A fine mapping of single nucleotide variants and haplotype analysis of IL13 gene in patients with Leishmania guyanensis-cutaneous leishmaniasis and plasma cytokines IL-4, IL-5, and IL-13

IntroductionLeishmaniasis continues to pose a substantial health burden in 97 countries worldwide. The progression and outcome of Leishmania infection are influenced by various factors, including the cytokine milieu, the skin microbiota at the infection site, the specific Leishmania species involved...

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Main Authors: José do Espírito Santo Junior, Josué Lacerda de Souza, Lener Santos da Silva, Cilana Chagas da Silva, Tuanny Arruda do Nascimento, Mara Lúcia Gomes de Souza, Alyne Farias da Cunha, Jacqueline da Silva Batista, José Pereira de Moura Neto, Marcus Vinitius de Farias Guerra, Rajendranath Ramasawmy
Format: Article
Language:English
Published: Frontiers Media S.A. 2023-10-01
Series:Frontiers in Immunology
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Online Access:https://www.frontiersin.org/articles/10.3389/fimmu.2023.1232488/full
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author José do Espírito Santo Junior
José do Espírito Santo Junior
Josué Lacerda de Souza
Josué Lacerda de Souza
Lener Santos da Silva
Lener Santos da Silva
Cilana Chagas da Silva
Cilana Chagas da Silva
Tuanny Arruda do Nascimento
Tuanny Arruda do Nascimento
Mara Lúcia Gomes de Souza
Alyne Farias da Cunha
Jacqueline da Silva Batista
José Pereira de Moura Neto
Marcus Vinitius de Farias Guerra
Marcus Vinitius de Farias Guerra
Rajendranath Ramasawmy
Rajendranath Ramasawmy
Rajendranath Ramasawmy
Rajendranath Ramasawmy
Rajendranath Ramasawmy
Rajendranath Ramasawmy
author_facet José do Espírito Santo Junior
José do Espírito Santo Junior
Josué Lacerda de Souza
Josué Lacerda de Souza
Lener Santos da Silva
Lener Santos da Silva
Cilana Chagas da Silva
Cilana Chagas da Silva
Tuanny Arruda do Nascimento
Tuanny Arruda do Nascimento
Mara Lúcia Gomes de Souza
Alyne Farias da Cunha
Jacqueline da Silva Batista
José Pereira de Moura Neto
Marcus Vinitius de Farias Guerra
Marcus Vinitius de Farias Guerra
Rajendranath Ramasawmy
Rajendranath Ramasawmy
Rajendranath Ramasawmy
Rajendranath Ramasawmy
Rajendranath Ramasawmy
Rajendranath Ramasawmy
author_sort José do Espírito Santo Junior
collection DOAJ
description IntroductionLeishmaniasis continues to pose a substantial health burden in 97 countries worldwide. The progression and outcome of Leishmania infection are influenced by various factors, including the cytokine milieu, the skin microbiota at the infection site, the specific Leishmania species involved, the genetic background of the host, and the parasite load. In endemic regions to leishmaniasis, only a fraction of individuals infected actually develops the disease. Overexpression of IL-13 in naturally resistant C57BL/6 mice renders them susceptible to L. major infection. Haplotypes constructed from several single nucleotide variant (SNV) along a chromosome fragment may provide insight into any SNV near the fragment that may be genuinely associated with a phenotype in genetic association studies.MethodsWe investigated nine SNVs (SNV1rs1881457A>C, SNV2rs1295687C>G, SNV3rs2069744C>T, SNV4rs2069747C>T, SNV5rs20541A>G, SNV6rs1295685A>G, SNV7rs848A>C, SNV8rs2069750G >C, and SNV9rs847T>C) spanning the entire IL13 gene in patients with L. guyanensis cutaneous leishmaniasis (Lg-CL). ResultsOur analysis did not reveal any significant association between the SNVs and susceptibility/protection against Lg-CL development. However, haplotype analysis, excluding SNV4rs2069747 and SNV8rs2069750 due to low minor allele frequency, revealed that carriers of the haplotype CCCTAAC had a 93% reduced likelihood developing Lg-CL. Similarly, the haplotypes ACCCGCT (ORadj=0.02 [95% CI 0.00–0.07]; p-value, 6.0×10−19) and AGCTAAC (ORadj=0.00[95% CI 0.00–0.00]; p-value 2.7×10−12) appeared to provide protection against the development of Lg-CL. Conversely, carriers of haplotype ACCTGCC have 190% increased likelihood of developing Lg-CL (ORadj=2.9 [95%CI 1.68–5.2]; p-value, 2.5×10−6). Similarly, haplotype ACCCAAT (ORadj=2.7 [95%CI 1.5–4.7]; p-value, 3.2×10−5) and haplotype AGCCGCC are associated with susceptibility to the development of Lg-CL (ORadj=1.7[95%CI 1.04–2.8]; p-value, 0.01). In our investigation, we also found a correlation between the genotypes of rs2069744, rs20541, rs1295685, rs847, and rs848 and plasma IL-5 levels among Lg-Cl patients. Furthermore, rs20541 showed a correlation with plasma IL-13 levels among Lg-Cl patients, while rs2069744 and rs848 showed a correlation with plasma IL-4 levels among the same group. ConclusionsOverall, our study identifies three haplotypes of IL13 associated with resistance to disease development and three haplotypes linked to susceptibility. These findings suggest the possibility of a variant outside the gene region that may contribute, in conjunction with other genes, to differences in susceptibility and partially to the pathology.
