Variation in genes involved in the absorption, distribution, metabolism, and excretion of drugs (ADME) can influence individual response to a therapeutic treatment. The study of ADME genetic diversity in human populations has led to evolutionary hypotheses of adaptation to distinct chemical environments. Population differentiation in measured drug metabolism phenotypes is, however, scarcely documented, often indirectly estimated via genotype-predicted phenotypes. We administered seven probe compounds devised to target six cytochrome P450 enzymes and the P-glycoprotein (P-gp) activity to assess phenotypic variation in four populations along a latitudinal transect spanning over Africa, the Middle East, and Europe (349 healthy Ethiopian, Omani, Greek, and Czech volunteers). We demonstrate significant population differentiation for all phenotypes except the one measuring CYP2D6 activity. Genome-wide association studies (GWAS) evidenced that the variability of phenotypes measuring CYP2B6, CYP2C9, CYP2C19, and CYP2D6 activity was associated with genetic variants linked to the corresponding encoding genes, and additional genes for the latter three. Instead, GWAS did not indicate any association between genetic diversity and the phenotypes measuring CYP1A2, CYP3A4, and P-gp activity. Genome scans of selection highlighted multiple candidate regions, a few of which included ADME genes, but none overlapped with the GWAS candidates. Our results suggest that different mechanisms have been shaping the evolution of these phenotypes, including phenotypic plasticity, and possibly some form of balancing selection. We discuss how these contrasting results highlight the diverse evolutionary trajectories of ADME genes and proteins, consistent with the wide spectrum of both endogenous and exogenous molecules that are their substrates.

Center for Global Genomics and Health Equity Department of Genetics Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA

Center for Innovative Drug Development and Therapeutic Trials for Africa College of Health Sciences Addis Ababa University Addis Ababa Ethiopia

College of Pharmacy National University of Science and Technology Muscat Sultanate of Oman

Department of Anthropology and Human Genetics Faculty of Science Charles University Prague Czech Republic

Department of Genetics and Evolution University of Geneva Geneva Switzerland

Department of Genetics College of Medicine and Health Sciences Sultan Qaboos University Muscat Sultanate of Oman

Department of Genetics Sultan Qaboos University Hospital Muscat Sultanate of Oman

Department of Medical Genetics 3rd Faculty of Medicine Charles University Prague Czech Republic

Department of Medicine Democritus University of Thrace Medical School Alexandroupolis Greece

Department of Molecular Biology and Genetics Democritus University of Thrace Alexandroupolis Greece

Department of Pharmacology and Clinical Pharmacy College of Health Sciences Addis Ababa University Addis Ababa Ethiopia

Division of Clinical Pharmacology and Toxicology Geneva University Hospitals and University of Geneva Geneva Switzerland

Institute of Archaeology of the Academy of Sciences of the Czech Republic Prague Czech Republic

Institute of Genetics and Genomics of Geneva Geneva Switzerland

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