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

dc.creatorBezerra, Ohanna Cavalcanti de Lima
dc.creatorAlvarado-Arnez, Lucia Elena
dc.creatorMabunda, Nédio
dc.creatorSalomé, Graça
dc.creatorSousa, Amina de
dc.creatorKehd, Fernanda de Souza Gomes
dc.creatorMarques, Carolinne Sales
dc.creatorManta, Fernanda Saloum de Neves
dc.creatorAndrade, Rafaela Mota
dc.creatorFerreira, Laís Pereira
dc.creatorLeal-Calvo, Thyago
dc.creatorCardoso, Cynthia Chester
dc.creatorNunes, Kelly
dc.creatorGouveia, Mateus H.
dc.creatorMbulaiteve, Sam M.
dc.creatorYeboah, Edward D.
dc.creatorHsing, Ann
dc.creatorLatini, Ana Carla Pereira
dc.creatorLeturiondo, André Luiz
dc.creatorRodrigues, Fabíola da Costa
dc.creatorNoronha, Ariani Batista
dc.creatorFerreira, Cynthia de Oliveira
dc.creatorTalhari, Carolina
dc.creatorRêgo, Jamile Leão
dc.creatorCastellucci, Léa Cristina de Carvalho
dc.creatorSantos, Eduardo Tarazona
dc.creatorCarvalho, Elizeu Fagundes de
dc.creatorMeyer, Diogo
dc.creatorPinheiro, Roberta Olmo
dc.creatorJani, Ilesh V.
dc.creatorPacheco, Antonio Guilherme
dc.creatorMoraes, Milton Ozório
dc.date2022-02-10T19:27:33Z
dc.date2022-02-10T19:27:33Z
dc.date2021
dc.date.accessioned2023-09-27T00:14:53Z
dc.date.available2023-09-27T00:14:53Z
dc.identifierBEZERRA. 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.
dc.identifier1935-2727
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/51147
dc.identifier10.1371/journal. pntd.0009434
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8898929
dc.descriptionPyruvate 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.
dc.formatapplication/pdf
dc.languageeng
dc.publisherPublic Library of Science
dc.rightsopen access
dc.subjectPolimorfismos selecionados
dc.subjectPatógenos putativos
dc.subjectgene PKLR
dc.subjectAssociados à suscetibilidade a micobactérias
dc.subjectPopulações brasileiras e africanas
dc.subjectPutative pathogen
dc.subjectSelected polymorphisms
dc.subjectgene PKLR
dc.subjectAssociated with mycobacterial susceptibility
dc.subjectBrazlian populations
dc.subjectAfrican populations
dc.titlePutative pathogen-selected polymorphisms in the PKLR gene are associated with mycobacterial susceptibility in Brazilian and African populations
dc.typeArticle


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