title: Impact of changing drug treatment and malaria endemicity on the heritability of malaria phenotypes in a longitudinal family-based cohort study.
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. Evaluating their role in influencing the outcome of infection through host genotype by parasite genotype interactions warrants research effort.
authors.affiliation: Institut Pasteur, Unité de Génétique Fonctionnelle des Maladies Infectieuses, Paris, France.
authors.forename: Cheikh
authors.initials: C
authors.lastname: Loucoubar
authors.forename: Bronner
authors.initials: B
authors.lastname: Goncalves
authors.forename: Adama
authors.initials: A
authors.lastname: Tall
authors.forename: Cheikh
authors.initials: C
authors.lastname: Sokhna
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Trape
authors.forename: Fatoumata
authors.initials: F
authors.lastname: Diène Sarr
authors.forename: Joseph
authors.initials: J
authors.lastname: Faye
authors.forename: Abdoulaye
authors.initials: A
authors.lastname: Badiane
authors.forename: Alioune Badara
authors.initials: AB
authors.lastname: Ly
authors.forename: Aliou
authors.initials: A
authors.lastname: Diop
authors.forename: Avner
authors.initials: A
authors.lastname: Bar-Hen
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Bureau
authors.forename: Anavaj
authors.initials: A
authors.lastname: Sakuntabhai
authors.forename: Richard
authors.initials: R
authors.lastname: Paul
mesh_terms: D015331:Cohort Studies; D019353:Endemic Diseases; D006801:Humans; D008137:Longitudinal Studies; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000453:epidemiology; D010641:Phenotype
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