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spelling doaj.art-d40aefb16e124342829061094db7b5ee2023-10-16T06:57:56ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-10-011410.3389/fimmu.2023.12324881232488A fine mapping of single nucleotide variants and haplotype analysis of IL13 gene in patients with Leishmania guyanensis-cutaneous leishmaniasis and plasma cytokines IL-4, IL-5, and IL-13José do Espírito Santo Junior0José do Espírito Santo Junior1Josué Lacerda de Souza2Josué Lacerda de Souza3Lener Santos da Silva4Lener Santos da Silva5Cilana Chagas da Silva6Cilana Chagas da Silva7Tuanny Arruda do Nascimento8Tuanny Arruda do Nascimento9Mara Lúcia Gomes de Souza10Alyne Farias da Cunha11Jacqueline da Silva Batista12José Pereira de Moura Neto13Marcus Vinitius de Farias Guerra14Marcus Vinitius de Farias Guerra15Rajendranath Ramasawmy16Rajendranath Ramasawmy17Rajendranath Ramasawmy18Rajendranath Ramasawmy19Rajendranath Ramasawmy20Rajendranath Ramasawmy21Programa de Pós-Graduação em Imunologia Básica e Aplicada, Instituto de Ciências Biológicas, Universidade Federal do Amazonas, Manaus, Amazonas, BrazilFaculdade de Medicina Nilton Lins, Universidade Nilton Lins, Manaus, BrazilFaculdade de Medicina Nilton Lins, Universidade Nilton Lins, Manaus, BrazilPrograma de Pós-Graduação em Biodiversidade e Biotecnologia da Amazonia Legal (Rede Bionorte), Universidade do Estado do Amazonas, Manaus, BrazilFaculdade de Medicina Nilton Lins, Universidade Nilton Lins, Manaus, BrazilPrograma de Pós-Graduação em Biodiversidade e Biotecnologia da Amazonia Legal (Rede Bionorte), Universidade do Estado do Amazonas, Manaus, BrazilFundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, BrazilPrograma de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas, Manaus, BrazilFaculdade de Medicina Nilton Lins, Universidade Nilton Lins, Manaus, BrazilFundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, BrazilFundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, BrazilInstituto Nacional de Pesquisa da Amazônia, Manaus, BrazilInstituto Nacional de Pesquisa da Amazônia, Manaus, BrazilFaculdade de Ciência Farmacêuticas, Universidade Federal do Amazonas, Manaus, BrazilFundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, BrazilPrograma de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas, Manaus, BrazilPrograma de Pós-Graduação em Imunologia Básica e Aplicada, Instituto de Ciências Biológicas, Universidade Federal do Amazonas, Manaus, Amazonas, BrazilFaculdade de Medicina Nilton Lins, Universidade Nilton Lins, Manaus, BrazilPrograma de Pós-Graduação em Biodiversidade e Biotecnologia da Amazonia Legal (Rede Bionorte), Universidade do Estado do Amazonas, Manaus, BrazilFundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, BrazilPrograma de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas, Manaus, BrazilGenomic Health Surveillance Network: Optimization of Assistance and Research in The State of Amazonas – REGESAM, Manaus, Amazonas, BrazilIntroductionLeishmaniasis continues to pose a substantial health burden in 97 countries worldwide. The progression and outcome of Leishmania infection are influenced by various factors, including the cytokine milieu, the skin microbiota at the infection site, the specific Leishmania species involved, the genetic background of the host, and the parasite load. In endemic regions to leishmaniasis, only a fraction of individuals infected actually develops the disease. Overexpression of IL-13 in naturally resistant C57BL/6 mice renders them susceptible to L. major infection. Haplotypes constructed from several single nucleotide variant (SNV) along a chromosome fragment may provide insight into any SNV near the fragment that may be genuinely associated with a phenotype in genetic association studies.MethodsWe investigated nine SNVs (SNV1rs1881457A>C, SNV2rs1295687C>G, SNV3rs2069744C>T, SNV4rs2069747C>T, SNV5rs20541A>G, SNV6rs1295685A>G, SNV7rs848A>C, SNV8rs2069750G >C, and SNV9rs847T>C) spanning the entire IL13 gene in patients with L. guyanensis cutaneous leishmaniasis (Lg-CL). ResultsOur analysis did not reveal any significant association between the SNVs and susceptibility/protection against Lg-CL development. However, haplotype analysis, excluding SNV4rs2069747 and SNV8rs2069750 due to low minor allele frequency, revealed that carriers of the haplotype CCCTAAC had a 93% reduced likelihood developing Lg-CL. Similarly, the haplotypes ACCCGCT (ORadj=0.02 [95% CI 0.00–0.07]; p-value, 6.0×10−19) and AGCTAAC (ORadj=0.00[95% CI 0.00–0.00]; p-value 2.7×10−12) appeared to provide protection against the development of Lg-CL. Conversely, carriers of haplotype ACCTGCC have 190% increased likelihood of developing Lg-CL (ORadj=2.9 [95%CI 1.68–5.2]; p-value, 2.5×10−6). Similarly, haplotype ACCCAAT (ORadj=2.7 [95%CI 1.5–4.7]; p-value, 3.2×10−5) and haplotype AGCCGCC are associated with susceptibility to the development of Lg-CL (ORadj=1.7[95%CI 1.04–2.8]; p-value, 0.01). In our investigation, we also found a correlation between the genotypes of rs2069744, rs20541, rs1295685, rs847, and rs848 and plasma IL-5 levels among Lg-Cl patients. Furthermore, rs20541 showed a correlation with plasma IL-13 levels among Lg-Cl patients, while rs2069744 and rs848 showed a correlation with plasma IL-4 levels among the same group. ConclusionsOverall, our study identifies three haplotypes of IL13 associated with resistance to disease development and three haplotypes linked to susceptibility. These findings suggest the possibility of a variant outside the gene region that may contribute, in conjunction with other genes, to differences in susceptibility and partially to the pathology.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1232488/fullLeishmania guyanensisIL-13single nucleotide variantscutaneous leishmaniasissusceptibility
spellingShingle José do Espírito Santo Junior
José do Espírito Santo Junior
Josué Lacerda de Souza
Josué Lacerda de Souza
Lener Santos da Silva
Lener Santos da Silva
Cilana Chagas da Silva
Cilana Chagas da Silva
Tuanny Arruda do Nascimento
Tuanny Arruda do Nascimento
Mara Lúcia Gomes de Souza
Alyne Farias da Cunha
Jacqueline da Silva Batista
José Pereira de Moura Neto
Marcus Vinitius de Farias Guerra
Marcus Vinitius de Farias Guerra
Rajendranath Ramasawmy
Rajendranath Ramasawmy
Rajendranath Ramasawmy
Rajendranath Ramasawmy
Rajendranath Ramasawmy
Rajendranath Ramasawmy
A fine mapping of single nucleotide variants and haplotype analysis of IL13 gene in patients with Leishmania guyanensis-cutaneous leishmaniasis and plasma cytokines IL-4, IL-5, and IL-13
Frontiers in Immunology
Leishmania guyanensis
IL-13
single nucleotide variants
cutaneous leishmaniasis
susceptibility
title A fine mapping of single nucleotide variants and haplotype analysis of IL13 gene in patients with Leishmania guyanensis-cutaneous leishmaniasis and plasma cytokines IL-4, IL-5, and IL-13
title_full A fine mapping of single nucleotide variants and haplotype analysis of IL13 gene in patients with Leishmania guyanensis-cutaneous leishmaniasis and plasma cytokines IL-4, IL-5, and IL-13
title_fullStr A fine mapping of single nucleotide variants and haplotype analysis of IL13 gene in patients with Leishmania guyanensis-cutaneous leishmaniasis and plasma cytokines IL-4, IL-5, and IL-13
title_full_unstemmed A fine mapping of single nucleotide variants and haplotype analysis of IL13 gene in patients with Leishmania guyanensis-cutaneous leishmaniasis and plasma cytokines IL-4, IL-5, and IL-13
title_short A fine mapping of single nucleotide variants and haplotype analysis of IL13 gene in patients with Leishmania guyanensis-cutaneous leishmaniasis and plasma cytokines IL-4, IL-5, and IL-13
title_sort fine mapping of single nucleotide variants and haplotype analysis of il13 gene in patients with leishmania guyanensis cutaneous leishmaniasis and plasma cytokines il 4 il 5 and il 13
topic Leishmania guyanensis
IL-13
single nucleotide variants
cutaneous leishmaniasis
susceptibility
url https://www.frontiersin.org/articles/10.3389/fimmu.2023.1232488/full
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