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Title: Impact of changing drug treatment and malaria endemicity on the heritability of malaria phenotypes in a longitudinal family-based cohort study
Authors: Cheikh Loucoubar
Bronner Goncalves
Adama Tall
Cheikh Sokhna
Jean François Trape
Fatoumata Diène Sarr
Joseph Faye
Abdoulaye Badiane
Alioune Badara Ly
Aliou Diop
Avner Bar-Hen
Jean François Bureau
Anavaj Sakuntabhai
Richard Paul
Institut Pasteur, Paris
Universite Paris Descartes
Universite Cheikh Anta Diop
Ecole des hautes etudes en sante publique
Institut de Recherche pour le Developpement Dakar
Universite Gaston Berger de Saint-Louis
Mahidol University
Keywords: Agricultural and Biological Sciences;Biochemistry, Genetics and Molecular Biology;Medicine
Issue Date: 3-Nov-2011
Citation: PLoS ONE. Vol.6, No.11 (2011)
Abstract: Despite considerable success of genome wide association (GWA) studies in identifying causal variants for many human diseases, their success in unraveling the genetic basis to complex diseases has been more mitigated. Pathogen population structure may impact upon the infectious phenotype, especially with the intense short-term selective pressure that drug treatment exerts on pathogens. Rigorous analysis that accounts for repeated measures and disentangles the influence of genetic and environmental factors must be performed. Attempts should be made to consider whether pathogen diversity will impact upon host genetic responses to infection. We analyzed the heritability of two Plasmodium falciparum phenotypes, the number of clinical malaria episodes (PFA) and the proportion of these episodes positive for gametocytes (Pfgam), in a family-based cohort followed for 19 years, during which time there were four successive drug treatment regimes, with documented appearance of drug resistance. Repeated measures and variance components analyses were performed with fixed environmental, additive genetic, intra-individual and maternal effects for each drug period. Whilst there was a significant additive genetic effect underlying PFA during the first drug period of study, this was lost in subsequent periods. There was no additive genetic effect for Pfgam. The intra-individual effect increased significantly in the chloroquine period. The loss of an additive genetic effect following novel drug treatment may result in significant loss of power to detect genes in a GWA study. Prior genetic analysis must be a pre-requisite for more detailed GWA studies. The temporal changes in the individual genetic and the intra-individual estimates are consistent with those expected if there were specific host-parasite interactions. The complex basis to the human response to malaria parasite infection likely includes dominance/epistatic genetic effects encompassed within the intra-individual variance component. Ev aluating their role in influencing the outcome of infection through host genotype by parasite genotype interactions warrants research effort. © 2011 Loucoubar et al.
ISSN: 19326203
Appears in Collections:Scopus 2011-2015

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