Human Genomic Population Structure and Phenotype-genotype Variation in ADME Genes in Four Populations

Exploratory Study of the Variability, in Five Human Populations, of ADME (Administration, Distribution, Metabolism, Excretion) Genotypes and Phenotypes After the Intake of the "Geneva Micrococktail"

Physicians know that their patients can react differently to the same medical treatment: for some of them, the drug will prove inefficient, whereas for others it might provoke side-effects, sometimes rather serious. Such differences in response to drug intake are due to several factors, of which molecular variations in specific genes, named " ADME " (Absorption, Distribution, Metabolism, Excretion). This project aims at investigating the evolutionary mechanisms responsible for the diversity of ADME genes in human populations. Because of their role at the interface between the organism and its chemical environment, ADME genes are likely targets of recent selective pressures linked to changes in the environments in which humans evolved, such as changes in dietary habits for instance.

The aim of this project is to study the diversity of ADME genes and of their expression in five populations located along a latitudinal axis that extends from East Africa to Central Europe, passing through the Arabian Peninsula and the Mediterranean area, so as to take into account environmental factors that might have influenced the evolution of this diversity. This project is thus intended to evidence the evolutionary mechanisms that shaped genomic regions that are functionally important from the clinical and epidemiological point of view. Moreover, it will allow us to extend the knowledge of human molecular diversity and its evolution to a key-region of the peopling history of our species.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Phenotyping; Genetic: Genotyping

• Study Type: Interventional
• Enrollment (Actual): 367
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Czechia
  • Praha 2, Czechia, 128 43
    • Charles University in Prague/Faculty of Science/Department of Anthropology and Human Genetics
• Ethiopia
  • Addis Ababa, Ethiopia, P.O.Box 9086
    • Addis Ababa University/College of Health Sciences
• Greece
  • Alexandroupolis, Greece, 68100
    • Democritus University of Thrace/School of Health Sciences/University Campus, Dragana
• Oman
  • Muscat, Oman, P. O. Box 50
    • Sultan Qaboos University/College of Medicine and Health Sciences/Department of Pharmacology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Women and men in good health
• Aged between 18 and 50 years
• Students or staff in the Academic Institutions where sampling will take place
• With the 2 parents and four grand-parents born to the population;
• Able to provide informed consent

Exclusion Criteria:

• Pregnant or breastfeeding women; or women that consider that being pregnant is a possibility;
• Allergic to one of the compounds included in micrococktail (Caffeine, Bupropion, Flurbiprofen, Omeprazole, Dextromethorphan, Midazolam, and Fexofenadine);
• Pedigree related to another volunteer participant (siblings, cousins, uncles/aunts, nephews, etc.);

