Putative pathogen-selected polymorphisms in the PKLR gene are associated with mycobacterial susceptibility in Brazilian and African populations.
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...
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oai:doaj.org-article:27f786c7db174a1b9892efcd1ad0d8da2021-12-02T20:23:36ZPutative pathogen-selected polymorphisms in the PKLR gene are associated with mycobacterial susceptibility in Brazilian and African populations.1935-27271935-273510.1371/journal.pntd.0009434https://doaj.org/article/27f786c7db174a1b9892efcd1ad0d8da2021-08-01T00:00:00Zhttps://doi.org/10.1371/journal.pntd.0009434https://doaj.org/toc/1935-2727https://doaj.org/toc/1935-2735Pyruvate 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.Ohanna Cavalcanti de Lima BezerraLucia Elena Alvarado-ArnezNédio MabundaGraça SaloméAmina de SousaFernanda de Souza Gomes KehdyCarolinne Sales-MarquesFernanda Saloum de Neves MantaRafaela Mota AndradeLaís Pereira FerreiraThyago Leal-CalvoCynthia Chester CardosoKelly NunesMateus H GouveiaSam M MbulaiteveEdward D YeboahAnn HsingAna Carla Pereira LatiniAndré Luiz LeturiondoFabíola da Costa RodriguesAriani Batista NoronhaCynthia de Oliveira FerreiraCarolina TalhariJamile Leão RêgoLéa Cristina de Carvalho CastellucciEduardo Tarazona-SantosElizeu Fagundes de CarvalhoDiogo MeyerRoberta Olmo PinheiroIlesh V JaniAntonio Guilherme PachecoMilton Ozório MoraesPublic Library of Science (PLoS)articleArctic medicine. Tropical medicineRC955-962Public aspects of medicineRA1-1270ENPLoS Neglected Tropical Diseases, Vol 15, Iss 8, p e0009434 (2021) |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 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 Putative pathogen-selected polymorphisms in the PKLR gene are associated with mycobacterial susceptibility in Brazilian and African populations. |
| description |
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. |
| format |
article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Ohanna Cavalcanti de Lima Bezerra |
| title |
Putative pathogen-selected polymorphisms in the PKLR gene are associated with mycobacterial susceptibility in Brazilian and African populations. |
| title_short |
Putative pathogen-selected polymorphisms in the PKLR gene are associated with mycobacterial susceptibility in Brazilian and African populations. |
| title_full |
Putative pathogen-selected polymorphisms in the PKLR gene are associated with mycobacterial susceptibility in Brazilian and African populations. |
| title_fullStr |
Putative pathogen-selected polymorphisms in the PKLR gene are associated with mycobacterial susceptibility in Brazilian and African populations. |
| title_full_unstemmed |
Putative pathogen-selected polymorphisms in the PKLR gene are associated with mycobacterial susceptibility in Brazilian and African populations. |
| title_sort |
putative pathogen-selected polymorphisms in the pklr gene are associated with mycobacterial susceptibility in brazilian and african populations. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2021 |
| url |
https://doaj.org/article/27f786c7db174a1b9892efcd1ad0d8da |
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