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Pathogen-Selected Polymorphisms in the PKLR Gene Are Associated with Mycobacterial Susceptibility in Brazilian and African Populations

60 Pages Posted: 15 May 2020

See all articles by Ohanna C.L. Bezerra

Ohanna C.L. Bezerra

Laboratory of Leprosy, Oswaldo Cruz Institute, FIOCRUZ

Nédio Mabunda

Instituto Nacional de Saude

Lucia Elena Alvarado-Arnez

Laboratory of Leprosy, Oswaldo Cruz Institute, FIOCRUZ

Graça Salomé

Laboratory of Molecular Virology, Instituto Nacional de Saúde

Amina de Sousa

Laboratory of Molecular Virology, Instituto Nacional de Saúde

Fernanda S.G. Kehdy

Laboratory of Leprosy, Oswaldo Cruz Institute, FIOCRUZ

Caroline de Sales-Marques

Laboratory of Leprosy, Oswaldo Cruz Institute, FIOCRUZ

Fernanda S. N. Manta

Oswaldo Cruz Foundation (FIOCRUZ)

Rafaela M. Andrade

Laboratory of Leprosy, Oswaldo Cruz Institute, FIOCRUZ

Lais F. Pereira

Laboratory of Leprosy, Oswaldo Cruz Institute, FIOCRUZ

Kelly Nunes

LaboratoryofEvolutionaryGeneticsandBiology, Institutode Biociências, University of São Paulo

Mateus H. Gouveia

Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institute of Health (NIH)

Sam M. Mbulaiteve

Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institute of Health (NIH)

Edward D. Yeboah

University of Ghana Medical School

Ann Hsing

Stanford University - Stanford Prevention Research Center

Thyago L. Calvo

Laboratory of Leprosy, Oswaldo Cruz Institute, FIOCRUZ

Ana Carla P. Latini

Sector of Pharmacology, Lauro de Souza Lima Institute(ILSL)

André Luiz Leturiondo

Laboratory of Cellular Biology, Alfredo da Matta Foundation

Fabíola C. Rodrigues

Laboratory of Cellular Biology, Alfredo da Matta Foundation

Ariani B. Noronha

Laboratory of Cellular Biology, Alfredo da Matta Foundation

Cynthia O. Ferreira

Laboratory of Cellular Biology, Alfredo da Matta Foundation

Carolina Talhari

Laboratory of Cellular Biology, Alfredo da Matta Foundation

Jamile L. Rêgo

Immunology Service, Hospital Universitário Professor Edgard Santos, Federal University of Bahia

Lea Cristina C. Castellucci

Immunology Service, Hospital Universitário Professor Edgard Santos, Federal University of Bahia

Eduardo Tarazona-Santos

Federal University of Minas Gerais (UFMG)

Elizeu F. Carvalho

DNADiagnosticLaboratory(LDD),StateUniversityofRiodeJaneiro(UERJ)

Diogo Meyer

LaboratoryofEvolutionaryGeneticsandBiology, Institutode Biociências, University of São Paulo

Roberta O. Pinheiro

Laboratory of Leprosy, Oswaldo Cruz Institute, FIOCRUZ

Ilesh V. Jani

Laboratory of Molecular Virology, Instituto Nacional de Saúde

Antonio Guilherme Pacheco

Science Computational Program (PROCC), FIOCRUZ

Milton Moraes

Oswaldo Cruz Foundation (FIOCRUZ) - Laboratory of Leprosy

More...

Abstract

Background: Pyruvate kinase (PK) gene (PKLR) is a key player in glycolysis controlling the integrity of erythrocytes. Due to Plasmodium selection, mutations for PK deficiency, leading to hemolytic anemia, are associated with resistance to malaria in sub-Saharan Africa and also with susceptibility to intracellular pathogens in experimental models. We investigated whether PKLR malaria-protective single nucleotide polymorphisms (SNPs) are associated with susceptibility to leprosy in Brazil and tuberculosis in Africa.

Methods: We fine-mapped the PKLR variants and performed independent case-control studies in different populations across Brazil and Mozambique by Real-Time PCR. We also applied natural selection tests in the PKLR genomic region and evaluated serum iron proteins levels among subjects.

