The genetic landscape of major drug metabolizing cytochrome P450 genes-an updated analysis of population-scale sequencing data

Abstract

Genes encoding cytochrome P450 enzymes (CYPs) are extremely polymorphic and multiple CYP variants constitute clinically relevant biomarkers for the guidance of drug selection and dosing. We previously reported the distribution of the most relevant CYP alleles using population-scale sequencing data. Here, we update these findings by making use of the increasing wealth of data, incorporating whole exome and whole genome sequencing data from 141,614 unrelated individuals across 12 human populations. We furthermore extend our previous studies by systematically considering also uncharacterized rare alleles and reveal that they contribute between 1.5% and 17.5% to the overall genetically encoded functional variability. By using established guidelines, we aggregate and translate the available sequencing data into population-specific patterns of metabolizer phenotypes. Combined, the presented data refine the worldwide landscape of ethnogeographic variability in CYP genes and aspire to provide a relevant resource for the optimization of population-specific genotyping strategies and precision public health.

Fig. 1. Ethnogeographic distribution of the inferred functional consequences of well-characterized CYP star alleles.

Frequencies of inactive (dark red), reduced activity (light red), normal (blue) and increased activity (green) alleles shown in Tables 1–5 were aggregated for CYP2A6 (a), CYP2B6 (b), CYP2C8 (c), CYP2C9 (d), CYP2C19 (e), CYP2D6 (f), CYP3A4 (g) and CYP3A5 (h) genes across 12 populations. Star alleles with unclear functional consequences were considered as normal. EUR European, SE South European, NEW North-West European, FIN Finnish, EAS East Asian, JP Japanese, KR South Korean, SAS South Asian.

Fig. 2. The landscape of genetic variability in major drug-metabolizing CYP genes.

a Across 141,614 individuals, a total of 10,176 genetic variants were identified 6016 of which were exonic. Pie charts indicate the distribution of exonic variants across variant classes. b The majority of exonic variants have MAFs < 1% (98.8%) or <0.1% (96.8%). c Stacked column plot showing the number of identified exonic variants for each analyzed CYP gene (left y-axis). White dots indicate the number of variants per base pair (bp; right y-axis). All variants were categorized into deleterious (red) or neutral (green) using the ADME Prediction Framework (see Methods). The fraction of putatively deleterious variants (including both reduced function and loss-of-function variants) for each CYP gene is shown. A list of all putatively deleterious variants and their estimated activity scores is provided in Supplementary Table 2. d Functional contribution of star alleles and non-star alleles to the overall functional variability of CYP genes. Black numbers indicate the aggregated frequencies of functional star alleles and non-star alleles. The ratio of the genetically encoded functional variability allotted to non-star alleles and star alleles is indicated by the red percentage values. e Functional contribution of non-star alleles to the population-specific functional variability of CYP genes. Only the top 5 and bottom 5 gene-population pairs are shown. All population-specific contributions of non-star alleles are shown in Supplementary Table 3. AFR African, EAS East Asian, SAS South Asian, AMR admixed Americans, FIN Finnish, AJ Ashkenazi Jewish, MAF minor allele frequency, UTR untranslated region.

Fig. 3. Global distributions of metabolic phenotypes.

Frequencies of inferred population-specific metabolic phenotypes are shown for CYP2A6 (a), CYP2B6 (b), CYP2C8 (c), CYP2C9 (d), CYP2C19 (e), CYP2D6 (f), CYP3A4 (g) and CYP3A5 (h). Numbers indicate the fraction of poor metabolizers (PM; dark red), intermediate metabolizers (IM; light red) and rapid metabolizers (RM; green). The fraction of non-normal metabolizers is indicated by the size of circles on the respective world maps. AFR African, EAS East Asian, SAS South Asian, AMR admixed Americans, FIN Finnish, AJ Ashkenazi Jewish, ME Middle Eastern, EUR non-Finnish European.