Worldwide Distribution of Cytochrome P450 Alleles: A Meta-analysis of Population-scale Sequencing Projects

Abstract

Genetic polymorphisms in cytochrome P450 (CYP) genes can result in altered metabolic activity toward a plethora of clinically important medications. Thus, single nucleotide variants and copy number variations in CYP genes are major determinants of drug pharmacokinetics and toxicity and constitute pharmacogenetic biomarkers for drug dosing, efficacy, and safety. Strikingly, the distribution of CYP alleles differs considerably between populations with important implications for personalized drug therapy and healthcare programs. To provide a global distribution map of CYP alleles with clinical importance, we integrated whole-genome and exome sequencing data from 56,945 unrelated individuals of five major human populations. By combining this dataset with population-specific linkage information, we derive the frequencies of 176 CYP haplotypes, providing an extensive resource for major genetic determinants of drug metabolism. Furthermore, we aggregated this dataset into spectra of predicted functional variability in the respective populations and discuss the implications for population-adjusted pharmacological treatment strategies.

Figure 1

Distribution of the relative contributions of major cytochrome P450 (CYP) alleles in European, African, Asian, and American populations. Pie charts showing the relative contribution of common variants in CYP2A6 (a), CYP2B6 (b), CYP2C8 (c), CYP2C9 (d), CYP2C19 (e), CYP2D6 (f), CYP3A4 (g), and CYP3A5 (h) in five major populations. Only variants with a minor allele frequency in the respective population above 1% are shown, whereas all other variants analyzed in this study are summarized as “rare” (grey).

Figure 2

The genetic variability and their functional consequences differ drastically between major cytochrome P450 (CYP) genes and across populations. (a) Cumulative frequencies of all major variant alleles in Europeans (EUR; blue), Africans (AFR; red), East Asians (EAS; green), South Asians (SAS; purple), and admixed Americans (AMR; turquoise) are shown for each major CYP gene. Overall, CYP2D6 constitutes the most variable gene, whereas CYP3A4 is most conserved. (b) The expected functional consequences of allelic distributions across world populations are shown. Frequencies of haplotypes with decreased (blue), increased (green), and normal (red) functionality, as defined in Tables 1, 2, 3, 4, 5, were aggregated for each gene and population, revealing the spectrum of functional variability in major world populations.