Findings: Haplotype T/G/G (rs1052176/rs4971072/rs11264359) is associated with leprosy susceptibility in Rio de Janeiro (OR=1.26, p=0.02) and Salvador (OR=1.35, p=0.07), and with tuberculosis in Mozambique (OR=1.52, p=0.07). TT (rs1052176) was the common risk genotype within populations. Increased frequency of T/G/G was observed in Africa and Brazilian African-descendants compared to Europeans, and Brazilian European-descendants, suggesting the presence of selective footprints in the PKLR. We observed evidences of balancing selection in Africans (Tajima’s D) and positive selection in the HCN3 gene (xpEHH>2 in Europe), of which 6 SNPs are PKLR eQTLs. Ferritin and haptoglobin levels presented a subtle variation in TT (rs1052176) carriers.

Interpretation: We provide evidence that PKLR malaria-resistant loci in Africans contribute to mycobacterial susceptibility in African descent population and also highlight, for first, PKLR as a susceptibility gene for leprosy and TB.

Funding: Brazilian National Council for Scientific and Technological Development, Coordination for the Improvement of Higher Education Personnel, Foundation for Research Support of the State of Rio de Janeiro, and the Brazilian Ministry of Health.

Funding Statement: This study was financed by the Brazilian National Council for Scientific and Technological Development (CNPq; 421852/2017-2018; 307489/2018-3), Brazilian Coordination for the Improvement of Higher Education Personnel (CAPES), Foundation for Research Support of the State of Rio de Janeiro (FAPERJ;E-26/203.053/2016; E-26/203.172/2017), and the National Fund for Health/Brazilian Ministry of Health (MS/SCTIE/DECIT; 404277/2012-8).

Declaration of Interests: The authors declare no conflict of interest.

Ethics Approval Statement: All collected samples and procedures described in this study were approved by local ethics boards and the Brazilian National Board for Ethics in Research. A written informed consent was obtained from all voluntary participants (Rio de Janeiro – IRB protocol - Fiocruz 151/01; Rondonópolis – ILSL 172/09; Salvador – CEP50/2010 and CONEP 11019; Manaus – 555.620 - 13/03/2013; and Mozambique – Nº 399/CNBS/11).

Keywords: PKLR; genetic association; mycobacteria; pathogen selection; infectious diseases

Suggested Citation

Bezerra, Ohanna C.L. and Mabunda, Nédio and Alvarado-Arnez, Lucia Elena and Salomé, Graça and de Sousa, Amina and Kehdy, Fernanda S.G. and de Sales-Marques, Caroline and Manta, Fernanda S. N. and Andrade, Rafaela M. and Pereira, Lais F. and Nunes, Kelly and Gouveia, Mateus H. and Mbulaiteve, Sam M. and Yeboah, Edward D. and Hsing, Ann and Calvo, Thyago L. and Latini, Ana Carla P. and Leturiondo, André Luiz and Rodrigues, Fabíola C. and Noronha, Ariani B. and Ferreira, Cynthia O. and Talhari, Carolina and Rêgo, Jamile L. and Castellucci, Lea Cristina C. and Tarazona-Santos, Eduardo and Carvalho, Elizeu F. and Meyer, Diogo and Pinheiro, Roberta O. and Jani, Ilesh V. and Pacheco, Antonio Guilherme and Moraes, Milton, Pathogen-Selected Polymorphisms in the PKLR Gene Are Associated with Mycobacterial Susceptibility in Brazilian and African Populations (3/18/2020). Available at SSRN: https://ssrn.com/abstract=3559519 or http://dx.doi.org/10.2139/ssrn.3559519

Ohanna C.L. Bezerra

Laboratory of Leprosy, Oswaldo Cruz Institute, FIOCRUZ

Rio de Janeiro
Brazil

Nédio Mabunda

Instituto Nacional de Saude

Avenida Eduardo Mondlane, No. 1008
Maputo
Mozambique

Lucia Elena Alvarado-Arnez

Laboratory of Leprosy, Oswaldo Cruz Institute, FIOCRUZ

Rio de Janeiro
Brazil

Graça Salomé

Laboratory of Molecular Virology, Instituto Nacional de Saúde

Avenida Eduardo Mondlane, No. 1008
Maputo
Mozambique

Amina De Sousa

Laboratory of Molecular Virology, Instituto Nacional de Saúde

Avenida Eduardo Mondlane, No. 1008
Maputo
Mozambique

Fernanda S.G. Kehdy

Laboratory of Leprosy, Oswaldo Cruz Institute, FIOCRUZ

Rio de Janeiro
Brazil

Caroline De Sales-Marques

Laboratory of Leprosy, Oswaldo Cruz Institute, FIOCRUZ

Rio de Janeiro
Brazil

Fernanda S. N. Manta

Oswaldo Cruz Foundation (FIOCRUZ)

