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

NCT02789527 | Completed

• 1 other identifier: 15-169
• Study Type: interventional
• Target: 367
• Locations: 4 countries
• Sites: 4

Brief Summary

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.

Conditions

Healthy

Keywords

healthy volunteers

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (1)

• 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

  through study completion, an average of 3 year

Study Arms (4)

Healthy volunteers in Ethiopia

EXPERIMENTAL

Phenotype and genotype of enzymes involved in drug metabolism in Ethiopia population

Drug: Phenotyping; Genetic: Genotyping

Healthy volunteers in Oman

EXPERIMENTAL

Phenotype and genotype of enzymes involved in drug metabolism in Oman population

Drug: Phenotyping; Genetic: Genotyping

Healthy volunteers in the Czech Republic

EXPERIMENTAL

Phenotype and genotype of enzymes involved in drug metabolism in Czech Republic population

Drug: Phenotyping; Genetic: Genotyping

Healthy volunteers in Greece

EXPERIMENTAL

Phenotype and genotype of enzymes involved in drug metabolism in Greek population

Drug: Phenotyping; Genetic: Genotyping

Interventions

Phenotyping DRUG

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

Healthy volunteers in Ethiopia; Healthy volunteers in Greece; Healthy volunteers in Oman; Healthy volunteers in the Czech Republic

Genotyping GENETIC

DNA sampling from a saliva sample

Healthy volunteers in Ethiopia; Healthy volunteers in Greece; Healthy volunteers in Oman; Healthy volunteers in the Czech Republic

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.);

Sponsors & Collaborators

• Estella S. Poloni: lead
• Swiss National Science Foundation: collaborator

Study Sites (4)

Charles University in Prague/Faculty of Science/Department of Anthropology and Human Genetics

Prague, 128 43, Czechia

Location

Addis Ababa University/College of Health Sciences

Addis Ababa, P.O.Box 9086, Ethiopia

Location

Democritus University of Thrace/School of Health Sciences/University Campus, Dragana

Alexandroupoli, 68100, Greece

Location

Sultan Qaboos University/College of Medicine and Health Sciences/Department of Pharmacology

Muscat, P. O. Box 50, Oman

Location

Related Publications (1)

• 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.

  PMID: 32851583 DERIVED

MeSH Terms

Interventions

Immunophenotyping; Genotype

Intervention Hierarchy (Ancestors)

Immunologic Tests; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Immunologic Techniques; Genetic Phenomena

Study Officials

• Estella S. Poloni, Dr

  University of Geneva/Department of Genetics and Evolution

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Dr

Study Record Dates

• First Submitted: May 11, 2016
• First Posted: June 3, 2016
• Study Start: November 1, 2015
• Primary Completion: April 1, 2017
• Study Completion: April 1, 2017
• Last Updated: May 10, 2017

Record last verified: 2017-05

Locations

CZ (1); ET (1); GR (1); OM (1)