Polymorphism in the pklr gene, pyruvate kinase deficiency in red blood cells, and malaria risk in the Brazilian Amazon

• Grant number: 24/21891-5
• Support Opportunities: Scholarships in Brazil - Master
• Start date: May 01, 2025
• End date: April 30, 2027
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Marcelo Urbano Ferreira
• Grantee: Evelyn Gonçalves Macedo
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 22/11963-3 - Individual variation in malaria risk: causes and consequences in Amazonian populations, AP.TEM

Abstract

Pyruvate kinase deficiency (PKD) in red blood cells (RBC), with autosomal recessive inheritance, is caused by mutations in the pklr gene on chromosome 1q21. There are more than 300 mutations described in this gene, which can result in hemolytic anemia of varying severity. PKD limits the growth of Plasmodium falciparum within human RBC but may paradoxically increase the risk of vivax malaria. Because heterozygotes for pklr mutations are commonly found in malaria-endemic areas of sub-Saharan Africa, with a high prevalence of PKD, some mutations in the pklr gene that confer resistance to P. falciparum infection are likely to have been selected in malaria-exposed populations. However, the mutations associated with PKD and the prevalence of this enzymopathy in people exposed to vivax malaria, e.g. in the Amazon, remain unknown. The present project leverages data and biological samples collected from a random, household-based sample of approximately 2,000 residents in the town of Mâncio Lima, the main urban malaria hotspot in the Brazilian Amazon. We aim to: (1) identify new or previously known pklr polymorphisms potentially associated with low PK activity, with affects nearly 10% of the Mâncio Lima residents; (2) estimate the frequency of these pklr polymorphisms among participants in a population-based study in Mâncio Lima, and (3) test whether these polymorphisms are positively or negatively associated with the risk of infection and malaria. To this end, we will sequence the promoter region and the 12 exons of the pklr gene from local people with PKD and, based on these findings, we will design allelic discrimination assays to estimate the frequency of pklr polymorphisms with likely functional impact and to test for an association between their presence and the risk of infection and malaria among participants in the Mâncio Lima cohort.