Results and challenges of Cytochrome P450 2D6 (CYP2D6) testing in an ethnically diverse South Florida population

Abstract

Background This study focuses on the implementation of CYP2D6 genetic test profiling and the challenges associated with using standard pharmacogenetics panels in a diverse South Florida population. Methods A total of 413 participants were recruited to participate in this study through Nicklaus Children's Hospital. Buccal swabs were collected and tested using an extended CYP2D6 panel including 22 alleles. Phenotype, genotype, and allelic frequencies were compared among different racial and ethnic groups. Results The majority of participants (75.0%) self‐identified as Hispanics. Four alleles, CYP2D6*4, *17, *41, and *2A, showed a statistically significant difference between White Hispanics and Black Non‐Hispanics. Aggregate frequency of all alleles with decreased function varied between 2.8% and 50.0% in different racial and ethnic groups. Additionally, rare allele combinations were observed in this South Florida cohort. Conclusions The heterogeneity among Hispanic groups demonstrated in previous literature and by this study reflects the complexity of ethnicity and suggests that a more granular categorization is needed, one based on ancestry and migration history rather than primary language. Overall, we have determined that there are statistically significant differences in CYP2D6 allele frequencies in the distinct racial and ethnic populations of South Florida, demonstrating a unique genetic makeup within South Florida. However, overall, the frequencies of Poor Metabolizer, Normal Metabolizer, Intermediate Metabolizer, and Ultrarapid Metabolizer did not differ between racial and ethnic groups at a statistically significant level.

Cyrius: accurate CYP2D6 genotyping using whole genome sequencing data

“…Similarly, *10 is overestimated 4 in East-Asians and South-Asians and *4 is overestimated 38 in Europeans, particularly because a fraction of reported *10 or *4 alleles are *36 + *10 or *68 + *4 . Finally, we report a lower frequency for *41 in Africans, and *41 has not been consistently tested by its defining SNP across studies and is expected to be overestimated in Africans 31,40,41 .…”

Associations between Selected ADRB1 and CYP2D6 Gene Polymorphisms in Children with Ventricular and Supraventricular Arrhythmias

“…The family of the cytochrome P450 system consists of the isoenzyme CYP2D6 (Debrisoquine 4-hydroxylase), the most representative in liver tissue (6% of all CYP450: CYP3A4, CYP2C9, and others) [29,30] is involved in phase I metabolism of almost 25% of clinically important drugs [31][32][33]. The autosomal CYP2D6 gene is located on the long arm of chromosome 22 fragment q 13.1 (22q13.1); it consists of 4383 bp [34] grouped in nine exons and eight introns that produces an mRNA of 1655 bp [35,36], with a 1383 bp open reading frame encoding a 497 amino acid protein [29,37]. CYP2D6*4 (g.1846G > A, rs3892097) is characterized by a single-nucleotide polymorphism (transition from guanine to adenine) at position 1846 (first nucleotide) of exon 4, causing a truncated protein due to a defect in splicing [38][39][40][41].…”

Frequency of CYP2D6*3 and *4 and metabolizer phenotypes in three mestizo Peruvian populations

“…The CYP2D locus is made up of a gene cluster, a CYP2D6 gene, and two pseudogenes (CYP2D7 and CYP2D8), with 97% and 92% similarity, respectively (Kimura et al 1989;Zhou 2009). The autosomal CYP2D6 gene is located on the long arm of chromosome 22 fragment q 13.1 (22q13.1), it consists of 4383 bp (Ur Rasheed et al 2017) grouped in nine exons and eight introns that produces an mRNA of 1655 bp (Zanger et al 2004;Dorado et al 2017), with a 1383 bp open reading frame encoding a 497 amino acid protein (Salyakina et al 2019;Leitão et al 2020). More than 100 allelic variants have been described for this gene (https://www.pharmvar.org/gene/CYP2D6).…”

“…A high percentage (> 50%) of the mestizo population was observed in Lima, Tacna, and Junin (INEI 2018). Due to these considerations, we have decided to study CYP2D6*3 and CYP2D6*4 in populations of the three aforementioned provinces, the alleles being selected, as they are the most frequent in Latin American populations (Muñoz et al 1998) and in the world (Da Silva et al 2009), due to their population and interethnic variability and because they metabolize more 25% of drugs for clinical use (Sa- mer et al 2013;Salyakina et al 2019;Leitão et al 2020), mostly with a narrow therapeutic margin, so at standard doses with certain drugs, potential adverse effects (tricyclic antidepressants) can be observed, or absence of the pharmacological effect as in the case of codeine (Madadi and Koren 2008;Llerena et al 2014).…”