Rio de Janeiro
Brazil

Rafaela M. Andrade

Laboratory of Leprosy, Oswaldo Cruz Institute, FIOCRUZ

Rio de Janeiro
Brazil

Lais F. Pereira

Laboratory of Leprosy, Oswaldo Cruz Institute, FIOCRUZ

Rio de Janeiro
Brazil

Kelly Nunes

LaboratoryofEvolutionaryGeneticsandBiology, Institutode Biociências, University of São Paulo

Rua Luciano Gualberto, 315
São Paulo, São Paulo 14800-901
Brazil

Mateus H. Gouveia

Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institute of Health (NIH)

9000 Rockville Pike
Bethesda, MD 20892
United States

Sam M. Mbulaiteve

Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institute of Health (NIH)

9000 Rockville Pike
Bethesda, MD 20892
United States

Edward D. Yeboah

University of Ghana Medical School

PO Box 25
Legon, Accra LG
Ghana

Ann Hsing

Stanford University - Stanford Prevention Research Center ( email )

Stanford, CA
United States

Thyago L. Calvo

Laboratory of Leprosy, Oswaldo Cruz Institute, FIOCRUZ

Rio de Janeiro
Brazil

Ana Carla P. Latini

Sector of Pharmacology, Lauro de Souza Lima Institute(ILSL)

Bauru
Brazil

André Luiz Leturiondo

Laboratory of Cellular Biology, Alfredo da Matta Foundation

Manaus
Brazil

Fabíola C. Rodrigues

Laboratory of Cellular Biology, Alfredo da Matta Foundation

Manaus
Brazil

Ariani B. Noronha

Laboratory of Cellular Biology, Alfredo da Matta Foundation

Manaus
Brazil

Cynthia O. Ferreira

Laboratory of Cellular Biology, Alfredo da Matta Foundation

Manaus
Brazil

Carolina Talhari

Laboratory of Cellular Biology, Alfredo da Matta Foundation

Manaus
Brazil

Jamile L. Rêgo

Immunology Service, Hospital Universitário Professor Edgard Santos, Federal University of Bahia

Av. Reitor Miguel Calmon, s/n
Vale do Canela
Salvador, Bahia
Brazil

Lea Cristina C. Castellucci

Immunology Service, Hospital Universitário Professor Edgard Santos, Federal University of Bahia

Av. Reitor Miguel Calmon, s/n
Vale do Canela
Salvador, Bahia
Brazil

Eduardo Tarazona-Santos

Federal University of Minas Gerais (UFMG)

Av. Antonio Carlos, 6627
Belo Horizonte, Minas Gerais 31270-901
Brazil

Elizeu F. Carvalho

DNADiagnosticLaboratory(LDD),StateUniversityofRiodeJaneiro(UERJ)

Av; Pasteur, 250
terreo - Bairro Maracana
Rio de Janeiro, Rio de Janeiro 23890000
Brazil

Diogo Meyer

LaboratoryofEvolutionaryGeneticsandBiology, Institutode Biociências, University of São Paulo

Rua Luciano Gualberto, 315
São Paulo, São Paulo 14800-901
Brazil

Roberta O. Pinheiro

Laboratory of Leprosy, Oswaldo Cruz Institute, FIOCRUZ

Rio de Janeiro
Brazil

Ilesh V. Jani

Laboratory of Molecular Virology, Instituto Nacional de Saúde

Avenida Eduardo Mondlane, No. 1008
Maputo
Mozambique

Antonio Guilherme Pacheco

Science Computational Program (PROCC), FIOCRUZ

Rio de Janeiro
Brazil

Milton Moraes (Contact Author)

Oswaldo Cruz Foundation (FIOCRUZ) - Laboratory of Leprosy ( email )

Rio de Janeiro
Brazil

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