Does ethnicity impact CYP2D6 genotype–phenotype relationships?

Abstract

Polymorphism of the CYP2D6 gene leads to substantial interindividual variability in CYP2D6 enzyme activity. Despite improvements in prediction of CYP2D6 activity based on genotype information, large interindividual variability within CYP2D6 genotypes remains and ethnicity could be a contributing factor. The aim of this study was to investigate interethnic differences in CYP2D6 activity using clinical datasets of three CYP2D6 substrates: (i) brexpiprazole (N = 476), (ii) tedatioxetine (N = 500), and (iii) vortioxetine (N = 1073). The CYP2D6 activity of all individuals in the dataset was estimated through population pharmacokinetic analyses as previously reported. Individuals were assigned a CYP2D6 phenotype and CYP2D6 genotype group based on their CYP2D6 genotype and interethnic differences were investigated within each group. Among individuals categorized as CYP2D6 normal metabolizers, African Americans had a lower CYP2D6 activity compared to Asians (p < 0.01) and in the tedatioxetine and vortioxetine analyses also compared to Whites (p < 0.01). Among CYP2D6 intermediate metabolizers, interethnic differences were also observed, but the findings were not consistent across the substrates. Asian carriers of CYP2D6 decreased function alleles tended to exhibit higher CYP2D6 activity compared to Whites and African Americans.The observed interethnic differences within the CYP2D6 phenotype and genotype groups appeared to be driven by differences in CYP2D6 allele frequencies across ethnicities rather than interethnic differences in enzyme activity for individuals carrying identical CYP2D6 genotypes. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Substantial interindividual variability in CYP2D6 activity exists which is largely explained by genetic polymorphism. It has been hypothesized that other factors, such as ethnicity, may also contribute to the variability.

Using population pharmacokinetic analyses of drugs metabolized by CYP2D6 to study the genotype–phenotype translation

“…For example, a study comparing Ethiopians in Ethiopia, Ethiopians in Sweden and Caucasian Swedes with the same CYP2D6 genotypes found significant differences in their CYP2D6 metabolic capacity measured by the MR for debrisoquine, suggesting that ethnicity as well as environmental factors may contribute to variability in CYP2D6 enzyme activity 48 . In a recent study investigating interethnic differences in CYP2D6 genotype–phenotype relationships based on the three popPK analyses, we did not find evidence to suggest a significant impact of ethnicity on CYP2D6 metabolism of vortioxetine, tedatioxetine or brexpiprazole 49 …”

“…48 In a recent study investigating interethnic differences in CYP2D6 genotype-phenotype relationships based on the three popPK analyses, we did not find evidence to suggest a significant impact of ethnicity on CYP2D6 metabolism of vortioxetine, tedatioxetine or brexpiprazole. 49 Although it is widely recognized that genetic variation is the most important single factor explaining variability in CYP2D6 enzyme activity, the contribution of other factors cannot be overlooked. The impact of physiological, pathological and environmental factors on CYP2D6 activity is still poorly understood.…”