title: Modulation of Malaria Phenotypes by Pyruvate Kinase (PKLR) Variants in a Thai Population.
abstract: Pyruvate kinase (PKLR) is a critical erythrocyte enzyme that is required for glycolysis and production of ATP. We have shown that Pklr deficiency in mice reduces the severity (reduced parasitemia, increased survival) of blood stage malaria induced by infection with Plasmodium chabaudi AS. Likewise, studies in human erythrocytes infected ex vivo with P. falciparum show that presence of host PK-deficiency alleles reduces infection phenotypes. We have characterized the genetic diversity of the PKLR gene, including haplotype structure and presence of rare coding variants in two populations from malaria endemic areas of Thailand and Senegal. We investigated the effect of PKLR genotypes on rich longitudinal datasets including haematological and malaria-associated phenotypes. A coding and possibly damaging variant (R41Q) was identified in the Thai population with a minor allele frequency of ~4.7%. Arginine 41 (R41) is highly conserved in the pyruvate kinase family and its substitution to Glutamine (R41Q) affects protein stability. Heterozygosity for R41Q is shown to be associated with a significant reduction in the number of attacks with Plasmodium falciparum, while correlating with an increased number of Plasmodium vivax infections. These results strongly suggest that PKLR protein variants may affect the frequency, and the intensity of malaria episodes induced by different Plasmodium parasites in humans living in areas of endemic malaria.
authors.affiliation: Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Rebekah
authors.initials: R
authors.lastname: van Bruggen
authors.affiliation: Department of Biochemistry, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Gualtieri
authors.affiliation: Department of Biochemistry, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Iliescu
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, 10330.
authors.forename: Chalisa
authors.initials: C
authors.lastname: Louicharoen Cheepsunthorn
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, 10330.
authors.forename: Punchalee
authors.initials: P
authors.lastname: Mungkalasut
authors.affiliation: Laboratoire de Paludologie et Zoologie Médicale, Institut de Recherche pour le Développement, Dakar, Sénégal.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Trape
authors.affiliation: Department of Public Health and Infectious Diseases, Instituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
authors.forename: David
authors.initials: D
authors.lastname: Modiano
authors.affiliation: Centre National de Recherche et de Formation sur le Paludisme, Ministry of Health, Ouagadougou, Burkina Faso.
authors.forename: Bienvenu Sodiomon
authors.initials: BS
authors.lastname: Sirima
authors.affiliation: Department of Tropical Hygiene (Biomedical and Health Informatics), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Pratap
authors.initials: P
authors.lastname: Singhasivanon
authors.affiliation: Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.affiliation: Unité de la Génétique Fonctionnelle des Maladies Infectieuses, Institut Pasteur, Paris, France.|Centre National de la Recherche Scientifique, URA3012, F-75015, Paris, France.
authors.forename: Anavaj
authors.initials: A
authors.lastname: Sakuntabhai
authors.affiliation: Unité de la Génétique Fonctionnelle des Maladies Infectieuses, Institut Pasteur, Paris, France.|Centre National de la Recherche Scientifique, URA3012, F-75015, Paris, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Bureau
authors.affiliation: Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.|Department of Biochemistry, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gros
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D004198:Disease Susceptibility; D004912:Erythrocytes / Q000201:enzymology / Q000469:parasitology; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D008288:Malaria / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016778:Malaria, Falciparum / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D016780:Malaria, Vivax / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018512:Parasitemia / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D016788:Plasmodium chabaudi / Q000502:physiology; D010963:Plasmodium falciparum / Q000502:physiology; D010966:Plasmodium vivax / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D055550:Protein Stability; D011770:Pyruvate Kinase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012675:Senegal / Q000453:epidemiology; D016415:Sequence Alignment; D012720:Severity of Illness Index; D013785:Thailand / Q000453:epidemiology
chemical_list: D011770:Pyruvate Kinase