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

Healthy Clinical Trial

Official title:

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"

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02789527
• Other study ID #: 15-169
• Status: Completed
• Phase: N/A
• First received: May 11, 2016
• Last updated: May 9, 2017
• Start date: November 2015
• Est. completion date: April 2017

Study information

• Verified date: May 2017
• Source: University Hospital, Geneva
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 367
• Est. completion date: April 2017
• Est. primary completion date: April 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

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.);

Related Conditions & MeSH terms

• Healthy

Intervention

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

Locations

Country	Name	City	State
Czechia	Charles University in Prague/Faculty of Science/Department of Anthropology and Human Genetics	Praha 2
Ethiopia	Addis Ababa University/College of Health Sciences	Addis Ababa
Greece	Democritus University of Thrace/School of Health Sciences/University Campus, Dragana	Alexandroupolis
Oman	Sultan Qaboos University/College of Medicine and Health Sciences/Department of Pharmacology	Muscat

Sponsors (2)

Lead Sponsor	Collaborator
Estella S. Poloni	Swiss National Science Foundation

Countries where clinical trial is conducted

Czechia,  Ethiopia,  Greece,  Oman, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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