Putative pathogen-selected polymorphisms in the PKLR gene are associated with mycobacterial susceptibility in Brazilian and African populations.

Autor: Ohanna Cavalcanti de Lima Bezerra, Lucia Elena Alvarado-Arnez, Nédio Mabunda, Graça Salomé, Amina de Sousa, Fernanda de Souza Gomes Kehdy, Carolinne Sales-Marques, Fernanda Saloum de Neves Manta, Rafaela Mota Andrade, Laís Pereira Ferreira, Thyago Leal-Calvo, Cynthia Chester Cardoso, Kelly Nunes, Mateus H Gouveia, Sam M Mbulaiteve, Edward D Yeboah, Ann Hsing, Ana Carla Pereira Latini, André Luiz Leturiondo, Fabíola da Costa Rodrigues, Ariani Batista Noronha, Cynthia de Oliveira Ferreira, Carolina Talhari, Jamile Leão Rêgo, Léa Cristina de Carvalho Castellucci, Eduardo Tarazona-Santos, Elizeu Fagundes de Carvalho, Diogo Meyer, Roberta Olmo Pinheiro, Ilesh V Jani, Antonio Guilherme Pacheco, Milton Ozório Moraes
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: PLoS Neglected Tropical Diseases, Vol 15, Iss 8, p e0009434 (2021)
Druh dokumentu: article
ISSN: 1935-2727
1935-2735
DOI: 10.1371/journal.pntd.0009434
Popis: 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 case-control 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; Rondonópolis-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.
Databáze: Directory of Open Access Journals
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