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Healthy volunteers in Ethiopia; Phenotype and genotype of enzymes involved in drug metabolism in Ethiopia population	Drug: Phenotyping; finger-tip blood drop : enzymatic activities assessed by specific single point concentration ratios after oral intake of the Geneva micrococktail made of : CYP1A2: paraxanthine/caffeine CYP2B6: 4-hydroxybupropion/bupropion CYP2C9: 4-hydroxyflurbiprofen/flurbiprofen CYP2C19: 5-hydroxyomeprazole/omeprazole CYP2D6: dextrorphan/dextromethorphan CYP3A4: 1-hydroxymidazolam/midazolam; Genetic: Genotyping; DNA sampling from a saliva sample
Experimental: Healthy volunteers in Oman; Phenotype and genotype of enzymes involved in drug metabolism in Oman population	Drug: Phenotyping; finger-tip blood drop : enzymatic activities assessed by specific single point concentration ratios after oral intake of the Geneva micrococktail made of : CYP1A2: paraxanthine/caffeine CYP2B6: 4-hydroxybupropion/bupropion CYP2C9: 4-hydroxyflurbiprofen/flurbiprofen CYP2C19: 5-hydroxyomeprazole/omeprazole CYP2D6: dextrorphan/dextromethorphan CYP3A4: 1-hydroxymidazolam/midazolam; Genetic: Genotyping; DNA sampling from a saliva sample
Experimental: Healthy volunteers in the Czech Republic; Phenotype and genotype of enzymes involved in drug metabolism in Czech Republic population	Drug: Phenotyping; finger-tip blood drop : enzymatic activities assessed by specific single point concentration ratios after oral intake of the Geneva micrococktail made of : CYP1A2: paraxanthine/caffeine CYP2B6: 4-hydroxybupropion/bupropion CYP2C9: 4-hydroxyflurbiprofen/flurbiprofen CYP2C19: 5-hydroxyomeprazole/omeprazole CYP2D6: dextrorphan/dextromethorphan CYP3A4: 1-hydroxymidazolam/midazolam; Genetic: Genotyping; DNA sampling from a saliva sample
Experimental: Healthy volunteers in Greece; Phenotype and genotype of enzymes involved in drug metabolism in Greek population	Drug: Phenotyping; finger-tip blood drop : enzymatic activities assessed by specific single point concentration ratios after oral intake of the Geneva micrococktail made of : CYP1A2: paraxanthine/caffeine CYP2B6: 4-hydroxybupropion/bupropion CYP2C9: 4-hydroxyflurbiprofen/flurbiprofen CYP2C19: 5-hydroxyomeprazole/omeprazole CYP2D6: dextrorphan/dextromethorphan CYP3A4: 1-hydroxymidazolam/midazolam; Genetic: Genotyping; DNA sampling from a saliva sample

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequencies of genotypes and haplotypes of genes involved in drug responses (240,000 Single Nucleotide Polymorphisms) in 4 human populations : 100 Ethiopian, 100 Omani, 100 Czech and 100 Greek	Estimation of genotype/allele/haplotype frequencies of variants in genes involved in drug responses	through study completion, an average of 2 years
Activities of 6 cytochrome P450 enzymes and P-gp in 4 human populations : 100 Ethiopian, 100 Omani, 100 Czech and 100 Greek	Estimation of frequency distributions of classes of drug metabolizers (metabolizers' profiles: slow/normal/rapid)	through study completion, an average of 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of frequency distributions of variants in genes involved in drug responses and of associated metabolizers' profiles in 4 human populations : 100 Ethiopian, 100 Omani, 100 Czech and 100 Greek	Estimation of indices of population genetic/phenotypic diversity and differentiation (expected heterozygosity, Fst). Inferences on the evolutionary mechanisms explaining the estimated diversity among and between populations.	through study completion, an average of 3 year

Collaborators and Investigators

• Sponsor: Estella S. Poloni
• Collaborators: Swiss National Science Foundation
• Investigators: Study Chair: Estella S. Poloni, Dr, University of Geneva/Department of Genetics and Evolution

Publications and helpful links

General Publications

• Rollason V, Mouterde M, Daali Y, Cizkova M, Priehodova E, Kulichova I, Posova H, Petanova J, Mulugeta A, Makonnen E, Al-Habsi A, Davidson R, Al-Balushi KK, Al-Thihli K, Cerna M, Al-Yahyaee S, Cerny V, Yimer G, Poloni ES, Desmeules J. Safety of the Geneva Cocktail, a Cytochrome P450 and P-Glycoprotein Phenotyping Cocktail, in Healthy Volunteers from Three Different Geographic Origins. Drug Saf. 2020 Nov;43(11):1181-1189. doi: 10.1007/s40264-020-00983-8.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Actual): April 1, 2017
• Study Completion (Actual): April 1, 2017

Study Registration Dates

• First Submitted: May 11, 2016
• First Submitted That Met QC Criteria: May 27, 2016
• First Posted (Estimate): June 3, 2016

Study Record Updates

• Last Update Posted (Actual): May 10, 2017
• Last Update Submitted That Met QC Criteria: May 9, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: healthy volunteers
• Other Study ID Numbers: 15-169

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided