Polymorphism in the Pyruvate Kinase Liver and Red Blood Cells Genomic Region, Pyruvate Kinase Activity, and Association with Malaria Risk in Amazonians

Polymorphisms in the pyruvate kinase liver and red blood cells ( PKLR ) gene that reduce the activity of the pyruvate kinase (PK) isoforms of the liver and red blood cells can lower Plasmodium falciparum ( P. falciparum ) malaria risk in Africans; however, their impact remains unclear in admixed Amazonian populations exposed to both P. falciparum and Plasmodium vivax ( P. vivax ). In the present study, participants in a large cohort study in the main urban malaria hotspot of Amazonian Brazil were genotyped for three single-nucleotide polymorphisms (SNPs) spanning the PKLR genomic region that are commonly found in Africans and their descendants: rs1052176 ( PKLR gene exon), rs4971072 (intergenic), and rs11264359 ( farnesyl diphosphate synthase gene intron). Pyruvate kinase activity was measured in 151 participants, and malaria incidence was compared across genotypes using multivariable negative binomial regression models. Overall, across 5 years of follow-up, 1,591 participants experienced 1,944 P. vivax infections and 268 P. falciparum infections (average: 27.0 and 3.7 cases/100 person-years at risk, respectively). Mutant allele frequencies ranged from 0.41 to 0.53, and homozygosity for mutated alleles was associated with slightly but significantly lower PK activity, but not with anemia. Unexpectedly, after adjustment for sociodemographic covariates and population stratification, the incidence of P. falciparum infection increased by 27% to 41% among homozygous carriers of mutated alleles at the tag SNP loci, with no significant change in P. vivax infection risk. These findings suggest that uncharacterized genetic variants at or near the PKLR locus, which are unlikely to cause clinically significant PK activity reduction but are in linkage disequilibrium with the study tag SNPs, may increase susceptibility to P. falciparum infection in Amazonians.