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Assessment of the contribution of pharmacogenetics in overall treatment efficacy against malaria by DNA chip technology: an aid for the selection of appropriate drugs in malaria endemic areas

English title Assessment of the contribution of pharmacogenetics in overall treatment efficacy against malaria by DNA chip technology: an aid for the selection of appropriate drugs in malaria endemic areas
Applicant Genton Blaise
Number 112479
Funding scheme Project funding (Div. I-III)
Research institution Swiss Tropical and Public Health Institute
Institution of higher education University of Basel - BS
Main discipline Tropical Medicine
Start/End 01.06.2006 - 31.05.2009
Approved amount 335'000.00
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Keywords (6)

malaria; pharmacogenetic; chip technology; molecular markers; parasite resistance; drug efficacy

Lay Summary (English)

Lead
Lay summary
Background
Parasite resistance to antimalarial drugs has always been considered as the main contributor to treatment failure. Almost no research has been conducted on the role of human host genetics in treatment outcome. Inter-individual variability in drug response is partly attributed to differences in drug metabolizing enzymes, due to single point mutations, mainly members of the Cytochrome P450 (CYP) superfamily, and transporters. We propose here to estimate the contribution of pharmacogenetics in overall malaria treatment efficacy, using an extension of the DNA chip technology that we developed to monitor molecular markers of parasite resistance to drugs.
Specific aims
-To further develop and complement our microarray chip detect both parasite and human genetic markers relevant for decision-making on the most suitable first-line treatment are included
-To compare the pharmacogenetic profile (SNP) for genes encoding proteins relevant for the metabolism of the main antimalarials currently available in populations of different malaria endemic zones
-To study the effect of the pharmacogenetic make-up of malaria patients on the pharmacokinetic profile and treatment outcome

Methods and experimental design
The laboratory component will consist on the extensio of our current chip to assess SNP polymorphism in human genes relevant for the metabolism of currently available antimalarials (chloroquine, amodiaquine, quinine, sulfadoxine/pyrymethamine, artemisine and derivatives, mefloquine, lumefantrine), namely i) CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, ii) NAT2.
The field component will consist on:
1) Community-based cross-sectional surveys in PNG, Tanzania and Cambodia to assess human polymorphism for genes encoding enzymes relevant for the metabolism of currently available antimalarial drugs.
2) Drug level /clinical treatment studies conducted in nearby health facilities i) to investigate the effect of pharmacogenetic make-up on the pharmacokinetics of antimalarial drugs, and on treatment outcome (Adequate Clinical and Parasitological Response or treatment failure) in malaria patients, ii) to estimate the contribution of pharmacogenetics in overall treatment efficacy using models that take into account parasite resistance markers (assessed by our current chip), age and pre-existing immunity (assessed by antibody concentration to msp2).

Expected Value of the proposed project
The project will i) optimize a highly parallel novel molecular technique which allows comprehensive assessment of polymorphism in human genes coding for drug metabolism enzymes and parasite resistance marker genes, ii) estimate for the first time the role of pharmacogenetics in the overall efficacy of treatment against malaria, taking into account the other major factors identified so far, iii) deliver population specific data for use in policy-making for malaria in endemic areas
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
121314 Demande de soutien pour l'acquisition d'un instrument de chromatographie à ultra performance couplé à un détecteur de masse triple quadripôles en tandem (UPLC-MS/MS) pour la recherche biomédicale 01.08.2008 R'EQUIP
103968 DNA chip technology to assess drug resistance in malaria: an epidemiological tool to help treatment policy making and monitoring of resistance 01.06.2004 Project funding (Div. I-III)

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