Prevalence of the CYP2D6*10 (C100T), *4 (G1846A), and *14 (G1758A) alleles among Iranians of different ethnicities

Ali Bagheri, Behnam Kamalidehghan, Maryam Haghshenas, Parisa Azadfar, Leila Akbari, Mohammad Hossein Sangtarash, Faramarz Vejdandoust, Fatemeh Ahmadipour, Goh Yong Meng, Massoud Houshmand, Ali Bagheri, Behnam Kamalidehghan, Maryam Haghshenas, Parisa Azadfar, Leila Akbari, Mohammad Hossein Sangtarash, Faramarz Vejdandoust, Fatemeh Ahmadipour, Goh Yong Meng, Massoud Houshmand

Abstract

The presence of polymorphisms in the CYP2D6 gene may modulate enzyme level and activity, thereby affecting individual responses to pharmacological treatment. Here, we compared the prevalence of the CYP2D6*10, *4, and 14* alleles in an Iranian population of different ethnicities with those of other populations. Allele and genotype frequency distributions of CYP2D6*10 variants and predicted phenotypes including extensive metabolizers, intermediate metabolizers, and poor metabolizers were analysed in blood samples of 300 unrelated healthy individuals in an Iranian population using polymerase chain reaction (PCR)-restriction fragment length polymorphism, PCR-single-strand conformation polymorphism, and direct genomic DNA sequencing. The CYP2D6*4 (G1846A) and *14 (G1758A) allelic frequencies were not detected in different ethnicities, demonstrating the absence of a significant contribution of these alleles in Iranian populations. However, the T/T, C/T, and C/C genotype frequencies of the CYP2D6*10 allele were significantly different (P<0.01) in all Iranian ethnic groups. Additionally, the frequency of the homozygous T/T variant of the CYP2D6*10 allele was significantly high in the Lure (P<0.017) and low in the Kurd (P<0.002) ethnicities. The frequency of the T/T variant of the CYP2D6*10 allele in central Iran was the highest (P<0.001), while the south of Iran had the lowest frequency (P<0.001). The frequency of the C/T variant of the CYP2D6*10 allele was significantly a bit high (P<0.001) in females compare to males, while the frequencies of the T/T variant in females is similar to males, which are 24.4% and 24.3%, respectively. In contrast to absence of the CYP2D6*4 (G1846A) and *14 (G1758A) alleles in Iranian populations of different ethnicities, the prediction of the CYP2D6*10 allele is required in drug research and routine treatment, where the information would be helpful for clinicians to optimize therapy or identify persons at risk of adverse drug reactions before clinical trials. Approximately 39.3% of subjects (24.3% homozygous T/T CYP2D6*10 as poor metabolizers and 15% heterozygous C/T CYP2D6*10 as intermediate metabolizers) had this allele; therefore, the harmful effects of drugs are relatively common among Iranians.

Keywords: CYP; Iranian population; antidepressants; antipsychotics; cytochrome P450 genes; pharmacogenetics; polymorphism.

Figures

Figure 1
Figure 1
PCR-RFLP analysis of the CYP2D6*10 allele using the HphI enzyme. Notes: Lane 1 indicates the PCR product; This enzyme generated four fragments of 362 bp, 262 bp, 100 bp, and 71 bp (lane 2) in the heterozygous C/T genotype; three fragments of 262 bp, 100 bp, and 71 bp (lane 3) in the homozygous T/T genotype; and two fragments of 362 bp and 71 bp (lane 4) in length in the wild-type C/C genotype. Abbreviation: PCR-RFLP, polymerase chain reaction-restriction fragment length polymorphism.
Figure 2
Figure 2
PCR-SSCP analysis of the CYP2D6*10. Notes: The two, three, and four bands in each lane represent the homozygous wild-type (C/C), homozygous (T/T), and heterozygous (C/T) alleles of the CYP2D6*10, respectively; Lanes 1 and 2 represent the heterozygous C/T genotype (four fragments), lane 3 represents the homozygous T/T genotype (three fragments), while lane 4 represents the wild-type C/C genotype (two fragments). Abbreviation: PCR-SSCP, polymerase chain reaction-single-strand conformation polymorphism.
Figure 3
Figure 3
PCR-sequencing of the CYP2D6*10 allele (C100T). Notes: The chromatogram shows the mutant allele (A) compared to the wild-type allele as highlighted in blue color (B); The arrows mark the polymorphism. Abbreviation: PCR, polymerase chain reaction.
Figure 4
Figure 4
Geographical distribution of the CYP2D6*10 genotypes among 300 normal Iranian individuals of different ethnicities. Notes: The T/T, C/T, and C/C genotype frequencies of CYP2D6*10 were significantly different (χ2=90.02, P<0.01): 24.3%, 15%, and 60.7%, respectively; The results indicate that the frequency of the homozygous T/T variant of CYP2D6*10 in the central Iran was the highest (χ2=15.354, P<0.001), while the south of Iran had the lowest frequency (χ2=23.164, P<0.001); The frequency of the heterozygous C/T variant of CYP2D6*10 allele is highest in the east and lowest in the west; The green, pink, yellow, blue, and red colors indicate the north, south, east, west, and center of Iran, respectively.
Figure 5
Figure 5
Frequency of the CYP2D6*10 allele in different populations.
Figure 6
Figure 6
Frequency of the CYP2D6*4 and CYP2D6*14 alleles in different populations. Notes: The CYP2D6*14 allele frequency was not determined in the Middle Eastern population. Americas is a study from a white North American population. Permission to reprint data from Clinical Pharmacogenetics Implementa tion Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Crews KR, Gaedigk A, Dunnenberger HM, et al; Clinical Pharmacogenetics Implementation Consortium. Clin Pharmacol Ther. 91(2). Copyright © (2012).

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Source: PubMed

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