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

Not Applicable

Completed

• Conditions: Healthy
• Interventions: Drug: Phenotyping; Genetic: Genotyping

• Registration Number: NCT02789527
• Lead Sponsor: Estella S. Poloni

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2015-11
• Study First Submitted: 2016-05-11
• Study First Submitted QC: 2016-05-27
• Study First Posted: 2016-06-03
• Primary Completion: 2017-04
• Study Completion: 2017-04
• Status Verified: 2017-05
• Last Update Submitted: 2017-05-09
• Last Update Posted: 2017-05-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 367

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Healthy volunteers in Oman	Genotyping	Phenotype and genotype of enzymes involved in drug metabolism in Oman population
Healthy volunteers in Ethiopia	Phenotyping	Phenotype and genotype of enzymes involved in drug metabolism in Ethiopia population
Healthy volunteers in Ethiopia	Genotyping	Phenotype and genotype of enzymes involved in drug metabolism in Ethiopia population
Healthy volunteers in Oman	Phenotyping	Phenotype and genotype of enzymes involved in drug metabolism in Oman population
Healthy volunteers in the Czech Republic	Phenotyping	Phenotype and genotype of enzymes involved in drug metabolism in Czech Republic population
Healthy volunteers in the Czech Republic	Genotyping	Phenotype and genotype of enzymes involved in drug metabolism in Czech Republic population
Healthy volunteers in Greece	Genotyping	Phenotype and genotype of enzymes involved in drug metabolism in Greek population
Healthy volunteers in Greece	Phenotyping	Phenotype and genotype of enzymes involved in drug metabolism in Greek population

Primary Outcome Measures

Name	Time	Method
Activities of 6 cytochrome P450 enzymes and P-gp in 4 human populations : 100 Ethiopian, 100 Omani, 100 Czech and 100 Greek	through study completion, an average of 2 years	Estimation of frequency distributions of classes of drug metabolizers (metabolizers' profiles: slow/normal/rapid)
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	through study completion, an average of 2 years	Estimation of genotype/allele/haplotype frequencies of variants in genes involved in drug responses

Secondary Outcome Measures

Name	Time	Method
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	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.

Trial Locations

Locations (4)

Charles University in Prague/Faculty of Science/Department of Anthropology and Human Genetics; 🇨🇿 Praha 2, Czechia

Addis Ababa University/College of Health Sciences; 🇪🇹 Addis Ababa, Ethiopia

Democritus University of Thrace/School of Health Sciences/University Campus, Dragana; 🇬🇷 Alexandroupolis, Greece

Sultan Qaboos University/College of Medicine and Health Sciences/Department of Pharmacology; 🇴🇲 Muscat, Oman