Article
Putative pathogen-selected polymorphisms in the PKLR gene are associated with mycobacterial susceptibility in Brazilian and African populations
Registro en:
BEZERRA. Ohanna Cavalcanti de Lima et al. Putative pathogen-selected polymorphisms in the PKLR gene are associated with mycobacterial susceptibility in Brazilian and African populations. PLoS Negl Trop Dis., v. 15, n. 8, e0009434, p. 1 - 26, Aug. 2021.
1935-2727
10.1371/journal. pntd.0009434
Autor
Bezerra, Ohanna Cavalcanti de Lima
Alvarado-Arnez, Lucia Elena
Mabunda, Nédio
Salomé, Graça
Sousa, Amina de
Kehd, Fernanda de Souza Gomes
Marques, Carolinne Sales
Manta, Fernanda Saloum de Neves
Andrade, Rafaela Mota
Ferreira, Laís Pereira
Leal-Calvo, Thyago
Cardoso, Cynthia Chester
Nunes, Kelly
Gouveia, Mateus H.
Mbulaiteve, Sam M.
Yeboah, Edward D.
Hsing, Ann
Latini, Ana Carla Pereira
Leturiondo, André Luiz
Rodrigues, Fabíola da Costa
Noronha, Ariani Batista
Ferreira, Cynthia de Oliveira
Talhari, Carolina
Rêgo, Jamile Leão
Castellucci, Léa Cristina de Carvalho
Santos, Eduardo Tarazona
Carvalho, Elizeu Fagundes de
Meyer, Diogo
Pinheiro, Roberta Olmo
Jani, Ilesh V.
Pacheco, Antonio Guilherme
Moraes, Milton Ozório
Resumen
Pyruvate kinase (PK), encoded by the PKLR gene, is a key player in glycolysis controlling
the integrity of erythrocytes. Due to Plasmodium selection, mutations for PK deficiency,
which leads to hemolytic anemia, are associated with resistance to malaria in sub-Saharan
Africa and with susceptibility to intracellular pathogens in experimental models. In this casecontrol
study, we enrolled 4,555 individuals and investigated whether PKLR single nucleotide
polymorphisms (SNPs) putatively selected for malaria resistance are associated with
susceptibility to leprosy across Brazil (Manaus–North; Salvador–Northeast; Rondono´ polis–
Midwest and Rio de Janeiro–Southeast) and with tuberculosis in Mozambique. Haplotype T/
G/G (rs1052176/rs4971072/rs11264359) was associated with leprosy susceptibility in Rio de Janeiro (OR = 2.46, p = 0.00001) and Salvador (OR = 1.57, p = 0.04), and with tuberculosis
in Mozambique (OR = 1.52, p = 0.07). This haplotype downregulates PKLR expression
in nerve and skin, accordingly to GTEx, and might subtly modulate ferritin and haptoglobin
levels in serum. Furthermore, we observed genetic signatures of positive selection in the
HCN3 gene (xpEHH>2 –recent selection) in Europe but not in Africa, involving 6 SNPs
which are PKLR/HCN3 eQTLs. However, this evidence was not corroborated by the other
tests (FST, Tajima’s D and iHS). Altogether, we provide evidence that a common PKLR
locus in Africans contribute to mycobacterial susceptibility in African descent populations
and also highlight, for first, PKLR as a susceptibility gene for leprosy and TB.