Frequencies of CYP2D6 genetic polymorphisms in Arab populations

Abstract

CYP2D6 is a key drug-metabolizing enzyme implicated in the biotransformation of approximately 25% of currently prescribed drugs. Interindividual and interethnic differences in CYP2D6 enzymatic activity, and hence variability in substrate drug efficacy and safety, are attributed to a highly polymorphic corresponding gene. This study aims at reviewing the frequencies of the most clinically relevant CYP2D6 alleles in the Arabs countries. Articles published before May 2021 that reported CYP2D6 genotype and allelic frequencies in the Arab populations of the Middle East and North Africa (MENA) region were retrieved from PubMed and Google Scholar databases. This review included 15 original articles encompassing 2737 individuals from 11 countries of the 22 members of the League of Arab States. Active CYP2D6 gene duplications reached the highest frequencies of 28.3% and 10.4% in Algeria and Saudi Arabia, respectively, and lowest in Egypt (2.41%) and Palestine (4.9%). Frequencies of the loss-of-function allele CYP2D6*4 ranged from 3.5% in Saudi Arabia to 18.8% in Egypt. The disparity in frequencies of the reduced-function CYP2D6*10 allele was perceptible, with the highest frequency reported in Jordan (14.8%) and the lowest in neighboring Palestine (2%), and in Algeria (0%). The reduced-function allele CYP2D6*41 was more prevalent in the Arabian Peninsula countries; Saudi Arabia (18.4%) and the United Arab Emirates (15.2%), in comparison with the Northern Arab-Levantine Syria (9.7%) and Algeria (8.3%). Our study demonstrates heterogeneity of CYP2D6 alleles among Arab populations. The incongruities of the frequencies of alleles in neighboring countries with similar demographic composition emphasize the necessity for harmonizing criteria of genotype assignment and conducting comprehensive studies on larger MENA Arab populations to determine their CYP2D6 allelic makeup and improve therapeutic outcomes of CYP2D6- metabolized drugs.

The frequencies of CYP2D6 alleles and their impact on clinical outcomes of adjuvant tamoxifen therapy in Syrian breast cancer patients

“…However, due to the highly polymorphic nature of the gene encoding CYP2D6 and the multitude of allelic variants (over 140), a major limitation of our study is the relatively limited alleles identified (23 star alleles), which may lead to a faulty assignment of the wild-type allele in patients carrying deleterious SNPs, and consequently some misclassification of patients’ phenotypes. Furthermore, we did not assess the UM phenotype which is mostly predominant among Arabs (9.2%) [ 10 ]. Duplication events are observed for numerous alleles, thus doubling the value assigned for the allele being duplicated.…”

“…Despite the multitude of genetic studies evaluating the frequencies of CYP2D6 alleles worldwide, the genetic profile of CYP2D6 in the Middle East populations is quite underestimated [ 10 ]. Moreover, pharmacogenetic studies assessing the influence of CYP2D6 genotypes on tamoxifen efficacy in breast cancer patients from this region are rather scarce.…”

Personalizing Atomoxetine Dosing in Children with ADHD: What Can We Learn from Current Supporting Evidence

“…Previous studies have shown that there are more than 100 alleles and 80 mutation sites on the CYP2D6 gene sequence, and its abundant genetic polymorphisms are the biological basis for individual activity differences (Alali, Ismail Al-Khalil, Rijjal, Al-Salhi, Saifo & Youssef, 2022;Brown et al, 2019b;Corponi, Fabbri & Serretti, 2019;Gaedigk et al, 2010). In general,CYP2D6 variant alleles can be divided into normal functional alleles (e.g., CYP2D6*1 , *2 , *27, and *35 , encoding functional proteins), decreased function of alleles (e.g.,CYP2D6*10 , *17 , *29 , *36 , *41, and*47 , markedly decreased enzyme activity), and non-functional alleles (e.g., CYP2D6*3 , *4 , *5 , *6, and*14 , inactive alleles, not encoding functional proteins) (Alali, Ismail Al-Khalil, Rijjal, Al-Salhi, Saifo & Youssef, 2022;Caudle et al, 2020;Crews et al, 2014;Dorji, Tshering & Na-Bangchang, 2019;Gaedigk, Simon, Pearce, Bradford, Kennedy & Leeder, 2008;Swen et al, 2011).…”

“…Collectively,CYP2D6*4 , CYP2D6*17 , and CYP2D6*10 are the most common polymorphisms for Caucasians, black Africans, and Asians, respectively (Zhou et al, 2022). Determining the frequency of the CYP2D6 allele in different populations has important implications for improving genotype-guided prediction of drug treatment response (Alali, Ismail Al-Khalil, Rijjal, Al-Salhi, Saifo & Youssef, 2022;Liang et al, 2016).…”

“…The complexity of the CYP2D6 gene and allele combinations makes it quite challenging to convert the CYP2D6 genotype to phenotype (Alali, Ismail Al-Khalil, Rijjal, Al-Salhi, Saifo & Youssef, 2022). The CPIC and Dutch Pharmacogenetics Working Group (DPWG) have adopted and standardized the CYP2D6 genotype-to-phenotype translation system and the activity score (AS) system, respectively (Brown et al, 2019b;Caudle et al, 2020;Swen et al, 2011).…”