Variants of MIRNA146A rs2910164 and MIRNA499 rs3746444 are associated with the development of cutaneous leishmaniasis caused by Leishmania guyanensis and with plasma chemokine IL-8

Leishmania are intracellular protozoan parasites that cause a wide spectrum of clinical manifestations in genetically susceptible individuals with an insufficient or balanced Th1 immune response to eliminate the parasite. MiRNAs play important regulatory role in numerous biological processes includi...

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Published in:	PLoS neglected tropical diseases Vol. 15; no. 9; p. e0009795
Main Authors:	de Mesquita, Tirza Gabrielle Ramos, Junior, José do Espírito Santo, de Lacerda, Thais Carneiro, Queiroz, Krys Layane Guimarães Duarte, Júnior, Cláudio Marcello da Silveira, Neto, José Pereira de Moura, Gomes, Lissianne Augusta Matos, de Souza, Mara Lúcia Gomes, Guerra, Marcus Vinitius de Farias, Ramasawmy, Rajendranath
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 01-09-2021 Public Library of Science (PLoS)
Subjects:	Adult Alleles Biological activity Biology and Life Sciences Biopsy Cell cycle Chemokines Cutaneous leishmaniasis Cytokines Cytokines - blood Defence mechanisms Development and progression Enzymes Exposure Female Gene expression Gene polymorphism Genetic aspects Genetic polymorphisms Genetic Predisposition to Disease Genotype Genotypes Health aspects Homozygosity Humans Immune response Immunity Infections Interleukin Interleukin 1 Interleukin 8 Interleukin-1 Receptor-Associated Kinases Interleukin-8 - blood Interleukin-8 - metabolism Interleukins Intracellular Signaling Peptides and Proteins IRAK protein Kinases Leishmania guyanensis Leishmaniasis, Cutaneous Leishmaniasis, Cutaneous - genetics Lymphocytes T Male Males Medicine and Health Sciences MicroRNA MicroRNAs MicroRNAs - genetics Middle Aged Necrosis Nucleotide sequence Parasites Parasitic diseases PCR Plasma Polymerase chain reaction Polymorphism Polymorphism, Restriction Fragment Length Polymorphism, Single Nucleotide Proteins Protozoa Receptors Restriction fragment length polymorphism Risk factors Sex Signal transduction Toll-like receptors TRAF6 protein Tropical diseases Tumor necrosis factor Tumor necrosis factor-TNF Tumors Vector-borne diseases Brazil United States > US
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Summary:	Leishmania are intracellular protozoan parasites that cause a wide spectrum of clinical manifestations in genetically susceptible individuals with an insufficient or balanced Th1 immune response to eliminate the parasite. MiRNAs play important regulatory role in numerous biological processes including essential cellular functions. miR146-a acts as an inhibitor of interleukin 1 receptor associated kinase 1 (IRAK1) and tumour necrosis factor (TNF) receptor associated factor 6 (TRAF6) present in the toll-like receptors pathway while miR499a modulates TGF-β and TNF signalling pathways. Here, we investigated whether MIRNA146A rs2910164 and MIRNA499 rs3746444 variants are associated with the development of L. guyanensis (Lg)-cutaneous leishmaniasis (CL). The variants MIR146A rs2910164 and MIR499A rs3746444 were assessed in 850 patients with Lg-CL and 891 healthy controls by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Plasma cytokines were measured using the BioPlex assay. Carriers of rs2910164 CC genotype have 30% higher odds of developing CL (ORadjage/sex = 1.3 [95%CI 0.9-1.8]; Padjage/sex 0.14) compared to individuals with the genotype GG (ORadjage/sex = 0.77 [95%CI 0.56-1.0]; Padjage/sex 0.14) if exposed to Lg-infection. Heterozygous GC individuals also showed lower odds of developing CL (ORadjage/sex = 0.77 [95%CI 0.5-1.1]; Padjage/sex 0.09). Homozygosity for the allele C is suggestive of an association with the development of Lg-CL among exposed individuals to Lg-infection. However, the odds of developing CL associated with the CC genotype was evident only in male individuals (ORadjage = 1.3 [95% CI = 0.9-2.0]; Padjage = 0.06). Individuals homozygous for the G allele tend to have higher plasma IL-8 and CCL5. Similarly, for the MIR499A rs3746444, an association with the G allele was only observed among male individuals (OR = 1.4 [1.0-1.9]; P = 0.009). In a dominant model, individuals with the G allele (GG-GA) when compared to the AA genotype reveals that carriers of the G allele have 40% elevated odds of developing Lg-CL (ORadjage = 1.4 [1.1-1.9]). Individuals with the GG genotype have higher odds of developing Lg-CL (ORadjage/sex = 2.0 [95%CI 0.83-5.0]; Padjage = 0.01. Individuals homozygous for the G allele have higher plasma IL-8. Genetic combinations of both variants revealed that male individuals exposed to Lg bearing three or four susceptible alleles have higher odds of developing Lg-CL (OR = 2.3 [95% CI 1.0-4.7]; p = 0.017). Both MIR146A rs2910164 and MIR499A rs3746444 are associated with the development of Lg-CL and this association is prevalent in male individuals.
Bibliography:	new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The authors have declared that no competing interests exist.
ISSN:	1935-2735 1935-2727 1935-2735
DOI:	10.1371/journal.pntd.0009795