The results of MDR-1 genotyping in Jordanian and Sudanese subjects may provide a framework for more rational use of drugs that are substrates for MDR-1. The description of these alleles does not exclude the possibility of the presence of new SNPs unique to these populations. This study put the base of future studies of the relationships between MDR1 polymorphisms and various diseases and drug responses.

Acknowledgment

The authors thank all people who willingly participated in this study. This work is supported by Arabian Gulf University grant number 60 to A.-H Salem.

Conflict of interest

The authors declared no conflict of interest.

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