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Modulation of Malaria Phenotypes by Pyruvate Kinase (PKLR) Variants in a Thai Population.

Authors :
van Bruggen, Rebekah
Gualtieri, Christian
Iliescu, Alexandra
Louicharoen Cheepsunthorn, Chalisa
Mungkalasut, Punchalee
Trape, Jean-François
Modiano, David
Sodiomon Sirima, Bienvenu
Singhasivanon, Pratap
Lathrop, Mark
Sakuntabhai, Anavaj
Bureau, Jean-François
Gros, Philippe
Source :
PLoS ONE. 12/14/2015, Vol. 10 Issue 12, p1-18. 18p.
Publication Year :
2015

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
19326203
Volume :
10
Issue :
12
Database :
Academic Search Index
Journal :
PLoS ONE
Publication Type :
Academic Journal
Accession number :
111571246
Full Text :
https://doi.org/10.1371/journal.pone.0144555