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

Autor: Fernanda Saloum de Neves Manta, Laís Pereira Ferreira, Fabíola da Costa Rodrigues, Edward D. Yeboah, Thyago Leal-Calvo, Ohanna Cavalcanti de Lima Bezerra, Mateus H. Gouveia, Lucia Elena Alvarado-Arnez, Cynthia Chester Cardoso, Antonio G. Pacheco, Carolina Talhari, Diogo Meyer, Fernanda de Souza Gomes Kehdy, Nédio Mabunda, Graca Salomé, Jamile Leão Rêgo, Ana Carla Pereira Latini, Sam M. Mbulaiteve, Roberta Olmo Pinheiro, Kelly Nunes, André Luiz Leturiondo, Carolinne Sales-Marques, Eduardo Tarazona-Santos, Milton Ozório Moraes, Ilesh V. Jani, Cynthia de Oliveira Ferreira, Ariani Batista Noronha, Amina de Sousa, Rafaela Mota Andrade, Ann W. Hsing, Elizeu Fagundes de Carvalho, Léa Cristina Castellucci
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Male
Bacterial Diseases
Heredity
Single Nucleotide Polymorphisms
RC955-962
Linkage Disequilibrium
Geographical locations
Medical Conditions
Gene Frequency
Arctic medicine. Tropical medicine
Medicine and Health Sciences
Mozambique
Genetics
Haptoglobin
Genomics
Middle Aged
Europe
Actinobacteria
Genetic Mapping
Infectious Diseases
TUBERCULOSE
Female
Public aspects of medicine
RA1-1270
Brazil
Research Article
Neglected Tropical Diseases
Adult
Pyruvate Kinase
Locus (genetics)
Single-nucleotide polymorphism
Biology
Polymorphism
Single Nucleotide
Mycobacterium tuberculosis
Young Adult
Leprosy
Parasitic Diseases
medicine
Humans
Genetic Predisposition to Disease
Gene
Genetic association
Bacteria
Haplotype
Organisms
Public Health
Environmental and Occupational Health
Biology and Life Sciences
South America
Tropical Diseases
medicine.disease
biology.organism_classification
Malaria
Logistic Models
Haplotypes
Case-Control Studies
biology.protein
People and places
Mycobacterium Tuberculosis
Zdroj: PLoS Neglected Tropical Diseases, Vol 15, Iss 8, p e0009434 (2021)
Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual)
Universidade de São Paulo (USP)
instacron:USP
PLoS Neglected Tropical Diseases
ISSN: 1935-2735
1935-2727
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.
Author summary Investigation of human genes under pathogen-driven selection as Plasmodium sp. has pinpointed genetic variants that participate in the adaptation to the environment and/or are related to severities of human diseases. The current study examined an example of an evolutionary trade-off in which genetic variants in the PKLR gene putatively selected for malaria resistance influence the susceptibility to mycobacterial diseases (leprosy and tuberculosis) in Brazilian population and Mozambique. A complete characterization of the biological effect of those risk variants may clarify the role of the PKLR gene in leprosy and tuberculosis. Deciphering the genetic basis of mycobacterial diseases has implications for the identification of true high-risk individuals in order to optimize screening strategies. Furthermore, the trade-off mechanism discussed in this work might occur in other central genes of immune response and biochemical pathways, controlling the susceptibility to other infectious diseases.
Databáze: OpenAIRE
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